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EXTRACELLULAR MATRIX AND CELL ADHESION MOLECULES
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of
extracellular matrix and cell
adhesion molecules and to the use of these sequences in the diagnosis,
treatment, and prevention of
genetic, immune/inflammatory, developmental, neurological, connective tissue,
and cell proliferative
disorders, including cancer and in the assessment of the effects of exogenous
compounds on the
expression of nucleic acid and amino acid sequences of extracellular matrix
and cell adhesion
molecules.
BACKGROUND OF THE INVENTION
Extracellular Matrix Proteins
The extracellular matrix (ECM) is a complex network of glycoproteins,
polysaccharides,
proteoglycans, and other macromolecules that are secreted from the cell into
the extracellular space.
The ECM remains in close association with the cell surface and provides a
suppoi~ive meshwork that
profoundly influences cell shape; motility, strength, flexibility, and
adhesion. In fact, adhesion of a cell
to its surrounding matrix is required for cell survival except in the case of
metastatic tumor cells, which
have overcome the need for cell-ECM anchorage. This phenomenon suggests that
the ECM plays a
critical role in the molecular mechanisms of growth control and metastasis.
(Reviewed in Ruoslahti,
E. (1996) Sci. Am. 275:72-77.) Furthermore, the ECM determines the structure
and physical
properties of connective tissue and is particularly important for
morphogenesis and other processes
associated with embryonic development and pattern formation.
The collagens comprise a family of ECM proteins that provide structure to
bone, teeth, skin,
ligaments, tendons, cartilage, blood vessels, and basement membranes. Multiple
collagen proteins
have been identified. Three collagen molecules fold together in a triple helix
stabilized by interchain
disulfide bonds. Bundles of these triple helices then associate to form
fibrils.
Elastin and related proteins confer elasticity to tissues such as skin, blood
vessels, and lungs.
Elastin is a highly hydrophobic protein of about 750 amino acids that is rich
in proline and glycine
residues. Elastin molecules are highly cross-linked, forming an extensive
extracellular network of
fibers and sheets. Elastin fibers are surrounded by a sheath of microfibrils
which are composed of a
number of glycoproteins, including fibrillin.
Fibronectin is a large ECM glycoprotein found in all vertebrates. Fibronectin
exists as a dimer
of two subunits, each containing about 2,500 a,rnino acids. Each subunit folds
into a rod-like structure
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containing multiple domains. The domains each contain multiple repeated
modules, the most common
of which is the type III fibronectin repeat. The type III fibronectin repeat
is about 90 amino acids in
length and is also found in other ECM proteins and in some plasma membrane and
cytoplasmic
proteins. Furthermore, some type III fibronectin repeats contain a
characteristic tripeptide consisting
of Arginine-Glycine-Aspartic acid (RGD). ~ The RGD sequence is recognized by
the integrin family of
cell surface receptors and is also found in other ECM proteins. (Reviewed in
Alberts, et al. (1994)
Molecular Biology of the Cell, Garland Publishing, New York, NY, pp. 986-987.)
Laminin is a major glycoprotein component of the basal lamina which underlies
and supports
epithelial cell sheets. Laminin is one of the first ECM proteins synthesized
in the developing embryo.
1o Laminin is an 850 kilodalton protein composed of three polypeptide chains
joined in the shape of a
cross by disulfide bonds. Laminin is especially important for angiogenesis
and, in particular, for guiding
the formation of capillaries. (Reviewed in Alberts, supra, pp. 990-991.)
Many proteinaceous ECM components are proteoglycans. Proteoglycans are
composed of
unbranched polysaccharide chains (glycosaminoglycans) attached to protein
cores. Common
proteoglycans include aggrecan, betaglycan, decorin, perlecan, serglycin, and
syndecan-1. Some of
these molecules not only provide mechanical support, but also bind to
extracellular signaling molecules,
such as fibroblast growth factor and transforming growth factor (3, suggesting
a role for proteoglycans
in cell-cell communication. (Reviewed in Alberts, supra, pp. 973-978.)
Dentin phosphoryn (DPP) is a major component of the dentin ECM. DPP is a
proteoglycan
that is synthesized and expressed by odontoblasts (Gu, K., et al. (1998) Eur.
J. Oral Sci. 106:1043
1047). DPP is believed to nucleate or modulate the formation of hydroxyapatite
crystals.
Mucins are highly glycosylated glycoproteins that are the major structural
component of the
mucus gel. The physiological functions of mucins are cytoprotection,
mechaxlical protection,
maintenance of viscosity in secretions, and cellular recognition. MUC6 is a
human gastric mucin that
is also found in gall bladder, pancreas, seminal vesicles, and female
reproductive tract (Toribara,~
N.W., et al. (1997) J. Biol. Chem. 272:16398-16403). The MUC6 gene has been
mapped to human
chromosome 11 (Toribara, N.W., et al. (1993) J. Biol. Chem. 268:5879-5885).
Hemomucin is a novel
Drosophila surface mucin that may be involved in the induction of
antibacterial effector molecules
(Theopold, U., et al. (1996) J. Biol. Chem. 217:12708-12715).
Olfactomedin was originally identified as the major component of the mucus
layer surrounding
the chemosensory dendrites of olfactory neurons. Olfactomedin-related proteins
are secreted
glycoproteins with conserved C-terminal motifs. The TIGR/myocilin protein, an
olfactomedin-related
protein expressed in the eye, is associated with the pathogenesis of glaucoma
(Kulkarni, N.H. et al.
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(2000) Genet. Res. 76:41-50).
Ankyrin (ANK) repeats mediate protein-protein interactions associated with
diverse
intracellular functions. ANK repeats are composed of about 33 amino acids that
form a helix-turn-
helix core preceded by a protruding "tip." These tips are of variable sequence
and may play a role in
protein protein interactions. The helix-turn-helix region of the ANK repeats
stack on top of one
another and are stabilized by hydrophobic interactions (Yang, Y. et al. (1998)
Structure 6:619-626).
Sushi repeats, also called short consensus repeats (SCR), are found in a
number of proteins
that share the common feature of binding to other proteins. For example, in
the C-terminal domain of
versican, the sushi domain is important for heparin binding. Sushi domains
contain basic amino acid
residues, which may play a role in binding (Oleszewski, M. et al. (2000) J.
Biol. Chem. 275:34478-
34485).
Link, or X-link, modules are hyaluronan-binding domains found in proteins
involved in the
assembly of extracellular matrix, cell adhesion, and migration. The Link
module superfamily includes
CD44, cartilage link protein, and aggrecan. There is close similarity between
the Link module and the
~15 C-type lectin domain, with the predicted hyaluronan-binding site at an
analogous position to the
carbohydrate-binding pocket in E-selectin (Kohda, D. et al. (1996) Cell, Vol.
86, 767-775).
Multidomain or mosaic proteins play an important role in the diverse functions
of the
extracellular matrix (Engel, J. et al. (1994) Development (Carob.) S35-42).
ECM proteins are
frequently characterized by the presence of one or more domains which may
contain a number of
potential intracellular disulfide bridge motifs. For example, domains which
match the epidermal growth
factor (EGF) tandem repeat consensus are present within several known
extracellular proteins that
promote cell growth, development, and cell signaling. This signature sequence
is about forty amino
acid residues in length and includes six conserved cysteine residues, and a
calcium-binding site near
the N-terminus of the signature sequence. The main structure is a two-stranded
beta-sheet followed
by a loop to a C-terminal short two-stranded sheet. Subdomains between the
conserved cysteines
vary in length (Davis, C.G. New Biol (1990) May;2(5):410-9). Post-
translational hydroxylation of
aspartic acid or asparagine residues has been associated with EGF-like domains
in several proteins
(Prosite PDOC00010 Aspartic acid and asparagine hydroxylation site).
A number of proteins that contain calcium-binding EGF-like domain signature
sequences are
3o involved in growth and differentiation. Examples include bone morphogenic
protein 1, which induces
the formation of cartilage and bone; crumbs, which is a Drosonhila epithelial
development protein;
Notch and a number of its homologs,. which are involved in neural growth and
differentiation, and
transforming growth factor beta-1 binding protein (Expasy PROSITE document
PDOC00913; Soler,
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C. and Carpenter, G., in Nicola, N.A. (1994) The Cytokine Facts Book, Oxford
University Press,
Oxford, UK, pp 193-197). EGF-like domains mediate protein-protein interactions
for a variety of
proteins. For example, EGF-like domains in the ECM glycoprotein fibulin-1 have
been shown to
mediate both self association and binding to fibronectin (Tram H. et al.
(1997) J. Biol. Chem.
272:22600-22606). Point mutations in the EGF-like domains of ECM proteins have
been identified as
the cause of human disorders such as Marfan syndrome and pseudochondroplasia
(Maurer, P. et al.
(1996) Curr. Opin. Cell Biol. 8:609-617).
The CUB domain is an extracellular domain of approximately 110 amino acid
residues found
mostly in developmentally regulated proteins. The CUB domain contains four
conserved cysteine
l0 residues and is predicted to have a structure similar to that of
immunoglobulins. Vertebrate bone
morphogenic protein 1, which induces cartilage and bone formation, and
fibropellins I and III from sea
urchin, which form the apical lamina component of the ECM, are examples of
proteins that contain
both CUB and EGF domains (PROSITE PDOC00908 CUB domain profile).
Other ECM proteins are members of the type A domain of von Willebrand factor
(vWFA)-
like module superfamily, a diverse group of proteins with a module sharing
high sequence similarity.
The vWFA-like module is found not only in plasma proteins but also in plasma
membrane and ECM
proteins (Colombatti, A. and Bonaldo, P. (1991) Blood 77:2305-2315). Crystal
structure analysis of an
integrin vWFA-like module shows a classic "Rossmann" fold and suggests a metal
ion-dependent
adhesion site for binding protein ligands (Lee, J.-O. et al. (1995) Cell
80:631-638). This family
includes the protein matrilin-2, an extracellular matrix protein that is
expressed in a broad range of
mammalian tissues and organs. Matxilin-2 is thought to play a role in ECM
assembly by bridging
collagen fibrils and the aggrecan network (beak, F. et al. (1997) J. Biol.
Chem. 272:9268-9274).
The thrombospondins are muItimeric, calcium-binding extracellular
glycoproteins found widely
in the embryonic extracellular matrix. These proteins are expressed in the
developing nervous system
or at specific sites in the adult nervous system after injury. Thrombospondins
contain multiple EGF-
type repeats, as well as a motif known as the thrombospondin type 1 repeat
(TSR). The TSR is
approximately 60 amino acids in length and contains six conserved cysteine
residues. Motifs within
TSR domains are involved in mediating cell adhesion through binding to
proteoglycans and sulfated
glycolipids. Thrombospondin-1 inhibits angiogenesis and modulates endothelial
cell adhesion, motility,
and growth. TSR domains are found in a diverse group of other proteins, most
of which are
expressed in the developing nervous system and have potential roles in the
guidance of cell and growth
cone migration. Proteins that share TSRs include the F-spondin gene family,
the semaphorin 5 family,
UNC-5, and SCO-spondin. The TSR superfamily includes the ADAMTS proteins which
contain an
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ADAM (A Disintegrin and Metalloproteinase) domain as well as one or more TSRs.
The ADAMTS
proteins have roles in regulating the turnover of cartilage matrix, regulation
of blood vessel growth, and
possibly development of the nervous system. (Reviewed in Adams, J.C. and
Tucker, R. P. (2000)
Dev. Dyn. 218:280-299).
Fibrinogen, the principle protein of vertebrate blood clotting, is a hexamer
consisting of two
sets of three different chains (alpha, beta, and gamma). The C-terminal domain
of the beta and
gamma chains comprises about 270 amino acid residues and contains four
cysteines involved in two
disulfide bonds. This domain has also been found in mammalian tenascin-X, an
ECM protein that
appears to be involved in cell adhesion (Prosite PDOC00445 Fibrinogen beta and
gamma chains C-
terminal domain signature).
Adhesion-Associated Proteins
The surface of a cell is rich in transmembrane proteoglycans, glycoproteins,
glycolipids, and
receptors. These macromolecules mediate adhesion with other cells and with
components of the
ECM. The interaction of the cell with its surroundings profoundly influences
cell shape, strength,
flexibility, motility, and adhesion. These dynamic properties are intimately
associated with signal
transduction pathways controlling cell proliferation and differentiation,
tissue construction, and
embryonic development. Families of cell adhesion molecules include the
cadherins, integrins, lectins,
neural cell adhesion proteins, and some members of the proline-rich proteins.
Cadherins comprise a family of calcium-dependent glycoproteins that function
in mediating
cell-cell adhesion in virtually all solid tissues of multicellular organisms.
These proteins share multiple
repeats of a cadherin-specific motif, and the repeats form the folding units
of the cadherin
extracellular domain. Cadherin molecules cooperate to form focal contacts, or
adhesion plaques,
between adjacent epithelial cells. The cadherin family includes the classical
cadherins and
protocadherins. Classical cadherins include the E-cadherin, N-cadherin, and P-
cadherin subfamilies.
E-cadherin is present on many types of epithelial cells and is especially
important for embryonic
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Integrins are ubiquitous transmembrane adhesion molecules that link the ECM to
the internal
cytoskeleton. lntegrins are composed of two noncovalently associated
transmembrane glycoprotein
subunits called a and (3. Integrins function as receptors that play a role in
signal transduction. For
example, binding of integrin to its extxacellular ligand may stimulate changes
in intracellular calcium
levels or protein kinase activity (Sjaastad, M.D. and Nelson, W.J. (1997)
BioEssays 19:47-55). At
least ten cell surface receptors of the integrin family recognize the ECM
component fibronectin, which
is involved in many different biological processes including cell migration
and embryogenesis
(Johansson, S. et al. (1997) Front. Biosci. 2:D126-D146).
Lectins comprise a ubiquitous family of extracellular glycoproteins which bind
cell surface
carbohydrates specifically and reversibly, resulting in the agglutination of
cells (reviewed in
Drickamer, I~. and Taylor, M. E. (1993) Annu. Rev. Cell Biol. 9:237-264). This
function is
particularly important for activation of the immune response. Lectins mediate
the agglutination and
mitogenic stimulation of lymphocytes at sites of inflammation (Lasky, L. A.
(1991) J. Cell. Biochem.
45:139-146; Paietta, E, et al. (1989) J. Immunol. 143:2850-2857).
Lectins are further classified into subfamilies based on carbohydrate-binding
specificity and
other criteria. The galectin subfamily, in particular, includes lectins that
bind (3-galactoside
carbohydrate moieties in a thiol-dependent manner (reviewed in Hadari, Y. R.
et al. (1998) J. Biol.
Chem. 270:3447-3453). Galectins are widely expressed and developmentally
regulated. Galectins
contain a characteristic carbohydrate recognition domain (CRD). The CRD is
about 140 amino acids
and contains several stretches of about 1 - 10 amino acids which are highly
conserved among all
galectins. A particular 6-amino acid motif within the CRD contains conserved
tryptophan and arginine
residues which are critical for carbohydrate binding. The CRD of some
galectins also contains
cysteine residues which may be important for disulfide bond formation.
Secondary strncture
predictions indicate that the CRD forms several (3-sheets.
Galectins play a number of roles in diseases and conditions associated with
cell-cell and cell-
matrix interactions. For example, certain galectins associate with sites of
inflammation and bind to cell
surface immunoglobulin E molecules. In addition, galectins may play an
important role in cancer
metastasis. Galectin overexpression is correlated with the metastatic
potential of cancers in humans
and mice. Moreover, anti-galectin antibodies inhibit processes associated with
cell transformation,
3o such as cell aggregation and anchorage-independent growth (see, for
example, Su, Z.-Z. et al. (1996)
Proc. Natl. Acad. Sci. USA 93:7252-7257).
Selectins, or LEC-CAMs, comprise a specialized lectin subfamily involved
primarily in
inflammation and leukocyte adhesion (Reviewed in Lasky, supra). Selectins
mediate the recruitment
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of leukocytes from the circulation to sites of acute inflammation and are
expressed on the surface of
vascular endothelial cells in response to cytokine signaling. Selectins bind
to specific ligands on the
leukocyte cell membrane and enable the leukocyte to adhere to and migrate
along the endothelial
surface. Binding of selectin to its ligand leads to polarized rearrangement of
the actin cytoskeleton
and stimulates signal transduction within the leukocyte (Brenner, B. et al.
(1997) Biochem. Biophys.
Res. Commun. 231:802-807; Hidari, K. I. et al. (1997) J. Biol. Chem. 272:28750-
28756). Members of
the selectin family possess three characteristic motifs: a lectin or
carbohydrate recognition domain; an
epidermal growth factor-like domain; and a variable number of short consensus
repeats (scr or "sushi"
repeats) which are also present in complement regulatory proteins.
l0 Neural cell adhesion proteins (NCAPs) play roles in the establishment of
neural networks
during development and regeneration of the nervous system (Uyemura et al.
(1996) Essays Biochem.
31:37-48~; Bmnmendorf and Rathjen (1996) Curr. Opin. Neurobiol. 6:584-593).
NCAP participates in
neuronal cell migration, cell adhesion, neurite outgrowth, axonal
fasciculation, pathfinding, synaptic
target-recognition, synaptic formation, myelination and regeneration. NCAPs
are expressed on the
surfaces of neurons associated with learning and memory. Mutations in genes
encoding NCAPS are
linked with neurological diseases, including hereditary neuropathy Charcot-
Marie-Tooth disease,
Dejerine-Sottas disease, X-linked hydrocephalus, MASA syndrome (mental
retardation, aphasia,
shuffling gait and adducted thumbs), and spastic paraplegia type I. In some
cases, expression of
NCAP is not restricted to the nervous system. L1 , for example, is expressed
in melanoma sells and
hematopoietic tumor cells where it is implicated in cell spreading and
migration, and may play a role in
tumor progression (Montgomery et al. (1996) J. Cell Biol. 132:475-485).
NCAPs have at least one immunoglobulin constant or variable domain (Uyemura et
al.,
s_~ra). They are generally linked to the plasma membrane through a
transmembrane domain and/or a
glycosyl-phosphatidylinositol (GPI) anchor. The GPI linkage can be cleaved by
GPI phospholipase C.
Most NCAPs consist of an extracellular region made up of one or more
immunoglobulin domains, a
membrane spanning domain, and an intracellular region. Many NCAPs contain post-
translational
modifications including covalently attached oligosaccharide, glucuronic acid,
and sulfate. NCAPs fall
into three subgroups: simple-type, complex-type, and mixed-type. Simple-type
NCAPs contain one or
more variable or constant immunoglobulin domains, but lack other types of
domains. Members of the
simple-type subgroup include Schwann cell myelin protein (SMP), limbic system-
associated membrane
protein (LAMP), opiate-binding cell-adhesion molecule (OBCAM), and myelin-
associated glycoprotein
(MAG). The complex-type NCAPs contain fibronectin type III domains in addition
to the
immunoglobulin domains. The complex-type subgroup includes neural cell-
adhesion molecule
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(NCAM), axonin-1, Fl l, Bravo, and Ll. Mixed-type NCAPs contain a combination
of
immunoglobulin domains and other motifs such as tyrosine kinase and epidermal
growth factor-like
domains. This subgroup includes Trk receptors of nerve growth factors such as
nerve growth factor
(NGF) and neurotropin 4 (NT4), Neu differentiation factors such as glial
growth factor II (GGFII) and
acetylcholine receptor-inducing factor (ARIA), and the semaphorin/collapsin
family such as
semaphorin B and collapsin.
Semaphorins are a large group of axonal guidance molecules consisting of at
least 30 different
members and are found in vertebrates, invertebrates, and even certain viruses.
All semaphorins
contain the sema domain which is approximately 500 amino acids in length.
Neuropilin, a semaphorin
receptor has been shown to promote neurite outgrowth in vitro. The
extracellular region of neuropilins
consists of three different domains: CUB, discoidin, and MAM domains. The CUB
and the MAM
motifs of neuropilin have been suggested as having roles in protein-protein
interactions and are
suggested to be involved in the binding of semaphorins through the sema and
the C-terminal domains
(reviewed in Raper, J.A. (2000) Curr. Opin. Neurobiol. 10:88-94).
An NCAP subfamily, the NCAP-LON subgroup, includes cell adhesion proteins
expressed on
distinct subpopulations of brain neurons. Members of the NCAP-LON subgroup
possess three
immunoglobulin domains and bind to cell membranes through GPI anchors. Kilon
(a kindred of
NCAP-LON), for example, is expressed in the brain cerebral cortex and
hippocampus (Funatsu et al.
(1999) J. Biol. Chem. 274:8224-8230). Immunostaining localizes Kilon to the
dendrites and soma of
pyramidal neurons. Kilon has three C2 type immunoglobulin-like domains, six
predicted glycosylation
sites, and a GPI anchor. Expression of Kilon is developmentally regulated. It
is expressed at higher
levels in adult brain in comparison to embryonic and early postnatal brains.
Confocal microscopy
shows the presence of Kilon in dendrites of hypothalamic magnocellular neurons
secreting
neuropeptides, oxytocin or arginine vasopressin (Miyata et al. (2000) J. Comp.
Neurol. 424:74-85).
Arginine vasopressin regulates body fluid homeostasis, extracellular
osmolarity and intravascular
volume. Oxytocin induces contractions of uterine smooth muscle during child
birth and of
myoepithelial cells in mammary glands during lactation. In magnocellular
neurons, Kilon. is proposed to
play roles in the reorganization of dendritic connections during neuropeptide
secretion.
Cell adhesion proteins also include some members of the proline-rich proteins
(PRPs). PRPs
3o are defined by a high frequency of proline, ranging from 20-50% of the
total amino acid content.
Some PRPs have short domains which are rich in proline. These proline-rich
regions are associated
with protein-protein interactions. One family of PRPs are the proline-rich
synapse-associated proteins
(ProSAPs) which have been shown to bind to members of the postsynaptic density
(PSD) protein
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family and subtypes of the somatostatin receptor (Yao, I. et al. (1999) J.
Biol. Chem. 274:
27463-27466; Zitzer, H. et al. (1999) J. Biol. Chem. 274:32997-33001). Members
of ProSAP contain
at the N-terminus six to seven ankyrin repeats, followed by an SH3 domain, a
PDZ domain, then by
seven proline-rich regions and a SAM domain at the C terminus. Several groups
of ProSAP are
important structural constituents of synaptic structures in human brain
(Zitzer et al.,
supra). Another member of PRP is the HLA-B-associated transcript 2 protein
(BAT2) which is xich
in proline and include short tracts of polyproline, polyglycine, and charged
amino acids. BAT2 also
contains four RGD (Arg-Gly-Asp) motifs typical of integrins (Banerji, J. et
al. (1990) Proc. Natl.
Acad. Sci. USA 87:2374-2378).
There are additional specific domains char acteristic of cell adhesion
proteins. One such
domain is the MAM domain, a domain of about 170 amino acids found in the
extracellular region of
diverse proteins. These proteins all share a receptor-like architecture
comprising a signal peptide,
followed by a large N-terminal extracellular domain, a transmembrane region,
and an intracellular
domain. (PROSTTE document PDOC00604 MAM domain signature and profile). MAM
domain
proteins include zonadhesin, a sperm-specific membrane protein that binds to
the zona pellucida of the
egg; neuropilin, a cell adhesion molecule that functions during the formation
of certain neuronal
circuits, and Xenopus laevis thyroid hormone induced protein B, which contains
four MAM domains
and is involved in metamorphosis (Brown, D.D. et al. (1996) Proc. Natl. Acad.
Sci. USA 93:1924-
1929).
The WSC domain was originally found in the yeast WSC (cell-wall integrity and
stress
response component) proteins which act as sensors of environmental stress. The
WSC domains are
extracellular and are thought to possess a carbohydrate binding role (Ponting,
C.P. et al. (1999) Curr.
Biol. 9:S1-S2). A WSC domain has recently been identified in polycystin-l, a
human plasma
membrane protein. Mutations in polycystin-1 are the cause of the commonest
form of autosomal
dominant polycystic kidney disease (Ponting, C.P. et al. (1999) C~rr. Biol.
9:8585-8588).
Toposome is a cell-adhesion glycoprotein isolated from mesenchyme-blastula
embryos.
Toposome precursors including vitellogenin promote cell adhesion of
dissociated blastula cells.
Leucine rich repeats (L88) are short motifs found in numerous proteins from a
wide range of
species. LRR motifs are of variable length, most commonly 20-29 amino acids
and multiple repeats
3o are typically present in tandem. LRR is important for proteinlprotein
interactions and cell adhesion,
and LRR proteins are involved in cell/cell interactions, morphogenesis, and
development (Kobe, B. and
Deisenhofer, J. (1995) Gtr. Opin. Struct. Biol. 5:409-416). The human ISLR
(immunoglobulin
superfamily containing leucine-rich repeat) protein contains'a C2-type
immunoglobulin domain as well
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as LRR. The ISLR gene is linked to the critical region for Bardet-Biedl
syndrome, a developmental
disorder of which the most common feature is retinal dystrophy (Nagasawa, A.
et al. (1999)
Genomics 61:37-43).
The sterile alpha motif (SAM) domain is a conserved protein binding domain,
approximately
70 amino acids in length, and is involved in the regulation of many
developmental processes in many
eukaryotes. The SAM domain can potentially function as a protein interaction
module through its
ability to form homo- or hetero-oligomers with other SAM domains (Schultz, J.
et al. (1997) Protein
Sci. 6:249-253).
The discovery of new extracellular matrix and cell adhesion molecules and the
polynucleotides
encoding them satisfies a need in the art by providing new compositions which
are useful in the
diagnosis, prevention, and treatment of genetic, immune/inflammatory,
developmental, neurological,
connective tissue, and cell proliferative disorders, including cancer, and in
the assessment of the
effects of exogenous compounds on the expression of nucleic acid and amino
acid sequences of
extracellular matrix and cell adhesion molecules.
SUMMARY OF THE INVENTION
The invention features purified polypeptides, extracellular matrix and cell
adhesion molecules,
referred to collectively as "ECMCAD" and individually as "ECMCAD-l," "ECMCAD-
2,"
"ECMCAD-3," "ECMCAD-4," "ECMCAD-5," "ECMCAD-6," "ECMCAD-7," "ECMCAD-8,"
"ECMCAD-9," "ECMCAD-10," "ECMCAD-11," "ECMCAD-12," "ECMCAD-13," "ECMCAD-
14," "ECMCAD-15," "ECMCAD-16," "ECMCAD-17," "ECMCAD-18," "ECMCAD-19,"
"ECMCAD-20," "ECMCAD-21," "ECMCAD-22," "ECMCAD-23," "ECMCAD-24," "ECMCAD-
25," "ECMCAD-26," "ECMCAD-27," "ECMCAD-28," "ECMCAD-29," "ECMCAD-30,"
"ECMCAD-31," "ECMCAD-32," "ECMCAD-33," "ECMCAD-34," "ECMCAD-35," and
"ECMCAD-36." In one aspect, the invention provides an isolated polypeptide
selected from the group
consisting of a) a polypeptide comprising an amino acid sequence selected from
the group consisting
of SEQ ID NO:1-36, b) a naturally occurring polypeptide comprising an amino
acid sequence at least
90% identical to an amino acid sequence selected from the group consisting of
SEQ ID N0:1-36, c) a
biologically active fragment of a polypeptide having an amino acid sequence
selected from the group
consisting of SEQ 117 N0:1-36, and d) an immunogenic fragment of a polypeptide
having an amino
acid sequence selected from the group consisting of SEQ 1D N0:1-36. In one
alternative, the
invention provides an isolated polypeptide comprising the amino acid sequence
of SEQ ~ N0:1-36.
The invention further provides an isolated polynucleotide encoding a
polypeptide selected from
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the group consisting of a) a polypeptide comprising an amino acid sequence
selected from the group
consisting of SEQ ID N0:1-36, b) a naturally occurring polypeptide comprising
an amino acid
sequence at least 90% identical to an amino acid sequence selected from the
group consisting of SEQ
D7 N0:1-36, c) a biologically active fragment of a polypeptide having an amino
acid sequence selected
from the group consisting of SEQ ID N0:1-36, and d) an immunogenic fragment of
a polypeptide
having an amino acid sequence selected from the group consisting of SEQ ID
NO:l-36. In one
alternative, the polynucleotide encodes a polypeptide selected from the group
consisting of SEQ ID
N0:1-36. In another alternative, the polynucleotide is selected from the group
consisting of SEQ m
N0:37-72.
Additionally, the invention provides a recombinant polynucleotide comprising a
promoter
sequence operably linked to a polynucleotide encoding a polypeptide selected
from the group
consisting of a) a polypeptide comprising an amino acid sequence selected from
the group consisting
of SEQ ID NO:1-36, b) a naturally occurring polypeptide comprising an amino
acid sequence at least
90% identical to an amino acid sequence selected from the group consisting of
SEQ ID NO:1-36, c) a
biologically active fragment of a polypeptide having an amino acid sequence
selected from the group
consisting of SEQ 1D N0:1-36, and d) an immunogenic fragment of a polypeptide
having an amino
acid sequence selected from the group consisting of SEQ ID N0:1-36. In one
alternative, the
invention provides a cell transformed with the recombinant polynucleodde. In
another alternative, the
invention provides a transgenic organism comprising the recombinant
polynucleotide.
The invention also provides a method for producing a polypeptide selected from
the group
consisting of a) a polypeptide comprising an amino acid sequence selected from
the group consisting
of SEQ ID N0:1-36, b) a naturally occurring polypeptide comprising an amino
acid sequence at least
90% identical to an amino acid sequence selected from the group consisting of
SEQ ID NO:1-36, c) a
biologically active fragment of a polypeptide having an amino acid sequence
selected from the group
consisting of SEQ ID N0:1-36, and d) an immunogenic fragment of a polypeptide
having an amino
acid sequence selected from the group consisting of SEQ ID NO:I-36. The method
comprises a)
culturing a cell under conditions suitable for expression of the polypeptide,
wherein said cell is
transformed with a recombinant polynucleotide comprising a promoter sequence
operably linked to a
polynucleotide encoding the polypeptide, and b) recovering the polypeptide so
expressed.
Additionally, the invention provides an isolated antibody which specifically
binds to a
polypeptide selected from the group consisting of a) a polypeptide comprising
an amino acid sequence
selected from the group consisting of SEQ ID N0:1-36, b) a naturally occurring
polypeptide
comprising an amino acid sequence at least 90% identical to an amino acid
sequence selected from
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the group consisting of SEQ ID NO:1-36, c) a biologically active fragment of a
polypeptide having an
amino acid sequence selected from the group consisting of SEQ )D N0:1-36, and
d) an immunogenic
fragment of a polypeptide having an amino acid sequence selected from the
group consisting of SEQ
)17 N0:1-36.
The invention further provides an isolated polynucleotide selected from the
group consisting of
a) a polynucleotide comprising a polynucleotide sequence selected from the
group consisting of SEQ
1D N0:37-72, b) a naturally occurring polynucleotide comprising a
polynucleotide sequence at least
90% identical to a polynucleotide sequence selected from the group consisting
of SEQ ID N0:37-72,
c) a polynucleotide complementary to the polynucleotide of a), d) a
polynucleotide complementary to
the polynucleotide of b), and e) an RNA equivalent of a)-d). In one
alternative, the polynucleotide
comprises at least 60 contiguous nucleotides.
Additionally, the invention provides a method for detecting a target
polynucleotide in a sample,
said target polynucleotide having a sequence of a polynucleotide selected from
the group consisting of
a) a polynucleotide comprising a polynucleotide sequence selected from the
group consisting of SEQ
1D N0:37-72, b) a naturally occurring polynucleotide comprising a
polynucleotide sequence at least
90% identical to a polynucleotide sequence selected from the group consisting
of SEQ ID N0:37-72,
c) a polynucleotide complementary to the polynucleotide of a), d) a
polynucleotide complementary to
the polynucleotide of b), and e) an RNA equivalent of a)-d). The method
comprises a) hybridizing the
sample with a probe comprising at least 20 contiguous nucleotides comprising a
sequence
complementary to said target polynucleotide in the sample, and which probe
specifically hybridizes to
said target polynucleotide, under conditions whereby a hybridization complex
is formed between said
probe and said target polynucleotide or fragments thereof, and b) detecting
the presence or absence of
said hybridization complex, and optionally, if present, the amount thereof. In
one alternative, the probe
comprises at least 60 contiguous nucleotides.
The invention further provides a method for detecting a target polynucleotide
in a sample, said
target polynucleotide having a sequence of a polynucleotide selected from the
group consisting of a) a
polynucleotide comprising a polynucleotide sequence selected from the group
consisting of SEQ 1D
N0:37-72, b) a naturally occurnng polynucleotide comprising a polynucleotide
sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of
SEQ ID N0:37-72, c) a
polynucleotide complementary to the polynucleotide of a), d) a polynucleotide
complementary to the
polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises
a) amplifying said
target polynucleotide or fragment thereof using polymerase chain reaction
amplification, and b)
detecting the presence or absence of said amplified target polynucleotide or
fragment thereof, and,
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optionally, if present, the amount thereof.
The. invention further provides a composition comprising an effective amount
of a polypeptide
selected from the group consisting of a) a polypeptide comprising an amino
acid sequence selected
from the group consisting of SEQ 1D NO:1-36, b) a naturally occurring
polypeptide comprising an
amino acid sequence at least 90% identical to an amino acid sequence selected
from the group
consisting of SEQ ID N0:1-36, c) a biologically active fragment of a
polypeptide having an amino acid
sequence selected from the group consisting of SEQ 1D N0:1-36, and d) an
immunogenic fragment of
a polypeptide having an amino acid sequence selected from the group consisting
of SEQ ID NO:1-36,
and a pharmaceutically acceptable excipient. In one embodiment, the
composition comprises an amino
acid sequence selected from the group consisting of SEQ ID N0:1-36. The
invention additionally
provides a method of treating a disease or condition associated with decreased
expression of
functional ECMCAD, comprising administering to a patient in need of such
treatment the composition.
The invention also provides a method for screening a compound for
effectiveness as an
agonist of a polypeptide selected from the group consisting of a) a
polypeptide comprising an amino
acid sequence selected from the group consisting of SEQ ID NO:1-36, b) a
naturally occurring
polypeptide comprising an amino acid sequence at least 90% identical to an
amino acid sequence
selected from the group consisting of SEQ 1D N0:1-36, c) a biologically active
fragment of a
polypeptide having an amino acid sequence selected from the group consisting
of SEQ ID NO:1-36,
and d) an immunogenic fragment of a polypeptide having an amino acid sequence
selected from the
group consisting of SEQ ID N0:1-36. The method comprises a) exposing a sample
comprising the
polypeptide to a compound, and b) detecting agonist activity in the sample. In
one alternative, the
invention provides a composition comprising an agonist compound identified by
the method and a
pharmaceutically acceptable excipient. In another alternative, the invention
provides a method of
treating a disease or condition associated with decreased expression of
functional ECMCAD,
comprising administering to a patient in need of such treatment the
composition.
Additionally, the invention provides a method for screening a compound for
effectiveness as
an antagonist of a polypeptide selected from the group consisting of a) a
polypeptide comprising an
amino acid sequence selected from the group consisting of SEQ 1D N0:1-36, b) a
naturally occurring
polypeptide comprising an amino acid sequence at least 90% identical to an
amino acid sequence
selected from the group consisting of SEQ ID NO:1-36, c) a biologically active
fragment of a
polypeptide having an amino acid sequence selected from the group consisting
of SEQ )D N0:1-36,
and d) an immunogenic fragment of a polypeptide having an amino acid sequence
selected from the
group consisting of SEQ 1D N0:1-36. The method comprises a) exposing a sample
comprising the
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polypeptide to a compound, and b) detecting antagonist activity in the sample.
In one alternative, the
invention provides a composition comprising an antagonist compound identified
by the method and a
pharmaceutically acceptable excipient. In another alternative, the invention
provides a method of
treating a disease or condition associated with overexpression of functional
ECMCAD, comprising
administering to a patient in need of such treatment the composition.
The invention further provides a method of screening for a compound that
specifically binds to
a polypeptide selected from the group consisting of a) a polypeptide
comprising an amino acid
sequence selected from the group consisting of SEQ m NO:l-36, b) a naturally
occurring polypeptide
comprising an amino acid sequence at least 90% identical to an amino acid
sequence selected from
to the group consisting of SEQ ID NO:l-36, c) a biologically active fragment
of a polypeptide having an
amino acid sequence selected from the group consisting of SEQ )D N0:1-36, and
d) an immunogenic
fragment of a polypeptide having an amino acid sequence selected from the
group consisting of SEQ
1D N0:1-36. The method comprises a) combining the polypeptide with at least
one test compound
under suitable conditions, and b) detecting binding of the polypeptide to the
test compound, thereby
identifying a compound that specifically binds to the polypeptide.
The invention further provides a method of screening for a compound that
modulates the
activity of a polypeptide selected from the group consisting of a) a
polypeptide comprising an amino
acid sequence selected from the group consisting of SEQ 1D NO:1-36, b) a
naturally occurring
polypeptide comprising an amino acid sequence at least 90% identical to an
amino acid sequence
selected from the group consisting of SEQ )D N0:1-36, c) a biologically active
fragment of a
polypeptide having an amino acid sequence selected from the group consisting
of SEQ )D NO:1-36,
and d) an immunogenic fragment of a polypeptide having an amino acid sequence
selected from the
group consisting of SEQ 1D N0:1-36. The method comprises a) combining the
polypeptide with at
least one test compound under conditions permissive for the activity of the
polypeptide, b) assessing
the activity of the polypeptide in the presence of the test compound, and c)
comparing the activity of
the polypeptide in the presence of the test compound with the activity of the
polypeptide in the
absence of the test compound, wherein a change in the activity of the
polypeptide in the presence of
the test compound is indicative of a compound that modulates the activity of
the polypeptide.
The invention further provides a method for screening a compound for
effectiveness in
altering expression of a target polynucleotide, wherein said target
polynucleotide comprises a sequence
selected from the group consisting of SEQ )D N0:37-72, the method comprising
a) exposing a sample
comprising the target polynucleotide to a compound, and b) detecting altered
expression of the target
polynucleotide.
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The invention further provides a method for assessing toxicity of a test
compound, said
method comprising a) treating a biological sample containing nucleic acids
with the test compound; b)
hybridizing the nucleic acids of the treated biological sample with a probe
comprising at least 20
contiguous nucleotides of a polynucleotide selected from the group consisting
of i) a polynucleotide
comprising a polynucleotide sequence selected from the group consisting of SEQ
m N0:37-72, ii) a
naturally occurring polynucleotide comprising a polynucleotide sequence at
least 90% identical to a
polynucleotide sequence selected from the group consisting of SEQ 1D N0:37-72,
iii) a polynucleotide
having a sequence complementary to i), iv) a polynucleotide complementary to
the polynucleotide of
ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions
whereby a specific
hybridization complex is formed between said probe and a target polynucleotide
in the biological
sample, said target polynucleotide selected from the group consisting of i) a
polynucleotide comprising
a polynucleotide sequence selected from the group consisting of SEQ ID N0:37-
72, ii) a naturally
occurring polynucleotide comprising a polynucleotide sequence at least 90%
identical to a
polynucleotide sequence selected from the group consisting of SEQ 1D N0:37-72,
iii) a polynucleotide
complementary to the polynucleotide of i), iv) a polynucleotide complementary
to the polynucleotide of
ii), and v) an RNA equivalent of i)-iv). Alternatively, the target
polynucleotide comprises a fragment
of a polynucleotide sequence selected from the group consisting of i)-v)
above; c) quantifying the
amount of hybridization complex; and d) comparing the amount of hybridization
complex in the treated
biological sample with the amount of hybridization complex in an untreated
biological sample, wherein
a difference in the amount of hybridization complex in the treated biological
sample is indicative of
toxicity of the test compound.
BRIEF DESCRIPTION OF THE TABLES
Table 1 summarizes the nomenclature for the full length polynucleotide and
polypeptide
sequences of the present invention.
Table 2 shows the GenBank identification number and annotation of the nearest
GenBank
homolog for polypeptides of the invention. The probability score for the match
between each
polypeptide and its GenBank homolog is also shown.
Table 3 shows structural features of polypeptide sequences of the invention,
including
predicted motifs and domains, along with the methods, algorithms, and
searchable databases used for
analysis of the polypeptides.
Table 4 lists the cDNA and/or genomic DNA fragments which were used to
assemble
polynucleotide sequences of the invention, along with selected fragments of
the polynucleotide
CA 02413186 2002-12-27
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sequences.
Table S shows the representative cDNA library for polynucleotides of the
invention.
Table 6 provides an appendix which describes the tissues and vectors used for
construction of
the cDNA libraries shown in Table 5.
Table 7 shows the tools, programs, and algorithms used to analyze the
polynucleotides and
polypeptides of the invention, along with applicable descriptions, references,
and threshold parameters.
DESCRIPTION OF THE INVENTION
Before the present proteins, nucleotide sequences, and methods a.re described,
it is understood
l0 that this invention is not limited to the particular machines, materials
and methods described, as these
may vary. It is also to be understood that the terminology used herein is for
the purpose of describing
particular embodiments only, and is not intended to limit the scope of the
present invention which will
be limited only by the appended claims.
It must be noted that as used herein and in the appended claims, the singular
forms "a," "an,"
15 and "the" include plural reference unless the context clearly dictates
otherwise. Thus, for example, a
reference to "a host cell" includes a plurality of such host cells, and a
reference to "an antibody" is a
reference to one or more antibodies and equivalents thereof known to those
skilled in the art, and so
forth.
Unless defined otherwise, all technical and scientific terms used herein have
the same
20 meanings as commonly understood by one of ordinary skill in the art to
which this invention belongs.
Although any machines, materials, and methods similar or equivalent to those
described herein can be
used to practice or test the present invention, the preferred machines,
materials and methods are. now
described. All publications mentioned herein are cited for the purpose of
describing and disclosing the
cell lines, protocols, reagents and vectors which are reported in the
publications and which might be
25 used in connection with the invention. Nothing herein is to be construed as
an admission that the
invention is not entitled to antedate such disclosure by virtue of prior
invention.
DEFINITIONS
"ECMCAD" refers to the amino acid sequences of substantially purified ECMCAD
obtained
from any species, particularly a mammalian species, including bovine, ovine,
porcine, marine, equine,
30 and human, and from any source, whether natural, synthetic, semi-synthetic,
or recombinant.
The teen "agonist" refers to a molecule which intensi~xes or mimics the
biological aetivity of
ECMCAD. Agonists may include proteins, nucleic acids, carbohydrates, small
molecules, or any other
compound or composition which modulates the activity of ECMCAD either by
directly interacting with
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ECMCAD or by acting on components of the biological pathway in which ECMCAD
participates.
An "allelic variant" is an alternative form of the gene encoding ECMCAD.
Allelic variants
may result from at least one mutation in the nucleic acid sequence and may
result in altered mRNAs
or in polypeptides whose structure or function may or may not be altered. A
gene may have none,
one, or many allelic variants of its naturally occurring form. Common
mutational changes which give
rise to allelic variants are generally ascribed to natural deletions,
additions, or substitutions of
nucleotides. Each of these types of changes may occur alone, or in combination
with the others, one
or more times in a given sequence.
"Altered" nucleic acid sequences encoding ECMCAD include those sequences with
deletions,
1o insertions, or substitutions of different nucleotides, resulting in a
polypeptide the same as ECMCAD or
a polypeptide with at least one functional characteristic of ECMCAD. Included
within this definition
are polymorphisms which may or may not be readily detectable using a
particular oligonucleotide
probe of the polynucleotide encoding ECMCAD, and improper or unexpected
hybridization to allelic
variants, with a locus other than the normal chromosomal locus for the
polynucleotide sequence
IS encoding ECMCAD. The encoded protein may also be "altered," and may contain
deletions,
insertions, or substitutions of amino acid residues which produce a silent
change and result in a
functionally equivalent ECMCAD. Deliberate amino acid substitutions may be
made on the basis of
similarity in polarity, chaxge, solubility, hydrophobicity, hydrophilicity,
and/or the amphipathic nature of
the residues, as long as the biological or immunological activity of ECMCAD is
retained. For example,
2o negatively chaxged amino acids may include aspartic acid and glutamic acid,
and positively charged
amino acids may include lysine and arginine. Amino acids with uncharged polar
side chains having
similar hydrophilicity values may include: asparagine and glutamine; and
serine and threonine. Amino
acids with uncharged side chains having similar hydrophilicity values may
include: leucine, isoleucine,
and valine; glycine and alanine; and phenylalanine and tyrosine.
25 The terms "amino acid" and "amino acid sequence" refer to an oligopeptide,
peptide,
polypeptide, or protein sequence, or a fragment of any of these, and to
naturally occurring or synthetic
molecules. Where "amino acid sequence" is recited to refer to a sequence of a
naturally occurring
protein molecule, "amino acid sequence" and like terms are not meant to limit
the amino acid sequence
to the complete native amino acid sequence associated with the recited protein
molecule.
30 "Amplification" relates to the production of additional copies of a nucleic
acid sequence.
Amplification is generally carried out using polymerase chain reaction (PCR)
technologies well known
in the art.
The term "antagonist" refers to a molecule which inhibits or attenuates the
biological activity
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of ECMCAD. Antagonists may include proteins such as antibodies, nucleic acids,
carbohydrates,
small molecules, or any other compound or composition which modulates the
activity of ECMCAD
either by directly interacting with ECMCAD or by acting on components of the
biological pathway in
which ECMCAD participates.
The term "antibody" refers to intact immunoglobulin molecules as well as to
fragments
thereof, such as Fab, F(ab')2, and Fv fragments, which are capable of binding
an epitopic determinant.
Antibodies that bind ECMCAD polypeptides can be prepared using intact
polypeptides or using
fragments containing small peptides of interest as the immunizing antigen. The
polypeptide or
oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit)
can be derived from the
translation of RNA, or synthesized chemically, and can be conjugated to a
carrier protein if desired.
Commonly used carriers that are chemically coupled to peptides include bovine
senun albumin,
thyroglobulin, and keyhole limpet hemocyanin (KLI~. The coupled peptide is
then used to immunize
the animal.
The term "antigenic determinant" refers to that region of a molecule (i.e., an
epitope) that
makes contact with a particular antibody. When a protein or a fragment of a
protein is used to
immunize a host animal, numerous regions of the protein may induce the
production of antibodies
which bind specifically to antigenic determinants (particular regions or three-
dimensional structures on
the protein). An antigenic determinant may compete with the intact antigen
(i.e., the immunogen used
to elicit the immune response) for binding to an antibody.
The term "antisense" refers to any composition capable of base-pairing with
the "sense"
(coding) strand of a specific nucleic acid sequence. Antisense compositions
may include DNA; RNA;
peptide nucleic acid (PNA); oIigonucleotides having modified backbone linkages
such as
phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides
having modified
sugar groups such'as 2'-methoxyethyl sugars or 2'-methoxyethoxy sugars; or
oligonucleotides having
modified bases such as 5-methyl cytosine, 2'-deoxyuracil, or 7-deaza-2'-
deoxyguanosine. Antisense
molecules may be produced by any method including chemical synthesis or
transcription. Once
introduced into a cell, the complementary antisense molecule base-pairs with a
naturally occurring
nucleic acid sequence produced by the cell to form duplexes which block either
transcription or
translation. The designation "negative" or "minus" can refer to the antisense
strand, and the
designation "positive" or "plus" can refer to the sense strand of a reference
DNA molecule.
The term "biologically active" refers to a protein having structural,
regulatory, or biochemical
functions of a naturally occurring molecule. Likewise, "immunologically
active" or "immunogenic"
refers to the capability of the natural, recombinant, or synthetic ECMCAD, or
of any oligopeptide
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WO 02/02634 PCT/USO1/21067
thereof, to induce a specific immune response in appropriate animals or cells
and to bind with specific
antibodies.
"Complementary" describes the relationship between two single-stranded nucleic
acid
sequences that anneal by base-pairing. For example, 5'-AGT-3' pairs with its
complement,
3'-TCA-5'.
A "composition comprising a given polynucleotide sequence" and a "composition
comprising a
given amino acid sequence" refer broadly to any composition containing the
given polynucleotide or
amino acid sequence. The composition may comprise a dry formulation or an
aqueous solution.
Compositions comprising polynucleotide sequences encoding ECMCAD or fragments
of ECMCAD
l0 may be employed as hybridization probes. The probes may be stored in freeze-
dried form and may be
associated with a stabilizing agent such as a carbohydrate. In hybridizations,
the probe may be
deployed in an aqueous solution containing salts (e.g., NaCI), detergents
(e.g., sodium dodecyl sulfate;
SDS), and other components (e.g., Denhardt's solution, dry milk, salmon sperm
DNA, etc.).
"Consensus sequence" refers to a nucleic acid sequence which has been
subjected to
repeated DNA sequence analysis to resolve uncalled bases, extended using the
XLrPCR kit (Applied
Biosystems, Foster City CA) in the 5' and/or the 3' direction, and
resequenced, or which has been
assembled from one or more overlapping cDNA, EST, or genomic DNA fragments
using a computer
program for fragment assembly, such as the GELVIEW fragment assembly system
(GCG, Madison
Wl7 or Phrap (University of Washington, Seattle WA). Some sequences have been
both extended
and assembled to produce the consensus sequence.
"Conservative amino acid substitutions" are those substitutions that axe
predicted to least
interfere with the properties of the original protein, i.e., the structure and
especially the function of the
protein is conserved and not significantly changed by such substitutions. The
table below shows amino
acids which may be substituted for an original amino acid in a protein and
which are regarded as
conservative amino acid substitutions.
Original Residue Conservative Substitution
Ala Gly, Ser
Arg His, Lys
Asn Asp, Gln, His
Asp Asn, Glu
Cys Ala, Ser
Gln Asn, Glu, His
Glu Asp, Gln, His
Gly Ala
His Asn, Arg, Gln, Glu
Ile Leu, Val
Leu Ile, Val
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Lys Arg, Gln, Glu
Met Leu, Ile
Phe His, Met, Leu, Trp, Tyr
Ser Cys, Thr
Thr Ser, Val
Trp Phe, Tyr
Tyr His, Phe, Trp
Val Ile, Leu, Thr
to Conservative amino acid substitutions generally maintain (a) the structure
of the polypeptide
backbone in the area of the substitution, for example, as a beta sheet or
alpha helical conformation,
(b) the charge or hydrophobicity of the molecule at the site of the
substitution, and/or (c) the bulk of
the side chain.
A "deletion" refers to a change in the amino acid or nucleotide sequence that
results in the
15 absence of one or more amino acid residues or nucleotides.
The term "derivative" refers to a chemically modified polynucleotide or
polypeptide.
Chemical modifications of a polynucleotide can include, for example,
replacement of hydrogen by an
alkyl, acyl, hydroxyl, or amino group. A derivative polynucleotide encodes a
polypeptide which retains
at least one biological or immunological function of the natural molecule. A
derivative polypeptide is
20 one modified by glycosylation, pegylation, or any similar process that
retains at least one biological or
immunological function of the polypeptide from which it was derived.
A "detectable label" refers to a reporter molecule or enzyme that is capable
of generating a
measurable signal and is covalently ar noncovalently joined to a
polynucleotide or polypeptide.
"Differential expression" refers to increased or upregulated; or decreased,
downregulated, or
25 absent gene or protein expression, determined by comparing at least two
different samples. Such
comparisons may be carried out between, for example, a treated and an
untreated sample, or a
diseased and a normal sample.
A "fragment" is a unique portion of ECMCAD or the polynucleotide encoding
ECMCAD
which is identical in sequence to but shorter in length than the parent
sequence. A fragment may
30 comprise up to the entire length of the defined sequence, minus one
nucleotide/amino acid residue.
For example, a fragment may comprise from 5 to 1000 contiguous nucleotides or
amino acid residues.
A fragment used as a probe; primer, antigen, therapeutic molecule, or for
other purposes, may be at
least 5, 10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500
contiguous nucleotides or
amino acid residues in length. Fragments may be preferentially selected from
certain regions of a
35 molecule. For example, a polypeptide fragment may comprise a certain length
of contiguous amino
acids selected from the first 250 or 500 amino acids (or first 25% or
50°Io) of a polypeptide as shown
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in a certain defined sequence. Clearly these lengths are exemplary, and any
length that is supported
by the specification, including the Sequence Listing, tables, and figures, may
be encompassed by the
present embodiments.
A fragment of SEQ ID N0:37-72 comprises a region of unique polynucleotide
sequence that
specifically identifies SEQ ID N0:37-72, for example, as distinct from any
other sequence in the
genome from which the fragment was obtained. A fragment of SEQ ID N0:37-72 is
useful, for
example, in hybridization and amplification technologies and in analogous
methods that distinguish SEQ
ID N0:37-72 from related polynucleotide sequences. The precise length of a
fragment of SEQ ID
N0:37-72 and the region of SEQ ID N0:37-72 to which the fragment corresponds
are routinely
l0 determinable by one of ordinary skill in the art based on the intended
purpose for the fragment.
A fragment of SEQ ID NO:l-36 is encoded by a fragment of SEQ ID N0:37-72. A
fragment of SEQ ID NO:1-36 comprises a region of unique amino acid sequence
that specifically
identifies SEQ ID NO:1-36. For example, a fragment of SEQ ID NO:1-36 is useful
as an
immunogenic peptide for the development of antibodies that specifically
recognize SEQ ID NO:1-36.
The precise length of a fragment of SEQ 1D N0:1-36 and the region of SEQ ID
N0:1-36 to which
the fragment corresponds are routinely determinable by one of ordinary skill
in the art based on the
intended purpose for the fragment.
A "full length" polynucleotide sequence is one containing at Ieast a
translation initiation codon
(e.g., methionine) followed by an open reading frame and a translation
termination codon. A "full
length" polynucleotide sequence encodes a "full length" polypeptide sequence.
"Homology" refers to sequence similarity or, interchangeably, sequence
identity, between two
or more polynucleotide sequences or two or more polypeptide sequences.
The terms "percent identity" and "% identity," as applied to polynucleotide
sequences, refer to
the percentage of residue matches between at least two polynucleotide
sequences aligned using a
standardized algorithm. Such an algorithm may insert, in a standardized and
reproducible way, gaps in
the sequences being compared in order to optimize alignment between two
sequences, and therefore
achieve a more meaningful comparison of the two sequences.
Percent identity between polynucleotide sequences may be determined using the
default
parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e
sequence alignment program. This program is part of the LASERGENE software
package, a suite of
molecular biological analysis programs (DNASTAR, Madison WI). CLUSTAL V is
described in
Higgins, D.G. and P.M. Sharp (1989) CABIOS 5:151-153 and in Higgins, D.G. et
al. (1992) CABIOS
8:189-191. For pairwise alignments of polynucleotide sequences, the default
parameters are set as
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follows: I~tuple=2, gap penalty=5, window=4, and "diagonals saved"=4. The
"weighted" residue
weight table is selected as the default. Percent identity is reported by
CLUSTAL V as the "percent
similarity" between aligned polynucleotide sequences.
Alternatively, a suite of commonly used and freely available sequence
comparison algorithms
is provided by the National Center for Biotechnology Information (NCBI) Basic
Local Alignment
Search Tool (BLAST) (Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410),
which is available from
several sources, including the NCBI, Bethesda, MD, and on the Internet at
http://www.ncbi.nlm.nih.govBLAST/. The BLAST software suite includes various
sequence analysis
programs including "blastn," that is used to align a known polynucleotide
sequence with other
l0 polynucleotide sequences from a variety of databases. Also available is a
tool called "BLAST 2
Sequences" that is used for direct pairwise comparison of two nucleotide
sequences. "BLAST 2
Sequences" can be accessed and used interactively at
http:/lwww.ncbi.nlm.nih.gov/gorf/bl2.html. The
"BLAST 2 Sequences" tool can be used for both blastn and blastp (discussed
below). BLAST
programs are commonly used with gap and other parameters set to default
settings. For example, to
compare two nucleotide sequences, one may use blastn with the "BLAST 2
Sequences" tool Version
2Ø12 (April-21-2000) set at default parameters. Such default parameters may
be, for example:
Matrix: BLOSUM62
Reward for match: 1
Penalty for mismatch: -2
Open Gap: 5 and Extension Gap: 2 penalties
Gap x drop-off. 50
Expect: l0
Word Size: 11
Filter: on
Percent identity may be measured over the length of an entire defined
sequence, for example,
as defined by a particular SEQ 1D number, or may be measured over a shorter
length, for example,
over the length of a fragment taken from a larger, defined sequence, for
instance, a fragment of at
least 20, at least 30, at least 40, at least 50, at least 70, at least 100, or
at least 200 contiguous
nucleotides. Such lengths are exemplary only, and it is understood that any
fragment length supported
by the sequences shown herein, in the tables, figures, or Sequence Listing,
may be used to describe a
length over which percentage identity may be measured.
Nucleic acid sequences that do not show a high degree of identity may
nevertheless encode
similar amino acid sequences due to the degeneracy of the genetic code. It is
understood that changes
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in a nucleic acid sequence can be made using this degeneracy to produce
multiple nucleic acid
sequences that all encode substantially the same protein.
The phrases "percent identity" and "% identity," as applied to polypeptide
sequences, refer to
the percentage of residue matches between at least two polypeptide sequences
aligned using a
standardized algorithm. Methods of polypeptide sequence alignment are well-
known. Some alignment
methods take into account conservative amino acid substitutions. Such
conservative substitutions,
explained in more detail above, generally preserve the charge and
hydrophobicity at the site.of
substitution, thus preserving the structuxe (and therefore function) of the
polypeptide.
Percent identity between polypeptide sequences may be determined using the
default
parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e
sequence alignment program (described and referenced above). For pairwise
alignments of
polypeptide sequences using CLUSTAL V, the default parameters are set as
follows: I~tuple=1, gap
penalty=3, window=5, and "diagonals saved"=5. The PAM250 matrix is selected as
the default
residue weight table. As with polynucleotide alignments, the percent identity
is reported by
CLUSTAL V as the "percent similarity" between aligned polypeptide sequence
pairs.
Alternatively the NCBI BLAST software suite may be used. For example, for a
pairwise
comparison of two polypeptide sequences, one may use the "BLAST 2 Sequences"
tool Version
2Ø12 (April-21-2000) with blastp set at default parameters. Such default
parameters ray be, for
example:
Matrix: BLOSUM62
Opera Gap: 11 and Extefasioyz Gap: I penalties
Gap x drop-off. 50
Expect: 10
Word Size: 3
Filter: ofi
Percent identity may be measured over the length of an entire defined
polypeptide sequence,
for example, as defined by a particular SEQ ID nwnber, or may be measured over
a shorter length,
for example, over the length of a fragment taken from a larger, defined
polypeptide sequence, for
instance, a fragment of at least 15, at least 20, at least 30, at least 40, at
least 50, at least 70 or at least
150 contiguous residues. Such lengths are exemplary only, and it is understood
that any fragment
length supported by the sequences shown herein, in the tables, figures or
Sequence Listing, may be
used to describe a length over which percentage identity may be measured.
"Human artificial chromosomes" (HACs) are linear microchromosomes which may
contain
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DNA 'sequences of about 6 kb to 10 Mb in size and which contain all of the
elements required for
chromosome replication, segregation and maintenance.
The term "humanized antibody" refers to an antibody molecule in which the
amino acid
sequence in the non-antigen binding regions has been altered so that the
antibody more closely
resembles a human antibody, and still retains its original binding ability.
"Hybridization" refers to the process by which a polynucleotide strand anneals
with a
complementary strand through base pairing under defined hybridization
conditions. Specific
hybridization is an indication that two nucleic acid sequences share a high
degree of complementarity.
Specific hybridization complexes form under permissive annealing conditions
and remain hybridized
l0 after the "washing" step(s). The washing steps) is particularly important
in determining the
stringency of the hybridization process, with more stringent conditions
allowing less non-specific
binding, i.e., binding between pairs of nucleic acid strands that axe not
perfectly matched. Permissive
conditions for annealing of nucleic acid sequences are routinely determinable
by one of ordinary skill in
the art and may be consistent among hybridization experiments, whereas wash
conditions may be
varied among experiments to achieve the desired stringency, and therefore
hybridization specificity.
Permissive annealing conditions occur, for example, at 68°C in the
presence of about 6 x SSC, about
1 % (w/v) SDS, and about 100 ~ g/ml sheared, denatured salmon sperm DNA.
Generally, stringency of hybridization is expressed, in part, with reference
to the temperature
under which the wash step is carried out. Such wash temperatures are typically
selected to be about
5°C to 20°C lower than the thermal melting point (T~ for the
specific sequence at a defined ionic
strength and pH. The Tm i5 the temperature (under defined ionic strength and
pH) at which 50% of
the target sequence hybridizes to a perfectly matched probe. An equation for
calculating Tm and
conditions for nucleic acid hybridization are well known and can be found in
Sambrook, J. et al. (1989)
Molecular Cloning: A Laboratory Manual, 2nd ed., vol. 1-3, Cold Spring Harbor
Press, Plainview NY;
specifically see volume 2, chapter 9.
High stringency conditions for hybridization between polynucleotides of the
present invention
include~'wash conditions of 68°C in the presence of about 0.2 x SSC and
about 0.1 % SDS, for 1 hour.
Alternatively, temperatures of about 65°C, 60°C, 55°C, or
42°C may be used. SSC concentration may
be varied from about 0.1 to 2 x SSC, with SDS being present at about 0.1 %.
Typically, blocking
reagents are used to block non-specific hybridization. Such blocking reagents
include, for instance,
sheared and denatured salmon sperm DNA at about 100-200 ~.g/ml. Organic
solvent, such as
formamide at a concentration of about 35-50% v/v, may also be used under
particular circumstances,
such as for RNA:DNA hybridizations. Useful variations on these wash conditions
will be readily
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WO 02/02634 PCT/USO1/21067
apparent to those of ordinary skill in the art. Hybridization, particularly
under high stringency
conditions, may be suggestive of evolutionary similarity between the
nucleotides. Such similarity is
strongly indicative of a similar role for the nucleotides and their encoded
polypeptides.
The term "hybridization complex" refers to a complex formed between two
nucleic acid
sequences by virtue of the formation of hydrogen bonds between complementary
bases. A
hybridization complex may be formed in solution (e.g., Cot or Rot analysis) or
foamed between one
nucleic acid sequence present in solution and another nucleic acid sequence
immobilized on a solid
support (e.g., paper, membranes, filters, chips, pins or glass slides, or any
other appropriate substrate
to which cells or their nucleic acids have been fixed).
The words "insertion" and "addition" refer to changes in an amino acid or
nucleotide
sequence resulting in the addition of one or more amino acid residues or
nucleotides, respectively.
"immune response" can refer to conditions associated with inflammation,
trauma, immune
disorders, or infectious or genetic disease, etc. These conditions can be
characterized by expression
of various factors, e.g., cytokines, chemokines, and other signaling
molecules, which may affect
cellular and systemic defense systems.
An "immunogenic fragment" is a polypeptide or oligopeptide fragment of ECMCAD
which is
capable of eliciting an immune response when introduced into a living
organism, for example, a
mammal. The term "immunogenic fragment" also includes any polypeptide or
oligopeptide fragment of
ECMCAD which is useful in any of the antibody production methods disclosed
herein or known in the
art.
The term "microarray" refers to an arrangement of a plurality of
polynucleotides,
polypeptides, or other chemical compounds on a substrate.
The terms "element" and "array element" refer to a polynucleotide,
polypeptide, or other
chemical compound having a unique and defined position on a microarray.
The term "modulate" refers to a change in the activity of ECMCAD. For example,
modulation may cause an increase or a decrease in protein activity, binding
characteristics, or any
other biological, functional, or immunological properties of ECMCAD.
The phrases "nucleic acid" and "nucleic acid sequence" refer to a nucleotide,
oligonucleotide,
polynucleotide, or any fragment thereof. These phrases also refer to DNA or
RNA of genomic or
synthetic origin which may be single-stranded or double-stranded and may
represent the sense or the
antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-
like matexial.
"Operably linked" refers to the situation in which a first nucleic acid
sequence is placed in a
functional relationship with a second nucleic acid sequence. For instance, a
promoter is operably
CA 02413186 2002-12-27
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linked to a coding sequence if the promoter affects the transcription or
expression of the coding
sequence. Operably linked DNA sequences may be in close proximity or
contiguous and, where
necessary to join two protein coding regions, in the same reading frame.
"Peptide nucleic acid" (PNA) refers to an antisense molecule or anti-gene
agent which
comprises an oligonucleotide of at least about 5 nucleotides in length linked
to a peptide backbone of
amino acid residues ending in lysine. The terminal lysine confers solubility
to the composition. PNAs
preferentially bind complementary single stranded DNA or RNA and stop
transcript elongation, and
may be pegylated to extend their lifespan in the cell.
"Post-translational modification" of an ECMCAD may involve lipidation,
glycosylation,
l0 phosphorylation, acetylation, racemization, proteolytic cleavage, and other
modifications known in the
art. These processes may occur synthetically or biochemically. Biochemical
modifications will vary
by cell type depending on the enzymatic milieu of ECMCAD.
"Probe" refers to nucleic acid sequences encoding ECMCAD, their complements,
or
fragments thereof, which are used to detect identical, allelic or related
nucleic acid sequences. Probes
are isolated oligonucleotides or polynucleotides attached to a detectable
label or reporter molecule.
Typical labels include radioactive isotopes, ligands, chemiluminescent agents,
and enzymes. "Primers'.'
are short nucleic acids, usually DNA oligonucleotides, which may be annealed
to a target
polynucleotide by complementary base-pairing. The primer may then be extended
along the target
DNA strand by a DNA polymerase enzyme. Primer pairs can be used for
amplification (and
identification) of a nucleic acid sequence, e.g., by the polymerase chain
reaction (PCR).
Probes and primers as used in the present invention typically comprise at
least 15 contiguous
nucleotides of a known sequence. In order to enhance specificity, longer
probes and primers may also
be employed, such as probes and primers that comprise at least 20, 25, 30, 40,
50, 60, 70, 80, 90, 100,
or at least 150 consecutive nucleotides of the disclosed nucleic acid
sequences. Probes and primers
may be considerably longer than these examples, and it is understood that any
length supported by the
specification, including the tables, figures, and Sequence Listing, may be
used.
Methods for preparing and using probes and primers are described in the
references, for
example Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2nd
ed., vol. 1-3, Cold
Spring Haxbor Press, Plainview NY; Ausubel, F.M. et al. (1987) Current
Protocols in Molecular
Biolo~v, Greene Publ. Assoc. & Wiley-Intersciences, New York NY; Innis, M. et
al. (1990) PCR
Protocols, A Guide to Methods and Applications, Academic Press, San Diego CA.
PCR primer pairs
can be derived from a known sequence, for example, by using computer programs
intended for that
purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical
Research, Cambridge
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MA).
Oligonucleotides for use as primers are selected using software known in the
art for such
purpose. For example, OLIGO 4.06 software is useful for the selection of PCR
primer pairs of up to
100 nucleotides each, and for the analysis of oligonucleotides and larger
polynucleotides of up to 5,000
nucleotides from an input polynucleotide sequence of up to 32 kilobases.
Similar primer selection
programs have incorporated additional features for expanded capabilities. For
example, the PrimOU
primer selection program (available to the public from the Genome Center at
University of Texas
South West Medical Center, Dallas TX) is capable of choosing specific primers
from megabase
sequences and is thus useful for designing primers on a genome-wide scope. The
Primer3 primer
selection program (available to the public from the Whitehead Institute/MIT
Center for Genome
Research, Cambridge MA) allows the user to input a "mispriming library," in
which sequences to
avoid as primer binding sites are user-specified. Primer3 is useful, in
particular, for the selection of
oligonucleotides for microarrays. (The source code for the latter two primer
selection programs may
also be obtained from their respective sources and modified to meet the user's
specific needs.) The
PrimeGen program (available to the public from the UK Human Genome Mapping
Project Resource
Centre, Cambridge UK) designs primers based on multiple sequence alignments,
thereby allowing
selection of primers that hybridize to either the most conserved or least
conserved regions of aligned
nucleic acid sequences. Hence, this program is useful for identification of
both unique and conserved
oligonucleotides and polynucleotide fragments. The oligonucleotides and
polynucleotide fragments
identified by any of the above selection methods are useful in hybridization
technologies, for example,
as PCR or sequencing primers, microarray elements, or specific probes to
identify fully or partially
complementary polynucleotides in a sample of nucleic acids. Methods of
oligonucleotide selection are
not limited to those described above.
A "recombinant nucleic acid" is a sequence that is not naturally occurring or
has a sequence
that is made by an artificial combination of two or more otherwise separated
segments of sequence.
This, artificial combination is often accomplished by chemical synthesis or,
more commonly, by the
artificial manipulation of isolated segments of nucleic acids, e.g., by
genetic engineering techniques ,
such as those described in Sambrook, supra. The term recombinant includes
nucleic acids that have
been altered solely by addition, substitution, or deletion of a portion of the
nucleic acid. Frequently, a
3o recombinant nucleic acid may include a nucleic acid sequence operably
linked to a promoter sequence.
Such a recombinant nucleic acid may be part of a vector that is used, for
example, to transform a cell.
Alternatively, such recombinant nucleic acids may be part of a viral vector,
e.g., based on a
vaccinia virus, that could be use to vaccinate a mammal wherein the
recombinant nucleic acid is
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WO 02/02634 PCT/USO1/21067
expressed, inducing a protective immunological response in the mammal.
A "regulatory element" refers to a nucleic acid sequence usually derived from
untranslated
regions of a gene and includes enhancers, promoters, introns, and 5' and 3'
untranslated regions
(UTRs). Regulatory elements interact with host or viral proteins which control
transcription,
translation, or RNA stability.
"Reporter molecules" are chemical or biochemical moieties used for labeling a
nucleic acid,
amino acid, or antibody. Reporter molecules include radionuclides; enzymes;
fluorescent,
chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors;
magnetic particles; and
other moieties known in the art.
An "RNA equivalent," in reference to a DNA sequence, is composed of the same
linear
sequence of nucleotides as the reference DNA sequence with the exception that
all occurrences of
the nitrogenous base thymine are replaced with uracil, and the sugar backbone
is composed of ribose
instead of deoxyribose.
The term "sample" is used in its broadest sense. A sample suspected of
containing
ECMCAD, nucleic acids encoding ECMCAD, or fragments thereof may comprise a
bodily fluid; an
extract from a cell, chromosome, organelle, or membrane isolated from a cell;
a cell; genomic DNA,
RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print;
etc.
The terms "specific binding" and "specifically binding" refer to that
interaction between a
protein or peptide and an agonist, an antibody, an antagonist, a small
molecule, or any natural or
synthetic binding composition. The interaction is dependent upon the presence
of a particular structure
of the protein, e.g., the antigenic determinant or epitope, recognized by the
binding molecule. For
example, if an antibody is specific for epitope "A," the presence of a
polypeptide comprising the
epitope A, or the presence of free unlabeled A, in a reaction containing free
labeled A and the
antibody will reduce the amount of labeled A that binds to the antibody.
The term "substantially purified" refers to nucleic acid or amino acid
sequences that are
removed from their natural environment and are isolated or separated, and are
at least 60% free,
preferably at least 75% free, and most preferably at least 90% free from other
components with
which they are naturally associated.
A "substitution" refers to the replacement of one or more amino acid residues
or nucleotides
by different amino acid residues or nucleotides, respectively.
"Substrate" refers to any suitable rigid or semi-rigid support including
membranes, filters,
chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing,
plates, polymers,
microparticles and capillaries. The substrate can have a variety of surface
forms, such as wells,
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trenches, pins, channels and pores, to which polynucleotides or polypeptides
are bound.
A "transcript image" refers to the collective pattern of gene expression by a
particular cell
type or tissue under given conditions at a given time.
"Transformation" describes a process by which exogenous DNA is introduced into
a recipient
cell. Transformation may occur under natural or artificial conditions
according to various methods
well known in the art, and may rely on any known method for the insertion of
foreign nucleic acid
sequences into a prokaryotic or eukaryotic host cell. The method for
transformation is selected based
on the type of host cell being transformed and may include, but is not limited
to, bacteriophage or viral
infection, electroporation, heat shock, lipofection, and particle bombardment.
The term "transformed
1o cells" includes stably transformed cells in which the inserted DNA is
capable of replication either as
an autonomously replicating plasmid or as part of the host chromosome, as well
as transiently,
transformed cells which express the inserted DNA or RNA for limited periods of
time.
A "txansgenic organism," as used herein, is any organism, including but not
limited to animals
and plants, in which one or more of the cells of the organism contains
heterologous nucleic acid
introduced by way of human intervention, such as by txansgenic techniques well
known in the art. The
nucleic acid is introduced into the cell, directly or indirectly by
introduction into a precursor of the cell,
by way of deliberate genetic manipulation, such as by microinjection or by
infection with a
recombinant virus. The term genetic manipulation does not include classical
cross-breeding, or in vitro
fertilization, but rather is directed to the introduction of a recombinant DNA
molecule. The transgenic
organisms contemplated in accordance with the present invention include
bacteria, cyanobacteria,
fungi, plants and animals. The isolated DNA of the present invention can be
introduced into the host
by methods known in the art, for example infection, transfection,
transformation or transconjugation.
Techniques for transferring the DNA of the present invention into such
organisms a~~e widely known
and provided in references such as Sambrook et al. (1989), supra.
A "variant" of a particular nucleic acid sequence is defined as a nucleic acid
sequence having
at least 40% sequence identity to the particular nucleic acid sequence over a
certain length of one of
the nucleic acid sequences using blastn with the "BLAST 2 Sequences" tool
Version 2Ø9 (May-07-
1999) set at default parameters. Such a pair of nucleic acids may show, for
example, at least 50%, at
least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91
%, at least 92%, at least
93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or
at least 99% or greater
sequence identity over a certain defined length. A variant may be described
as, for example, an
"allelic" (as defined above), "splice," "species," or "polymorphic" variant. A
splice variant may have
significant identity to a reference molecule, but will generally have a
greater or lesser number of
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polynucleotides due to alternative splicing of exons during mRNA processing.
The corresponding
polypeptide may possess additional functional domains or lack domains that are
present in the
reference molecule. Species variants are polynucleotide sequences that vary
from one species to
another. The resulting polypeptides will generally have significant amino acid
identity relative to each
other. A polymorphic variant is a variation in the polynucleotide sequence of
a particular gene
between individuals of a given species. Polymoiphic variants also may
encompass "single nucleotide
polymorphisms" (SNPs) in which the polynucleotide sequence varies by one
nucleotide base. The
presence of SNPs may be indicative of, for example, a certain population, a
disease state, or a
propensity for a disease state.
A "variant" of a particular polypeptide sequence is defined as a polypeptide
sequence having
at least 40% sequence identity to the particular polypeptide sequence over a
certain length of one of
the polypeptide sequences using blastp with the "BLAST 2 Sequences" tool
Version 2Ø9 (May-07-
1999) set at default parameters. Such a pair of polypeptides may show, for
example, at least 50%, at
least 60%, at Least 70%, at least 80%, at Ieast 90%, at least 91 %, at least
92%, at least 93%, at least
94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%
or greater sequence
identity over a certain defined length of one of the polypeptides.
THE INVENTION
The invention is based on the discovery of new human extxacellular matrix and
cell adhesion
molecules (ECMCAD), the polynucleotides encoding ECMCAD, and the use of these
compositions
for the diagnosis, treatment, or prevention of genetic, immune/inflammatory,
developmental, .
neurological, connective tissue, and cell proliferative disorders, including
cancer.
Table 1 summarizes the nomenclature for the full length polynucleotide and
polypeptide
sequences of the invention. Each polynucleotide and its corresponding
polypeptide are correlated to a
single Incyte project identification number (Incyte Project 1D). Each
polypeptide sequence is denoted
by both a polypeptide sequence identification number (Polypeptide SEQ 117 NO:)
and an Incyte
polypeptide sequence number (Incyte Polypeptide ID) as shown. Each
polynucleotide sequence is
denoted by both a polynucleotide sequence identification number
(Polynucleotide SEQ )D NO:) and an
Incyte polynucleotide consensus sequence number (Incyte Polynucleotide 1D) as
shown.
Table 2 shows sequences with homology to the polypeptides of the invention as
identified by
BLAST analysis against the GenBank protein (genpept) database. Columns 1 and 2
show the
polypeptide sequence identification number (Polypeptide SEQ ID NO:) and the
corresponding Incyte
polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the
invention. Column 3
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shows the GenBank identification number (Genbank ID NO:) of the nearest
GenBank homolo8.
Column 4 shows the probability score for the match between each polypeptide
and its GenBank
homolog. Column 5 shows the annotation of the GenBankhomolog along with
relevant citations
where applicable, all of which are expressly incorporated by reference herein.
Table 3 shows various structural features of the polypeptides of the
invention. Columns l and
2 show the polypeptide sequence identification number (SEQ m NO:) and the
corresponding Incyte
polypeptide sequence number (Incyte Polypeptide m) for each polypeptide of the
invention. Column
3 shows the number of amino acid residues in each polypeptide. Column 4 shows
potential
phosphorylation sites, and column 5 shows potential glycosylation sites, as
determined by the MOTIFS
to program of the GCG sequence analysis software package (Genetics Computer
Group, Madison WI).
Column 6 shows amino acid residues comprising signature sequences, domains,
and motifs. Column 7
shows analytical methods for protein structure/function analysis and in some
cases, searchable
databases to which the analytical methods were applied.
Together, Tables 2 and 3 summarize the properties of polypeptides of the
invention, and these
properties establish that the claimed polypeptides are extracellular matrix
and cell adhesion molecules.
For example, SEQ ID N0:2 is 48% identical over 46.% of its length to mouse
procollagen type I alpha
chain, (GenBank ID 8192264) as determined by the Basic Local Alignment Search
Tool (BLAST).
(See Table 2.) The BLAST probability score is 6.9e-46, which indicates the
probability of obtaining
the observed polypeptide sequence alignment by chance. SEQ ID N0:2 also
contains a collagen triple
helix repeat, as determined by searching for statistically significant matches
in the PFAM database.
(See Table 3.) HMMER and SPSCAN analyses indicate the presence of a signal
peptide at the N-
terminus of SEQ ID N0:2. Data from BLAST analysis of the PRODOM and DOMO
databases, as
well as MOTIFS analysis, provide further corroborative evidence that SEQ ID
N0:2 is a cellular
matrix protein associated with cell adhesion. In an alternative example, SEQ
ID N0:6 is 64%
identical to frog MAM domain protein (GenBank ID 81234793) as determined by
the Basic Local
Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is
4.2e-254, which
indicates the probability of obtaining the observed polypeptide sequence
alignment by chance. SEQ
ID N0:6 also contains four MAM domains as determined by searching for
statistically significant
matches in the hidden Markov model (HMM)-based PFAM database of conserved
protein family
3o domains. (See Table 3.) Data from MOTIFS analysis provide further
corroborative evidence that
SEQ ID N0:6 is a MAM domain cell adhesion protein. In an alternative example,
SEQ 1D N0:10 is
80% identical to marine semaphorin B (GenBank ID 8854326) as determined by the
Basic Local
Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is
6.0e-66, which
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indicates the probability of obtaining the observed polypeptide sequence
alignment by chance. SEQ
ID N0:10 also contains a sema domain as determined by searching for
statistically significant matches
in the hidden Markov model (I3MM)-based PFAM database of conserved protein
family domains.
(See Table 3.) The BLAST and HMMER analyses provide evidence that SEQ ID N0:10
is a
semaphorin. SEQ ID N0:12 is 44% identical to human cadherin superfamily
protein VR4-11
(GenBank )D 89622240) as determined by the Basic Local Alignment Search Tool
(BLAST). (See
Table 2.) The BLAST probability score is 9.9e-170, which indicates the
probability of obtaining the
observed polypeptide sequence alignment by chance. SEQ ID N0:12 also contains
a cadherin domain
as deternuned by searching for statistically significant matches in the hidden
Markov model (HIvIM)-
based PFAM database of conserved protein family domains. (See Table 3.) Data
from BLIMPS,
MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that
SEQ ID N0:12
is a cadherin. SEQ 1D N0:14 is 91 % identical to marine neuronal glycoprotein
(GenBank ID
8200057) as determined by the Basic Local Alignment Search Tool (BLAST). (See
Table 2.) The
BLAST probability score is 0.0, which indicates the probability of obtaining
the observed polypeptide
sequence alignment by chance. SEQ B? N0:14 also contains fibronectin type III
and immunoglobulin
domains as determined by searching for statistically significant matches in
the hidden Markov model .
(HMM)-based PFAM database of conserved protein family domains. (See Table 3.)
The BLAST
and HMMER analyses provide evidence that SEQ ID N0:14 is a cell adhesion
molecule. In an
alternative example, SEQ D7 N0:22 is 79% identical to mouse laminin 5 alpha
chain (GenBank ID
82599232) as determined by the Basic Local Alignment Search Tool (BLAST). (See
Table 2.) The .
BLAST probability score is 0.0, which indicates the probability of obtaining
the observed polypeptide
s sequence alignment by chance. SEQ ID N0:22 also contains a laminin N-
terminal domain, multiple
laminin EGF-like domains, a laminin B domain, and laminin G domains, as
determined by searching for
statistically significant matches in the hidden Markov model (HMM)-based PFAM
database of
conserved protein family domains. (See Table 3.) Data from BLIMPS, and MOTIFS
analyses
provide further corroborative evidence that SEQ ID N0:22 is a laminin. In an
alternative example,
SEQ ID N0:24 is 89% identical to Bos taurus brevican (GenBank ID 8452821) as
determined by the
Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 0.0,
which indicates the probability of obtaining the observed polypeptide sequence
alignment by chance.
SEQ 1D N0:24 also contains a lectin C-type domain, an extracellular link
domain, an EGF-like domain,
a sushi domain, and an immunoglobulin domain as determined by searching for
statistically significant
matches in the hidden Markov model (HMM)-based PFAM database of conserved
protein family
domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses
provide
32
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
further corroborative evidence that SEQ m N0:24 is a c-type lectin. In an
alternative example, SEQ
)D N0:31 is 87% identical to a mouse semaphorin homolog (GenBank ID 81110599)
as determined by
the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is
0.0, which indicates the probability of obtaining the observed polypeptide
sequence alignment by
chance. SEQ ID N0:31 also contains a Sema domain and a plexin repeat as
determined by searching
for statistically significant matches in the hidden Markov model (HMM)-based
PFAM database of
conserved protein fanuly domains. (See Table 3.) Data from BLAST analyses
against the DOMO
and PRODOM databases provide further corroborative evidence that SEQ ID N0:31
is a
semaphorin. In an alternative example, SEQ ID N0:35 is 61 % identical to
marine C-type lectin
l0 (GenBank 1D 84159801) as determined by the Basic Local Alignment Search
Tool (BLAST). (See
Table 2.) The BLAST probability score is 2.9e-75, which indicates the
probability of obtaining the
observed polypeptide sequence alignment by chance. SEQ~Il7 N0:35 also eontains
a lectin C-type
domain as determined by searching for statistically significant matches in the
hidden Markov model
(HMM)-based PFAM database of conserved protein family domains. (See Table 3.)
Data from
BLIMPS and PROFIL,ESCAN analyses provide further corroborative evidence that
SEQ ID NO:35
is a lectin. SEQ ID N0:1, SEQ >D N0:3-5, SEQ )D N0:7-9, SEQ )D NO:11, SEQ ID
N0:13, SEQ
ID NO:15-21, SEQ m NO:23, SEQ ID NO:25-30, SEQ ID N0:32-34 and SEQ 1D N0:36
were
analyzed and annotated in a similar manner. The algorithms and parameters for
the analysis of SEQ
ID NO:1-36 are described in Table 7.
As shown in Table 4, the full length polynucleotide sequences of the present
invention were
assembled using cDNA sequences or coding (exon) sequences derived from genomic
DNA, or any
combination of these two types of sequences. Columns 1 and 2 list the
polynucleotide sequence
identification number (Polynucleotide SEQ ID NO:) and the corxesponding Incyte
polynucleotide
consensus sequence number (Incyte Polynucleotide 1D) for each polynucleotide
of the invention.
Column 3 shows the length of each polynucleotide sequence in basepairs. Column
4 lists fragments of
the polynucleotide sequences which are useful, for example, in hybridization
or amplification
technologies that identify SEQ ID N0:37-72 or that distinguish between SEQ ID
NO:37-72 and
related polynucleotide sequences. Column. 5 shows identification numbers
corresponding to cDNA
sequences, coding sequences (exons) predicted from genomic DNA, and/or
sequence assemblages
3o comprised of both cDNA and genomic DNA. These sequences were used to
assemble the full length
polynucleotide sequences of the invention. Columns 6 and 7 of Table 4 show the
nucleotide start (5')
and stop (3') positions of the cDNA and/or genomic sequences in column 5
relative to their respective
full length sequences.
33
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The identification numbers in Column 5 of Table 4 may refer specifically, for
example, to
Incyte cDNAs along with their corresponding cDNA libraries. For example,
7347284H1 is the
identification number of an Incyte cDNA sequence, and LLTNLTLTE01 is the cDNA
library from
which it is derived. Incyte cDNAs for which cDNA libraries are not indicated
were derived from
pooled cDNA libraries (e.g., 71699406V1). Alternatively, the identification
numbers in column 5 may
refer to GenBank cDNAs or ESTs (e.g., g1242437) which contributed to the
assembly of the full
length polynucleotide sequences. Alternatively, the identification numbers in
column 5 may refer to
coding regions predicted by Genscan analysis of genomic DNA. For example,
GNN.g7923864_002 is
the identification number of a Genscan-predicted coding sequence, with
g7923864 being the GenBank
1o identification number of the sequence to which Genscan was applied. The
Genscan-predicted coding
sequences may have been edited prior to assembly. (See Example IV.)
Alternatively, the
identification numbers in column 5 may refer to assemblages of both cDNA and
Genscan-predicted
exons brought together by an "exon stitching" algorithm. (See Example V.)
Alternatively, the
identification numbers in column 5 may refer to assemblages of both cDNA and
Genscan-predicted
exons brought together by an "exon-stretching" algorithm. For example,
FL2428715_g6815043 000026_g8052237_1_3_4.edit is the identification number of
a "stretched"
sequence, with 2428715 being the Incyte project identification number,
g6815043 being the GenB ank
identification number of the human genomic sequence to which the "exon-
stretching" algorithm was .
applied, and g8052237 being the GenBank identification number of the nearest
GenBank protein
homolog. (See Example V.) In some cases, Incyte cDNA coverage redundant with
the sequence
coverage shown in column 5 was obtained to confirm the final consensus
polynucleotide sequence, but
the relevant Incyte cDNA identification numbers are not shown.
Table 5 shows the representative cDNA libraries for those full length
polynucleotide
sequences which were assembled using Incyte cDNA sequences. The representative
cDNA library
is the Incyte cDNA library which is most frequently represented by the Incyte
cDNA sequences
which were used to assemble and confirm the above polynucleotide sequences.
The tissues and
vectors which were used to construct the cDNA libraries shown in Table 5 are
described in Table 6.
The invention also encompasses ECMCAD variants. A preferred ECMCAD variant is
one
which has at least about 80%, or alternatively at least about 90%, or even at
least about 95% amino
acid sequence identity to the ECMCAD amino acid sequence, and which contains
at least one
functional or structural characteristic of ECMCAD.
The invention also encompasses polynucleotides which encode ECMCAD. In a
particular
embodiment, the invention encompasses a polynucleotide sequence comprising a
sequence selected
34
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
from the group consisting of SEQ ID N0:37-72, which encodes ECMCAD. The
polynucleotide
sequences of SEQ ID N0:37-72, as presented in the Sequence Listing, embrace
the equivalent RNA
sequences, wherein occurrences of the nitrogenous base thymine are replaced
with uracil, and the
sugar backbone is composed of ribose instead of deoxyribose.
The. invention also encompasses a variant of a polynucleotide sequence
encoding ECMCAD.
In particular, such a variant polynucleotide sequence will have at least about
70%, or alternatively at
least about 85%, ox even at least about 95% polynucleotide sequence identity
to the polynucleotide
sequence encoding ECMCAD. A particular aspect of the invention encompasses a
variant of a
polynucleotide sequence comprising a sequence selected from the group
consisting of SEQ )D N0:37-
72 which has at least about 70%, or alternatively at least about 85%, or even
at least about 95%
polynucleotide sequence identity to a nucleic acid sequence selected from the
group consisting of SEQ
ID N0:37-72. Any one of the polynucleotide variants described above can encode
an amino acid
sequence which contains at least one functional or structural characteristic
of ECMCAD.
It will be appreciated by those skilled in the art that as a result of the
degeneracy of the
genetic code, a multitude of polynucleotide sequences encoding ECMCAD, some
bearing minimal
similarity to the polynucleotide sequences of any known and naturally
occurring gene, may be
produced. Thus, the invention contemplates each and every possible variation
of polynucleotide
sequence that could be made by selecting combinations based on possible codon
choices. These
combinations are made in accordance with the standard triplet genetic code as
applied to the
polynucleotide sequence of naturally occurring ECMCAD, and all such variations
are to be considered
as being specifically disclosed.
Although nucleotide sequences which encode ECMCAD and its variants are
generally
capable of hybridizing to the nucleotide sequence of the naturally occurring
ECMCAD under
appropriately selected conditions of stringency, it may be advantageous to
produce nucleotide
sequences encoding ECMCAD or its derivatives possessing a substantially
different codon usage, e.g.,
inclusion of non-naturally occurring codons. Codons may be selected to
increase the rate at which
expression of the peptide occurs in a particular prokaryotic or eukaryotic
host in accordance with the
frequency with which particular codons are utilized by the host. Other reasons
for substantially
altering the nucleotide sequence encoding ECMCAD and its derivatives without
altering the encoded
amino acid sequences include the production of RNA transcripts having more
desirable properties,
such as a greater half life, than transcripts produced from the naturally
occurring sequence.
The invention also encompasses production of DNA sequences which encode ECMCAD
and
ECMCAD derivatives, or fragments thereof, entirely by synthetic chemistry.
After production, the
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
synthetic sequence may be inserted into any of the many available expression
vectors and cell systems
using reagents well known in the art. Moreover, synthetic chemistry may be
used to introduce
mutations into a sequence encoding ECMCAD or any fragment thereof.
Also encompassed by the invention are polynucleotide sequences that are
capable of
hybridizing to the claimed polynucleotide sequences, and, in particular, to
those shown in SEQ ID
N0:37-72 and fragments thereof under various conditions of stringency. (See,
e.g., Wahl, G.M. and
S.L. Berger (1987) Methods Enzymol. 152:399-407; I~immel, A.R. (1987) Methods
Enzymol. 152:507-
511.) Hybridization conditions, including annealing and wash conditions, are
described in "Definitions."
Methods for DNA sequencing are well known in the art and may be used to
practice any of
the embodiments of the invention. The methods may employ.such enzymes as the
Klenow fragment
of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase
(Applied
Biosystems), thermostable T7 polymerase (Amersham Pharmacia Biotech,
Piscataway NJ), or
combinations of polymerases and proofreading exonucleases such as those found
in the ELONGASE
amplification system (Life Technologies, Gaithersburg MD). Preferably,
sequence preparation is
automated with machines such as the MICROLAB 2200 liquid transfer system
(Hamilton, Reno NV),
PTC200 thermal cycler (MJ Research, Watertown MA) and ABI CATALYST 800 thermal
cycler
(Applied Biosystems). Sequencing is then carried out using either the ABI 373
or 377 DNA
sequencing system (Applied Biosystems), the MEGABACE 1000 DNA sequencing
system
(Molecular Dynamics, Sunnyvale CA), or other systems known in the art. The
resulting sequences
are analyzed using a variety of algorithms which are well known in the art.
(See, e.g., Ausubel, F.M.
(1997) Short Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY,
unit 7.7; Meyers,
R.A. (1995) Molecular Biolo~v and Biotechnology, Wiley VCH, New York NY, pp.
856-853.)
The nucleic acid sequences encoding ECMCAD may be extended utilizing a partial
nucleotide
sequence and employing various PCR-based methods known in the art to detect
upstream sequences,
such as promoters and regulatory elements. For example, one method which may
be employed,
restriction-site PCR, uses universal and nested primers to amplify unknown
sequence from genomic
DNA within a cloning vector. (See, e.g., Sarkar, G. (1993) PCR Methods Applic.
2:318-322.)
Another method, inverse PCR, uses ,primers that extend in divergent directions
to amplify unknown
sequence from a circularized template. The template is derived from
restriction fragments comprising
a known genomic locus and surrounding sequences. (See, e.g., Triglia, T. et
al. (1988) Nucleic Acids
Res. 16:8186.) A third method, capture PCR, involves PCR amplification of DNA
fragments adjacent
to known sequences in human and yeast artificial chromosome DNA. (See, e.g.,
Lagerstrom, M. et
al, (1991) PCR Methods Applic. 1:111-119.) In this method, multiple
restriction enzyme digestions and
36
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ligations may be used to insert an engineered double-stranded sequence into a
region of unlmown
sequence before performing PCR. Other methods which may be used to retrieve
unknown sequences
are known in the art. (See, e.g., Parker, J.D. et al. (1991) Nucleic Acids
Res. 19:3055-3060).
Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries
(Clontech, Palo
Alto CA) to walk genomic DNA. This procedure avoids the need to screen
libraries and is useful in
finding intron/exon junctions. For all PCR-based methods, primers may be
designed using
commercially available software, such as OLIGO 4.06 primer analysis software
(National
Biosciences, Plymouth MN) or another appropriate program, to be about 22 to 30
nucleotides in length,
to have a GC content of about 50% or more, and to anneal to the template at
temperatures of about
i0 68°C to 72°C.
When screening for full length cDNAs, it is preferable to use libraries that
have been
size-selected to include larger cDNAs. In addition, random-primed libraries,
which often include
sequences containing the 5' regions of genes, are preferable for situations in
which an oligo d(T)
library does not yield a full-length cDNA. Genomic libraries may be useful for
extension of sequence
into S' non-transcribed regulatory regions.
Capillary electrophoresis systems which are commercially available may be used
to analyze
the size or confirm the nucleotide sequence of sequencing or PCR products. In
particular, capillary
sequencing may employ flowable polymers for electrophoretic separation, four
different nucleotide-
specific, laser-stimulated fluorescent dyes, and a charge coupled device
camera for detection of the
emitted wavelengths. Outputllight intensity may be converted to electrical
signal using appropriate
software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), and the
entire
process from loading of samples to computer analysis and electronic data
display may be computer
controlled. Capillary electrophoresis is especially preferable for sequencing
small DNA fragments
which may be present in limited amounts in a particular sample.
In another embodiment of the invention, polynucleotide sequences or fragments
thereof which
encode ECMCAD may be cloned in recombinant DNA molecules that direct
expxession of
ECMCAD, or fragments or functional equivalents thereof, in appropriate host
cells. Due to the
inherent degeneracy of the genetic code, other DNA sequences which encode
substantially the same
or a functionally equivalent amino acid sequence may be produced and used to
express ECMCAD.
The nucleotide sequences of the present invention can be engineered using
methods generally
known in the art in order to alter ECMCAD-encoding sequences for a variety of
purposes including,
but not limited to, modification of the cloning, processing, and/or expression
of the gene product. DNA
shuffling by random fragmentation and PCR reassembly of gene fragments and
synthetic
37
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
oligonucleotides may be used to engineer the nucleotide sequences. For
example, oIigonucleotide-
mediated site-directed mutagenesis may be used to introduce mutations that
create new restriction
sites, alter glycosylation patterns, change codon preference, produce splice
variants, and so forth.
The nucleotides of the present invention may be subjected to DNA shuffling
techniques such
as MOLECULARBREEDING (Maxygen Inc., Santa Clara CA; described in U.S. Patent
Number
5,837,458; Chang, C.-C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians,
F.C. et al. (1999) Nat.
Biotechnol. 17:259-264; arid Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-
319) to alter or improve
the biological properties of ECMCAD, such as its biological or enzymatic
activity or its ability to bind
to other molecules or compounds. DNA shuffling is a process by which a library
of gene variants is
l0 produced using PCR-mediated recombination of gene fragments. The library is
then subjected to
selection or screening procedures that identify those gene variants with the
desired properties. These
preferred variants may then be pooled and further subjected to recursive
rounds of DNA shuffling and
selection/screening. Thus, genetic diversity is created through "artificial"
breeding and rapid molecular
evolution. For example, fragments of a single gene containing random point
mutations may be
recombined, screened, and then reshuffled until the desired properties are
optimized. Alternatively,
fragments of a given gene may be recombined with fragments of homologous genes
in the same gene
family, either from the same or different species, thereby maximizing the
genetic diversity of multiple
naturally occuW ng genes in a directed and controllable manner.
In another embodiment, sequences encoding ECMCAD may be synthesized, in whole
or in
part, using chemical methods well known in the art. (See, e.g., Caruthers,
M.H. et al. (1980) Nucleic
Acids Symp. Ser. 7:215-223; and Horn, T. et al. (1980) Nucleic Acids Symp.
Ser. 7:225-232.)
Alternatively, ECMCAD itself or a fragment thereof may be synthesized using
chemical methods.
For example, peptide synthesis can be performed using various solution-phase
or solid-phase
techniques. (See, e.g., Creighton, T. (1984) Proteins, Structures and
Molecular Properties, WH,
Freeman, New York NY, pp. 55-60; and Roberge, J.Y. et al. (1995) Science
269:202-204.)
Automated synthesis may be achieved using the ABI 431A peptide synthesizer
(Applied Biosystems).
Additionally, the amino acid sequence of ECMCAD, or any part thereof, may be
altered during direct
synthesis and/or combined with sequences from other proteins, or any part
thereof, to produce a
variant polypeptide or a polypeptide having a sequence of a naturally
occurring polypeptide.
The peptide may be substantially purified by preparative high performance
liquid
chromatography. (See, e.g., Chiez, R.M. and F.Z. Regnier (1990) Methods
Enzymol. 182:392-421.)
The composition of the synthetic peptides may be confirmed by amino acid
analysis or by sequencing.
(See, e.g., Creighton, supra, pp, 28-53.)
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CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
In order to express a biologically active ECMCAD, the nucleotide sequences
encoding
ECMCAD or derivatives thereof may be inserted into an appropriate expression
vector, i.e., a vector
which contains the necessary elements for transcriptional and translational
control of the inserted
coding sequence in a suitable host. These elements include regulatory
sequences, such as enhancers,
constitutive and inducible promoters, and 5' and 3' untranslated regions in
the vector and in
polynucleotide sequences encoding ECMCAD. Such elements may vary in their
strength and
specificity. Specific initiation signals may also be used to achieve more
efficient translation of
sequences encoding ECMCAD. Such signals include the ATG initiation codon and
adjacent
sequences, e.g. the Kozak sequence. In cases where sequences encoding ECMCAD
and its initiation
l0 codon and upstream regulatory sequences are inserted into the appropriate
expression vector, no
additional transcriptional or translational control signals may be needed.
However, in cases where
only coding sequence, or a fragment thereof, is inserted, exogenous
translational control signals
including an in-frame ATG initiation codon should be provided by the vector.
Exogenous translational
elements and initiation codons may be of various origins, both natural and
synthetic. The efficiency of
expression may be enhanced by the inclusion of enhancers appropriate for the
particular host cell
system used. (See, e.g., Scharf, D. et al. (1994} Results Probl. Cell Differ.
20:125-162.)
Methods which are well known to those skilled in the art may be used to
construct expression
vectors containing sequences encoding ECMCAD and appropriate transcriptional
and translational
control elements. These methods include in vitro recombinant DNA techniques,
synthetic techniques,
and in vivo genetic recombination. (See, e.g., Sambrook, J. et al. (1989)
Molecular Cloning, A
Laborator~i Manual, Cold Spring Harbor Press, Plainview NY, ch. 4, 8, and 16-
17; Ausubel, F.M. et
al. (1995) Current Protocols in Molecular Biolo~y, John Wiley & Sons, New York
NY, ch. 9, 13, and
16.)
A variety of expression vector/host systems may be utilized to contain and
express sequences
encoding ECMCAD, These include, but are not limited to, microorganisms such as
bacteria
transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression
vectors; yeast
transformed with yeast expression vectors; insect cell systems infected with
viral expression vectors
(e.g., baculovirus); plant cell systems transformed with viral expression
vectors (e.g., cauliflower
mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression
vectors (e.g., Ti or
pBR322 plasmids); or animal cell systems. (See, e.g., 'Sambrook, supra;
Ausubel, supra; Van Heeke,
G. and S.M. Schuster (1989) J. Biol. Chem. 264:5503-5509; Engelhard, E.K. et
aI. (1994) Proc. Natl.
Acad. Sci. LTSA 91:3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7:1937-
1945; Takamatsu, N.
(1987) EMBO J. 6:307-311; The McGraw Hill Yearbook of Science and Technolo~y
(1992) McGraw
39
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Hill, New York NY, pp. 191-196; Logan, J. and T. Shenk (1984) Proc. Natl.
Acad. Sci. USA
81:3655-3659; and Harrington, J.J. et al. (1997) Nat. Genet. 15:345-355.)
Expression vectors derived
from retroviruses, adenoviruses, or herpes or vaccinia viruses, or from
various bacterial plasmids, may
be used fox delivery of nucleotide sequences to the targeted organ, tissue, or
cell population. (See,
e.g., Di Nicola, M. et al. (1998) Cancer Gen. Ther. 5(6):350-356; Yu, M. et
al. (1993) Proc. Natl.
Acad. Sci. USA 90(13):6340-6344; Buller, R.M. et aI. (1985) Nature
317(6040):813-815; McGregor,
D.P. et al. (1994) Mol. Immunol. 31(3):219-226; and Verma, LM. and N. Somia
(1997) Nature
389:239-242.) The invention is not limited by the host cell employed.
In bacterial systems, a number of cloning and expression vectors may be
selected depending
i0 upon the use intended for polynucleotide sequences encoding ECMCAD. For
example, routine
cloning, subcloning, and propagation of polynucleotide sequences encoding
ECMCAD can be achieved
using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La
Jolla CA) or
PSPORTl plasmid (Life Technologies). Ligation of sequences encoding ECMCAD
into the vector's
multiple cloning site disrupts the lacZ gene, allowing a colorimetric
screening procedure for
identification of transformed bacteria containing recombinant molecules. In
addition, these vectors
may be useful for in vitro transcription, dideoxy sequencing, single strand
rescue with helper phage,
and creation of nested deletions in the cloned sequence. (See, e.g., Van
Heeke, G. and S.M. Schuster
(1989) J. Biol. Chem. 264:5503-5509.) When large quantities of ECMCAD are
needed, e.g. for the
production of antibodies, vectors which direct high level expression of ECMCAD
may be used. For
example, vectors containing the strong, inducible SP6 or T7 bacteriophage
promoter may be used.
Yeast expression systems may be used for production of ECMCAD. A number of
vectors
containing constitutive or inducible promoters, such as alpha factor, alcohol
oxidase, and PGH
promoters, may be used in the yeast Saccharomvces cerevisiae or Pichia
pastoris. In addition, such
vectors direct either the secretion ox intracellular retention of expressed
proteins and enable integration
of foreign sequences into the host genome for stable propagation. (See, e.g.,
Ausubel, 1995, supra;
Bitter, G.A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C.A. et
al. (1994)
BiolTechnology 12:181-184.)
Plant systems may also be used for expression of ECMCAD. Transcription of
sequences
encoding ECMCAD may be driven by viral promoters, e.g., the 35S and 19S
promoters of CaMV
used alone or in combination with the omega leader sequence from TMV
(Takamatsu, N. (1987)
EMBO J. 6:307-311). Alternatively, plant promoters such as the small subunit
of RUBISCO or heat
shock promoters may be used. (See, e.g., Coruzzi, G. et al. (1984) EMBO J.
3:1671-1680; Brogue, R.
et al. (1984) Science 224:838-843; and Winter, J. et al. (1991) Results Probl.
Cell Differ. 17:85-105.)
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
These constructs can be introduced into plant cells by direct DNA
transformation or
pathogen-mediated transfection. (See, e.g., The McGraw Hill Yearbook of
Science and Technolo~y
(1992) McGraw Hill, New York NY, pp. 191-196.)
In mammalian cells, a number of viral-based expression systems may be
utilized. In cases
where an adenovirus is used as an expression vector, sequences encoding ECMCAD
may be ligated
into an adenovirus transcription/translation complex consisting of the late
promoter and tripartite leader
sequence. Insertion in a non-essential El or E3 region of the viral genome may
be used to obtain
infective virus which expresses ECMCAD in host cells. (See, e.g., Logan, J.
and T. Shenk (1984)
Proc. Natl. Acad. Sci. USA 81:3655-3659.) In addition, transcription
enhancers, such as the Rous
l0 sarcoma virus (RSV) enhancer, may be used to increase expression in
mammalian host cells. SV40
or EBV-based vectors may also be used for high-level protein expression.
Human artificial chromosomes (HACs) may also be employed to deliver larger
fragments of
DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb
to 10 Mb are
constructed and delivered via conventional delivery methods (liposomes,
polycationic amino polymers,
or vesicles) for therapeutic purposes. (See, e.g., Harrington, J.J. et al.
(1997) Nat. Genet. 15:345-
355.)
For long term production of recombinant proteins in mammalian systems, stable
expression of
ECMCAD in cell lines is preferred. For example, sequences encoding ECMCAD can
be transformed
into cell lines using expression vectors which may contain viral origins of
replication and/or
2o endogenous expression elements and a selectable marker gene on the same or
on a separate vector.
Following the introduction of the vector, cells may be allowed to grow for
about 1 to 2 days in enriched
media before being switched to selective media. The purpose of the selectable
marker is to confer
resistance to a selective agent, and its presence allows growth and recovery
of cells which
successfully express the introduced sequences. Resistant clones of stably
transformed cells may be
propagated using tissue culture techniques appropriate to the cell type.
Any number of selection systems may be used to recover transformed cell lines.
These
include, but are not limited to, the herpes simplex virus thymidine kinase and
adenine
phosphoribosyltransferase genes, for use in tl~ and apr cells, respectively.
(See, e.g., Wigler, M. et
al. (1977) Cell 11:223-232; Lowy, I. et al. (1980) Cell 22:817-823.) Also,
antimetabolite, antibiotic, or
herbicide resistance can be used as the basis for selection. For example, dhfr
confers resistance to
methotrexate; neo confers resistance to the aminoglycosides neomycin and G-
418; and als and pat
confer resistance to chlorsulfuron and phosphinotricin acetyltransferase,
respectively. (See, e.g.,
Wigler, M. et al. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-
Garapin, F. et al. (1981)
41
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WO 02/02634 PCT/USO1/21067
J. Mol. Biol. 150:1-14.) Additional selectable genes have been described,
e.g., trpB and hisD, which
alter cellular requirements for metabolites. (See, e.g., Hartman, S.C. and
R.C. Mulligan (1988) Proc.
Nail. Acad. Sci. USA 85:8047-8051.) Visible markers, e.g., anthocyanins, green
fluorescent proteins
(GFP; Clontech),13 glucuronidase and its substrate J3-glucuronide, or
luciferase and its substrate
luciferin may be used. These markers can be used not only to identify
transformants, but also to
quantify the amount of transient or stable protein expression attributable to
a specific vector system.
(See, e.g., Rhodes, C.A. (1995) Methods Mol. Biol. 55:121-131.)
Although the presence/absence of marker gene expression suggests that the gene
of interest
is also present, the presence and expression of the gene may need to be
confirmed. For example, if
the sequence encoding ECMCAD is inserted within a marker gene sequence,
transformed cells
containing sequences encoding ECMCAD can be identified by the absence of
marker gene function.
Alternatively, a marker gene can be placed in tandem with a sequence encoding
ECMCAD under the
control of a single promoter. Expression of the marker gene in response to
induction or selection
usually indicates expression of the tandem gene as well.
In general, host cells that contain the nucleic acid sequence encoding ECMCAD
and that
express ECMCAD may be identified by a variety of procedures known to those of
skill in the art.
These procedures include, but are not limited to, DNA-DNA or DNA-RNA
hybridizations, PCR
amplification, and protein bioassay or immunoassay techniques which include
membrane, solution, or
chip based technologies for the detection andlor quantification of nucleic
acid or protein sequences.
2o T_m_m__unological methods for detecting and measuring the expression of
ECMCAD using either
specific polyclonal or monoclonal antibodies are known in the art. Examples of
such techniques
include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs),
and
fluorescence activated cell sorting (FACS). A two-site, monoclonal-based
immunoassay utilizing
monoclonal antibodies reactive to two non-interfering epitopes on ECMCAD is
preferred, but a
competitive binding assay may be employed. These and other assays are well
known in the art. (See,
e.g., Hampton, R. et al. (1990) Serological Methods, a Laboratory Manual, APS
Press, St. Paul MN,
Sect. IV; Coligan, J.E. et al. (1997) Current Protocols in Immunolo~v, Greene
Pub. Associates and
Wiley-Interscience, New York NY; and Pound, J.D. (1998) Immunochemical
Protocols, Humana
Press, Totowa NJ.)
A wide variety of labels and conjugation techniques are known by those skilled
in the art and
may be used in various nucleic acid and amino acid assays. Means for producing
labeled hybridization
or PCR probes for detecting sequences related to polynucleotides encoding
ECMCAD include
oligolabeling, nick translation, end-labeling, or PCR amplification using a
labeled nucleotide.
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WO 02/02634 PCT/USO1/21067
Alternatively, the sequences encoding ECMCAD, or any fragments thereof, may be
cloned into a
vector for the production of an mRNA probe. Such vectors are known in the art,
are commercially
available, and may be used to synthesize RNA probes in vitro by addition of an
appropriate RNA
polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures
may be conducted
using a variety of commercially available kits, such as those provided by
Amersham Pharmacia
Biotech, Promega (Madison WI), and LTS Biochemical. Suitable reporter
molecules or labels which
may be used for ease of detection include radionuclides, enzymes, fluorescent,
chemiluminescent, or
chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic
particles, and the like.
Host cells transformed with nucleotide sequences encoding ECMCAD may be
cultured under
conditions suitable for the expression and recovery of the protein from cell
culture. The protein
produced by a transformed cell may be secreted or retained intracellularly
depending on the sequence
and/or the vector used. As will be understood by those of skill in the art,
expression vectors containing
polynucleotides which encode ECMCAD may be designed to contain signal
sequences which direct
secretion of ECMCAD through a prokaryotic or eukaryotic cell membrane.
In addition, a host cell strain may be chosen for its ability to modulate
expression of the
inserted sequences or to process the expressed protein in the desired fashion.
Such modifications of
the polypeptide include, but are not limited to, acetylation, carboxylation,
glycosylation, phosphorylation,
lipidation, and acylation. Post-translational processing which cleaves a
"prepro" or "pro" form of the
protein may also be used to specify protein targeting, folding, and/or
activity. Different host cells
which have specific cellular machinery and characteristic mechanisms for post-
translational activities
(e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type
Culture
Collection (ATCC, Manassas VA) and may be chosen to ensure the correct
modification and
processing of the foreign protein.
In another embodiment of the invention, natural, modified, or recombinant
nucleic acid
sequences encoding ECMCAD may be ligated to a heterologous sequence resulting
in translation of a
fusion protein in any of the aforementioned host systems. For example, a
chimeric ECMCAD protein
containing a heterologous moiety that can be recognized by a commercially
available antibody may
facilitate the screening of peptide libraries for inhibitors of ECMCAD
activity. Heterologous protein
and peptide moieties may also facilitate purification of fusion proteins using
commercially available
affinity matrices. Such moieties include, but are not limited to, glutathione
S-transferase (GST),
maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide
(CBP), 6-His, FLAG, c-
nzyc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable
purification of their cognate
fusion proteins on immobilized glutathione, maltose, phenylarsine oxide,
calmodulin, and metal-chelate
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WO 02/02634 PCT/USO1/21067
resins, respectively. FLAG, c-nayc, and hemagglutinin (HA) enable
immunoaffinity purification of
fusion proteins using commercially available monoclonal and polyclonal
antibodies that speciEcally
recognize these epitope tags. A fusion protein may also be engineered to
contain a proteolytic
cleavage site located between the ECMCAD encoding sequence and the
heterologous protein
sequence, so that ECMCAD may be cleaved away from the heterologous moiety
following
purification. Methods for fusion protein expression and purification are
discussed in Ausubel (1995,
supra, ch. 10). A variety of commercially available kits may also be used to
facilitate expression and
purification of fusion proteins.
In a further embodiment of the invention, synthesis of radiolabeled ECMCAD may
be
l0 achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ
extract system (Promega).
These systems couple transcription and translation of protein-coding sequences
operably associated
with the T7, T3, or SP6 promoters. Translation takes place in the presence of
a radiolabeled amino
acid precursor, for example, 35S-methionine.
ECMCAD of the present invention or fragments thereof may be used to screen for
compounds that specifically bind to ECMCAD. At least one and up to a plurality
of test compounds
may be screened for specific binding to ECMCAD. Examples of test compounds
include antibodies,
oligonucleotides, proteins (e.g., receptors), or small molecules.
In one embodiment, the compound thus identified is closely related to the
natural ligand of
ECMCAD, e.g., a ligand or fragment thereof, a natural substrate, a structural
or functional mimetic, or
a natural binding partner. (See, e.g., Coligan, J.E. et al. (1991) Current
Protocols in Immunolo~y 1 (2):
Chapter 5.) Similarly, the compound can be closely related to the natural
receptor to which
ECMCAD binds, or to at least a fragment of the receptor, e.g., the ligand
binding site. In either case,
the compound can be rationally designed using known techniques. In one
embodiment, screening for
these compounds involves producing appropriate cells which express ECMCAD,
either as a secreted
protein or on the cell membrane. Preferred cells include cells from mammals,
yeast, Drosophila, or E.
coli. Cells expressing ECMCAD or cell membrane fractions which contain ECMCAD
are then
contacted with a test compound and binding, stimulation, or inhibition of
activity of either ECMCAD or
the compound is analyzed.
An assay may simply test binding of a test compound to the polypeptide,
wherein binding is
detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable
label. For example, the
assay may comprise the steps of combining at least one test compound with
ECMCAD, either in
solution or affixed to a solid support, and detecting the binding of ECMCAD to
the compound.
Alternatively, the assay may detect or measure binding of a test compound in
the presence of a
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WO 02/02634 PCT/USO1/21067
labeled competitor. Additionally, the assay may be carried out using cell-free
preparations, chemical
libraries, or natural product mixtures, and the test compounds) may be free in
solution or affixed to a
solid support.
ECMCAD of the present invention or fragments thereof may be used to screen for
compounds that modulate the activity of ECMCAD. Such compounds may include
agonists,
antagonists, or partial or inverse agonists. In one embodiment, an assay is
performed under conditions
permissive for ECMCAD activity, wherein ECMCAD is combined with at least one
test compound,
and the activity of ECMCAD in the presence of a test compound is compared with
the activity of
ECMCAD in the absence of the test compound. A change in the activity of ECMCAD
in the
presence of the test compound is indicative of a compound that modulates the
activity of ECMCAD.
Alternatively, a test compound is combined with an in vitro or cell-free
system comprising ECMCAD
under conditions suitable for ECMCAD activity, and the assay is performed. In
either of these
assays, a test compound which modulates the activity of ECMCAD may do so
indirectly and need not
come in direct contact with the test compound. At least one and up to a
plurality of test compounds
may be screened.
In another embodiment, polynucleotides,encoding ECMCAD or their mammalian
homologs
may be "knocked out" in an animal model system using homologous recombination
in embryonic stem
(ES) cells. Such techniques are well known in the art and are useful for the
generation of animal
models of human disease. (See, e.g., U.S. Patent Number 5,175,383 and U.S.
Patent Number
5,767,337.) For example, mouse ES cells, such as the mouse 1291SvJ cell line,
are derived from the
early mouse embryo and grown in culture. The ES cells are transformed with a
vector containing the
gene of interest disrupted by a marker gene, e.g., the neomycin
phosphotransferase gene (neo;
Capecchi, M.R. (1989) Science 244:1288-1292). The vector integrates into the
corresponding region
of the host genome by homologous recombination. Alternatively, homologous
recombination takes
place using the Cre-loxP system to knockout a gene of interest in a tissue- or
developmental stage-
specific manner (March, J.D. (1996) Clin. Invest. 97:1999-2002; Wagner, K.U.
et al. (1997) Nucleic
Acids Res. 25:4323-4330). Transformed ES cells are identified and
microinjected into mouse cell
blastocysts such as those from the C57BL16 mouse strain. The blastocysts are
surgically transferred
to pseudopregna,nt dams, and the resulting chimeric progeny are genotyped and
bred to produce
heterozygous or homozygous strains. Transgenic animals thus generated may be
tested with potential
therapeutic or toxic agents. ,
Polynucleotides encoding ECMCAD may also be manipulated in vitro in ES cells
derived from
human blastocysts. Human ES cells have the potential to differentiate into at
least eight separate cell
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
lineages including endoderm, mesoderm, and ectodermal cell types. These cell
lineages differentiate
into, for example, neural cells, hematopoietic fineages, and cardiomyocytes
(Thomson, J.A. et al.
(1998) Science 282:1145-1147).
Polynucleotides encoding ECMCAD can also be used to create "knockin" humanized
animals
(pigs) or transgenic animals (mice or rats) to model human disease. With
knockin technology, a region
of a polynucleotide encoding ECMCAD is injected into animal ES cells, and the
injected sequence
integrates into the animal cell genome. Transformed cells are injected into
blastulae, and the blastulae
are implanted as described above. Transgenic progeny or inbred lines are
studied and treated with
potential pharmaceutical agents to obtain information on treatment of a human
disease. Alternatively,
a mammal inbred to overexpress ECMCAD, e.g., by secreting ECMCAD in its milk,
may also serve
as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol.
Annu. Rev. 4:55-74).
THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and
motifs, exists between
regions of ECMCAD and extracellular matrix and cell adhesion molecules. ~ In
addition, the expression
of ECMCAD is closely associated with brain, prostate, atrial myxoma,
cerebellum, cervical dorsal root
ganglion, cardiac muscle, mesentery fat, kidney epithelium, thymus,
endothelium, ovary, placenta,
smooth muscle, fallopian tube, breast, cartilage, bladder, rib, colon, spine,
gall bladder, blood
granulocytes, submandibular gland, seminal vesicle, and intestine tissues;
with tumors of the brain,
prostate, rib, and fallopian tube; and with dermal nlicrovascular endothelial
cells, hNT2 cells derived
from a human teratocarcinoma, and 293-EBNA transformed embryonal cells derived
from kidney
epithelial tissue. Therefore, ECMCAD appears to play a role in genetic,
immune/inflammatory,
developmental, neurological, connective tissue, and cell proliferative
disorders, including cancer. In the
treatment of disorders associated with increased ECMCAD expression or
activity, it is desirable to
decrease the expression or activity of ECMCAD. In the treatment of disorders
associated with
decreased ECMCAD expression or activity, it is desirable to increase the
expression or activity of
ECMCAD.
Therefore, in one embodiment, ECMCAD or a fragment or derivative thereof may
be
administered to a subject to treat or prevent a disorder associated with
decreased expression or
activity of ECMCAD. Examples of such disorders include, but are not limited
to, a genetic disorder
such as adrenoleukodystrophy, Alport's syndrome, choroideremia, Duchenne and
Becker muscular
dystrophy, Down's syndrome, cystic fibrosis, chronic granulomatous disease,
Gaucher's disease,
Huntington's chorea, Marfan's syndrome, muscular dystrophy, myotonic
dystrophy, pycnodysostosis,
Refsum's syndrome, retinoblastoma, sickle cell anemia, thalassemia, Werner
syndrome, von
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Willebrand's disease, Wilms' tumor, Zellweger syndrome, peroxisomal acyl-CoA
oxidase deficiency,
peroxisomal thiolase deficiency, peroxisomal bifunctional protein deficiency,
mitochondrial carnitine
palmitoyl transferase and carnitine deficiency, mitochondrial very-long-chain
acyl-CoA dehydrogenase
deficiency, rnitochondrial medium-chain acyl-CoA dehydrogenase deficiency,
mitochondrial short-
s chain acyl-CoA dehydrogenase deficiency, mitochondrial electron transport
flavoprotein and electron
transport fiavoprotein:ubiquinone oxidoreductase deficiency, mitochondrial
trifunctional protein
deficiency, and mitochondrial short-chain 3-hydroxyacyl-CoA dehydrogenase
deficiency; an
immune/inflammatory disorder such as acquired immunodeficiency syndrome
(AIDS), X-linked
agammaglobinemia of Breton, common variable immunodeficiency (CVI], DiGeorge's
syndrome
l0 (thymic hypoplasia), thymic dysplasia, isolated IgA deficiency, severe
combined immunodeficiency
disease (SC1D), immunodeficiency with thrombocytopenia and eczema (Wiskott-
Aldrich syndrome),
Chediak-Higashi syndrome, chronic granulomatous diseases, hereditary
angioneurotic edema,
immunodeficiency associated with Cushing's disease, Addison's disease, adult
respiratory distress
syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma,
atherosclerosis, autoimmune
15 hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-
candidiasis-ectodeimal
dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's
disease, atopic dermatitis,
dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with
lymphocytotoxins,
eiythroblastosis fetalis, erythema nodosum, atrophic gastritis,
glomerulonephritis, Goodpasture's
syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia,
irritable bowel syndrome,
2o multiple sclerosis, myasthenia gravis, myocardial or pericardial
inflammation, osteoarthritis,
osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome,
rheumatoid arthritis, scleroderma,
Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus,
systemic sclerosis,
thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome,
complications of cancer,
hemodialysis, and extracorporeal circulation, viral, bacterial, fungal,
parasitic, protozoal, and helminthic
25 infections, and trauma; a developmental disorder such as renal tubular
acidosis, anemia, C~shing's
syndrome, achondroplastic dwarfism, Duchenne and Becker muscular dystrophy,
epilepsy, gonadal
dysgenesis, WAGR syndrome {Wilins' tumor, aniridia, genitourinary
abnormalities, and mental
retardation), Smith-Magenis syndrome, myelodysplastic syndrome, hereditary
mucoepithelial dysplasia,
hereditary keratodermas, hereditary neuropathies such as Charcot-Marie-Tooth
disease and
30 neurofibromatosis, hypothyroidism, hydrocephalus, seizure disorders such as
Syndenham's chorea and
cerebral palsy, spina bifida, anencephaly, craniorachischisis, congenital
glaucoma, cataract, and
sensorineural hearing loss; a neurological disorder such as epilepsy, ischemic
cerebrovascular disease,
stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's
disease, dementia,
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Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral
sclerosis and other motor
neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa,
hereditary ataxias, multiple
sclerosis and other demyelinating diseases, bacterial and viral meningitis,
brain abscess, subdural
empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis
and radiculitis, viral
central nervous system disease, prion diseases including kuru, Creutzfeldt-
Jakob disease, and
Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional
and metabolic diseases
of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal
hemangioblastomatosis,
encephalotrigeminal syndrome, mental retardation and other developmental
disorders of the central
nervous system including Down syndrome, cerebral palsy, neuroskeletal
disorders, autonomic nervous
system disorders, cranial nerve disorders, spinal cord diseases, muscular
dystrophy and other
neuromuscular disorders, peripheral nervous system disorders, dermatomyositis
and polymyositis,
inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis,
periodic paralysis, mental
disorders including mood, anxiety, and schizophrenic disorders, seasonal
affective disorder (SAD),
akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia,
dystonias, paranoid psychoses,
postherpetic neuralgia, Tourette's disorder, progressive supranuclear palsy,
corticobasal degeneration,
and familial frontotemporal dementia; a connective tissue disorder such as
osteogenesis irnperfecta,
Ehlers-Danlos syndrome, chondrodysplasias, Marfan syndrome, Alport syndrome,
familial aortic
aneurysm, achondroplasia, mucopolysaccharidoses, osteoporosis, osteopetrosis,
Paget's disease,
rickets, osteomalacia, hyperparathyroidism, renal osteodystrophy,
osteonecrosis, osteomyelitis,
osteoma, osteoid osteoma, osteoblastoma, osteosarcoma, osteochondroma,
chondroma,
chondroblastoma, chondromyxoid fibroma, chondrosarcoma, fibrous cortical
defect, nonossifying
fibroma, fibrous dysplasia, fibrosarcoma, malignant fibrous histiocytoma,
Ewing's sarcoma, primitive
neuroectodermal tumor, giant cell tumor, osteoarthritis, rheumatoid arthritis,
ankylosing
spondyloarthritis, Reiter's syndrome, psoriatic arthritis, enteropathic
arthritis, infectious arthritis, gout,
gouty arthritis, calcium pyrophosphate crystal deposition disease, ganglion,
synovial cyst, villonodular
synovitis, systemic sclerosis, Dupuytren's contracture, hepatic fibrosis,
lupus erythematosus, mixed
connective tissue disease, epidermolysis bullosa simplex, bullous congenital
ichthyosiform
erythroderma (epidermolytic hyperkeratosis), non-epidermolytic and
epidermolytic palmoplantar
keratoderma, ichthyosis bullosa of Siemens, pachyonychia congenita, and white
sponge nevus; and a
cell proliferative disorder such as actinic keratosis, arteriosclerosis,
atherosclerosis, bursitis, cirrhosis,
hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal
nocturnal
hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and
cancers including
adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma,
teratocarcinoma, and, in
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WO 02/02634 PCT/USO1/21067
particular, cancers of the adrenal gland, bladder, bone, bone marrow, brain,
breast, cervix, gall bladder,
ganglia, gastrointestinal tract, heart,.kidney, liver, lung, muscle, ovary,
pancreas, parathyroid, penis,
prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus.
In another embodiment, a vector capable of expressing ECMCAD or a fragment or
derivative
thereof may be administered to a subject to treat or prevent a disorder
associated with decreased
expression or activity of ECMCAD including, but not limited to, those
described above.
In a further embodiment, a composition comprising a substantially purified
ECMCAD in
conjunction with a suitable pharmaceutical carrier may be administered to a
subject to treat or prevent
a disorder associated with decreased expression or activity of ECMCAD
including, but not limited to,
l0 those provided above.
In still another embodiment, an agonist which modulates the activity of ECMCAD
may be
administered to a subject to treat or prevent a disorder associated with
decreased expression or
activity of ECMCAD including, but not limited to, those listed above.
In a fiuther embodiment, an antagonist of ECMCAD may be administered to a
subject to treat
or prevent a disorder associated with increased expression or activity of
ECMCAD. Examples of
such disorders include, but are not limited to, those genetic,
immune/inflammatory, developmental,
neurological, connective tissue, and cell proliferative disorders, including
cancer described above. In
one aspect, an antibody which specifically binds ECMCAD may be used directly
as an antagonist or
indirectly as a targeting or delivery mechanism for bringing a pharmaceutical
agent to cells or tissues
which express ECMCAD.
In an additional embodiment, a vector expressing the complement of the
polynucleotide
encoding ECMCAD may be administered to a subject to treat or prevent a
disorder associated with
increased expression or activity of ECMCAD including, but not limited to,
those described above.
In other embodiments, any of the proteins, antagonists, antibodies, agonists,
complementary
sequences, or vectors of the invention may be administered in combination with
other appropriate
therapeutic agents. Selection of the appropriate agents for use in combination
therapy may be made
by one of ordinary skill in the art, according to conventional pharmaceutical
principles. The
combination of therapeutic agents may act synergistically to effect the
treatment or prevention of the
various disorders described above. Using this approach, one may be able to
achieve therapeutic;
efficacy with lower dosages of each agent, thus reducing the potential for
adverse side effects.
An antagonist of ECMCAD may be produced using methods which are generally
known in
the art. In particular, purified ECMCAD may be used to produce antibodies or
to screen libraries of
pharmaceutical agents to identify those which specifically bind ECMCAD.
Antibodies to ECMCA,D
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WO 02/02634 PCT/USO1/21067
may also be generated using methods that are well known in the art. Such
antibodies may include, but
are not limited to, polyclonal, monoclonal, chimeric, and single chain
antibodies, Fab fragments, and
fragments produced by a Fab expression library. Neutralizing antibodies (i.e.,
those which inhibit
dimer formation) are generally preferred for therapeutic use.
For the production of antibodies, various hosts including goats, rabbits,
rats, mice, humans, and
others may be immunized by injection with ECMCAD or with any fragment or
oligopeptide thereof
which has immunogenic propeWes. Depending on the host species, various
adjuvants may be used to
increase immunological response. Such adjuvants include, but are not limited
to, Freund's, mineral gels
such as aluminum hydroxide, and surface active substances such as
lysolecithin, pluronic polyols,
l0 polyanions, peptides, oil emulsions, KLH, and dinitrophenol. Among
adjuvants used in humans, BCG
(bacilli Calmette-Guerin) and Corvnebacterium parvum are especially
preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce
antibodies to
ECMCAD have an amino acid sequence consisting of at least about 5 amino acids,
and generally will
consist of at least about 10 amino acids. Tt is also preferable that these
oligopeptides, peptides, or
fragments are identical to a portion of the amino acid sequence of the natural
protein. Short stretches
of ECMCAD amino acids may be fused with those of another protein, such as KLH,
and antibodies to
the chimeric molecule may be produced.
Monoclonal antibodies to ECMCAD may be prepared using any technique which
provides for ,
the production of antibody molecules by continuous cell lines in culture.
These include, but are not
limited to, the hybridoma technique, the human B-cell hybridoma technique, and
the EB V-hybridoma
technique. (See, e.g., Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D.
et al. (1985) J.
Immunol. Methods 81:31-42; Cote, R.J. et al. (1983) Proc. Natl. Acad. Sci. USA
80:2026-2030; and
Cole, S.P. et al. (1984) Mol. Cell Biol. 62:109-120.)
In addition, techniques developed for the production of "chimeric antibodies,"
such as the
splicing of mouse antibody genes to human antibody genes to obtain a molecule
with appropriate
antigen specificity and biological activity, can be used. (See, e.g.,
Morrison, S.L. et al. (1984) Proc.
Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M.S. et al. (1984) Nature
312:604-608; and Takeda,
S. et al. (1985) Nature 314:452-454.) Alternatively, techniques described for
the production of single
chain antibodies may be adapted, using methods known in the art, to produce
ECMCAD-specific
single chain antibodies. Antibodies with related specificity, but of distinct
idiotypic composition, may
be generated by chain shuffling from random combinatorial immunoglobulin
libraries. (See, e.g.,
Burton, D.R. (1991) Proc. Natl. Acad. Sci. USA 88:10134-10137.)
Antibodies may also be produced by inducing in vivo production in the
lymphocyte population
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or by screening immunoglobulin libraries or panels of highly specific binding
reagents as disclosed in
the literature. (See, e.g., Orlandi, R. et al. (1989) Proc. Natl. Acad. Sci.
USA 86:3833-3837; Winter,
G. et al. (1991) Nature 349:293-299.)
Antibody fragments which contain specific binding sites for ECMCAD may also be
generated. For example, such fragments include, but are not limited to, F(ab~2
fragments produced
by pepsin digestion of the antibody molecule and Fab fragments generated by
reducing the disulfide
bridges of the F(ab~2 fragments. Alternatively, Fab expression libraries may
be constructed to allow
rapid and easy identification of monoclonal Fab fragments with the desired
specificity. (See, e.g.,
Huse, W.D. et al. (1989) Science 246:1275-1281.)
Various immunoassays may be used for screening to identify antibodies having
the desired
specificity. Numerous protocols for competitive binding or immunoradiometric
assays using either
polyclonal or monoclonal antibodies with established specificities are well
known in the art. Such
immunoassays typically involve the measurement of complex formation between
ECMCAD and its
specific antibody. A two-site, monoclonal-based immunoassay utilizing
monoclonal antibodies reactive
to two non-interfering ECMCAD epitopes is generally used, but a competitive
binding assay may also .
be employed (Pound, supra).
Various methods such as Scatchard analysis in conjunction with
radioimmunoassay techniques
may be used to assess the affinity of antibodies for ECMCAD. Affinity is
expressed as an
association constant, I~, which is defined as the molar concentration of
ECMCAD-antibody complex
divided by the molar concentrations of free antigen and free antibody under
equilibrium conditions.
The I~ determined for a preparation of polyclonal antibodies, which are
heterogeneous in their
affinities for multiple ECMCAD epitopes, represents the average affinity, or
avidity, of the antibodies
for ECMCAD. The I~ determined for a preparation of monoclonal antibodies,
which are
monospecific for a particular ECMCAD epitope, represents a true measure of
affinity. High-affinity
antibody preparations with I~ ranging from about 109 to 1012 L/mole are
preferred for use in
immunoassays in which the ECMCAD-antibody complex must withstand rigorous
manipulations.
Low-affinity antibody preparations with I~ ranging from about 106 to 10'
L/mole are preferred for use
in immunopurification and similar procedures which ultimately require
dissociation of ECMCAD,
preferably in active form, from the antibody (Catty, D. (1988) Antibodies,
Volume I: A Practical
Approach, IRL Press, Washington DC; Liddell, J.E. and A. Cryer (1991) A
Practical Guide to
Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity of polyclonal antibody preparations may be further
evaluated to determine
the quality and suitability of such preparations for certain downstream
applications. For example, a
51
CA 02413186 2002-12-27
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polyclonal antibody preparation containing at least 1-2 mg specific
antibody/ml, preferably 5-10 mg
specific antibody/ml, is generally employed in procedures requiring
precipitation of ECMCAD-antibody
complexes. Procedures for evaluating antibody specificity, titer, and avidity,
and guidelines for
antibody quality and usage in various applications, are generally available.
(See, e.g., Catty, supra, and
Coligan et al. supra.)
In another embodiment of the invention, the polynucleotides encoding ECMCAD,
or any
fragment or complement thereof, may be used for therapeutic purposes. In one
aspect, modifications
of gene expression can be achieved by designing complementary sequences or
antisense molecules
(DNA, RNA, PNA, or modified oligonucleotides) to the coding or regulatory
regions of the gene
l0 encoding ECMCAD. Such technology is well known in the art, and antisense
oligonucleotides or
larger fragments can be designed from various locations along the coding or
control regions of
sequences encoding ECMCAD. (See, e.g., Agrawal, S., ed. (1996) Antisense
Therapeutics, Humana
Press Inc., Totawa NJ.)
In therapeutic use, any gene delivery system suitable for introduction of the
antisense
sequences into appropriate target cells can be used. Antisense sequences can
be delivered
intracellularly in the form of an expression plasmid which, upon
transcription, produces a sequence
complementary to at least a portion of the. cellular sequence encoding the
target protein. (See, e.g.,
Slater, J.E. et al. (1998) J. Allergy Cli. Immunol. 102(3):469-475; and
Scanlon, K.J. et al. (1995)
9(13):1288-1296.) Antisense sequences can also be introduced intracellularly
through the use of viral
2o vectors, such as retrovirus and adeno-associated virus vectors. (See, e.g.,
Miller, A.D. (1990) Blood
76:271; Ausubel, supra; Uekert, W, and W. Walther (1994) Pharmacol. Ther.
63(3):323-347.) Other
gene delivery mechanisms include liposome-derived systems, artificial viral
envelopes, and other
systems known in the art. (See, e.g., Rossi, J.J. (1995) Br. Med. Bull.
51(1):217-225; Boado, R.J. et
al. (1998) J. Pharm. Sci. 87(11):1308-1315; and Morxis, M.C. et al. (1997)
Nucleic Acids Res.
25(14):2730-2736.)
In another embodiment of the invention, polynucleotides encoding ECMCAD may be
used for
somatic or germline gene therapy. Gene therapy may be performed to (i) correct
a genetic deficiency
(e.g., in the cases of severe combined immunodeficiency (SCID)-Xl disease
characterized by X-
linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672),
severe combined
immunodeficiency syndrome associated with an inherited adenosine deaminase
(ADA) deficiency
(Blaese, R.M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995)
Science 270:470-475),
cystic fibxosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R.G. et
al. (1995) Hum. Gene
Therapy 6:643-666; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:667-703),
thalassamias, familial
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CA 02413186 2002-12-27
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hypercholesterolemia, and hemophilia resulting from Factor V)II or Factor IX
deficiencies (Crystal,
R.G. (1995) Science 270:404-410; Verma, LM. and N. Somia (1997) Nature 389:239-
242)), (ii)
express a conditionally lethal gene product (e.g., in the case of cancers
which result from unregulated
cell proliferation), or (iii) express a protein which affords protection
against intracellular paxasites (e.g.,
against human retroviruses, such as human immunodeficiency virus (HIV)
(Baltimore, D. (1988)
Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci. USA.
93:11395-11399),
hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans
and Paracoccidioides
brasiliensis; and protozoan parasites such as Plasmodium falciparum and
Trvaanosoma cruzi). In the
case where a genetic deficiency in ECMCAD expression or regulation causes
disease, the expression
of ECMCAD from an appropriate population of transduced cells may alleviate the
clinical
manifestations caused by the genetic deficiency.
In a further embodiment of the invention, diseases or disorders caused by
deficiencies in
ECMCAD axe treated by constructing mammalian expression vectors encoding
ECMCAD and
introducing these vectors by mechanical means into ECMCAD-deficient cells.
Mechanical transfer
technologies for use with cells in vivo or ex vitro include (i) direct DNA
microinjection into individual
Bells, (ii) ballistic gold particle delivery, (iii) liposome-mediated
transfection, (iv) receptor-mediated
gene transfer, and (v) the use of DNA transposons (Morgan, R.A. and W.F.
Anderson (1993) Annu.
Rev. Biochem. 62:191-217; Ivics, Z. (1997) Cell 91:501-510; Boulay, J-L. and
H. Recipon (1998) ,
C~rr. Opin. Bioteclmol. 9:445-450).
Expression vectors that may be effective for the expression of ECMCAD include,
but are not
limited to, the PCDNA 3.1, EPTTAG, PRCCMV2, PREP, PVAX vectors (Invitrogen,
Carlsbad CA),
PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV (Stratagene, La Jolla CA), and PTET-OFF,
PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto CA), ECMCAD may be
expressed using (i) a constitutively active promoter, (e.g., from
cytomegalovirus (CMV),.Rous
sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or (i-actin genes),
(ii) an inducible promoter
(e.g., the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992)
Proc. Natl. Acad. Sci.
USA 89:5547-5551; Gossen, M. et al. (1995) Science 268:1766-1769; Rossi,
F.M.V. and H.M. Blau
(1998) Cur. Opin. Bioteclmol. 9:451-456), commercially available in the T-REX
plasmid (Invitrogen));
the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND;
Invitrogen); the
FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible
promoter (Rossi, F.M.V.
and Blau, H.M, supra)), or (iii) a tissue-specific promoter or the native
promoter of the endogenous
gene encoding ECMCAD from a normal individual.
Commercially available liposome transformation kits (e.g., the PERFECT LIl'm
53
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
TRANSFECTION KIT, available from Invitrogen) allow one with ordinary skill in
the art to deliver
polynucleotides to target cells in culture and require minimal effort to
optimize experimental
parameters. In the alternative, transformation is performed using the calcium
phosphate method
(Graham, F.L. and A.J. Eb (1973) Virology 52:456-467), or by electroporation
(Neumann, E. et al.
(1982) EMBO J. 1:841-845). The introduction of DNA to primary cells requires
modification of these
standardized mammalian transfection protocols.
In another embodiment of the invention, diseases or disorders caused by
genetic defects with
respect to ECMCAD expression are treated by constructing a retrovirus vector
consisting of (i) the
polynucleotide encoding ECMCAD under the control of an independent promoter or
the retrovirus
long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals,
and (iii) a Rev-
responsive element (RRE) along with additional retrovirus cis-acting RNA
sequences and coding
sequences required for efficient vector propagation. Retrovirus vectors (e.g.,
PFB and PFBNEO) are
commercially available (Stratagene) and are based on published data (Riviere,
I. et al. (1995) Proc.
Natl. Aced. Sci. USA 92:6733-6737), incorporated by reference herein. The
vector is propagated in
an appropriate vector producing cell line (VPCL) that expresses an envelope
gene with a tropism for
receptors on the target cells or a promiscuous envelope protein such as VSVg
(Armentano, D. et al.
(1987) J. Virol. 61:1647-1650; Bender, M.A. et al. (1987) J. Virol. 61:1639-
1646; Adam, M.A. and
A.D. Miller (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol.
72:8463-8471; Zufferey, R. et
al. (1998) J. Virol. 72:9873-9880). U.S. Patent Number 5,910,434 to Rigg
("Method for obtaining
retrovirus packaging cell lines producing high transducing efficiency
retroviral supernatant") discloses
a method for obtaining retrovirus packaging cell lines and is hereby
incorporated by reference.
Propagation of retrovirus vectors, transduction of a population of cells
(e.g., CD4+ T-cells), and the
return of transduced cells to a patient are procedures well known to persons
skilled in the art of gene
therapy and have been well documented (Range, U. et al. (1997) J. Virol.
71:7020-7029; Bauer, G. et
al. (1997) Blood 89:2259-2267; Bonyhadi, M.L. (1997) J. Virol. 71:4707-4716;
Range, U. et al. (1998)
Proc. Natl. Aced. Sci. USA 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).
In the alternative, an adenovirus-based gene therapy delivery system is used
to deliver
polynucleotides encoding ECMCAD to cells which have one or more genetic
abnormalities with
respect to the expression of ECMCAD. The construction and packaging of
adenovirus-based vectors
are well known to those with ordinary skill in the art. Replication defective
adenovirus vectors have
proven to be versatile for importing genes encoding immunoregulatory proteins
into intact islets in the
pancreas (Csete, M.E. et al. (1995) Transplantation 27:263-268). Potentially
useful adenoviral vectors
are described in U.S. Patent Number 5,707,618 to Armentano ("Adenovirus
vectors for gene
54
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
therapy")> hereby incorporated by reference. For adenoviral vectors, see also
Antinozzi, P.A, et al.
(1999) Annu. Rev. Nutr. 19:511-544 and Verma, LM. and N. Somia (1997) Nature
18:389:239-242,
both incorporated by reference herein.
In another alternative, a herpes-based, gene therapy delivery system is used
to deliver
polynucleotides encoding ECMCAD to target cells which have one or more genetic
abnormalities with
respect to the expression of ECMCAD. The use of herpes simplex virus (HSV)-
based vectors may
be especially valuable for introducing ECMCAD to cells of the central nervous
system, for which
HSV has a tropism. The construction and packaging of herpes-based vectors are
well known to those
with ordinary skill in the art. A replication-competent herpes simplex virus
(HSV) type 1-based vector
l0 has been used to deliver a reporter gene to the eyes of primates (Liu, X.
et al. ( 1999) Exp. Eye Res.
169:385-395). The construction of a HSV-1 virus vector has also been disclosed
in detail in U.S.
Patent Number 5,804,413 to DeLuca ("Herpes simplex vims strains for gene
transfer"), which is
hereby incorporated by reference. U.S. Patent Number 5,804,413 teaches the use
of recombinant
HSV d92 which consists of a genome containing at least one exogenous gene to
be transferred to a
cell under the control of the appropriate promoter for purposes including
human gene therapy. Also
taught by this patent are the construction and use of recombinant HSV strains
deleted for ICP4,
ICP27 and ICP22. For HSV vectors, see also Goins, W.F. et al. (1999) J. Virol.
73:519-532 and Xu,
H. et al. (1994) Dev. Biol. 163:152-161, hereby incorporated by reference. The
manipulation of
cloned herpesvirus sequences, the generation of recombinant virus following
the transfection of
multiple plasmids containing different segments of the large herpesvirus
genomes, the growth and
propagation of herpesvirus, and the infection of cells with herpesvirus are
techniques well known to
those of ordinary skill in the art.
In another alternative, an alphavirus (positive, single-stranded RNA virus)
vector is used to
deliver polynucleotides encoding ECMCAD to target cells. The biology of the
prototypic alphavirus,
Semliki Forest Virus (SFV), has been studied extensively and gene transfer
vectors have been based
on the SFV genome (Garoff, H. and K.-J. Li (1998) Curr. Opin. Biotechnol.
9:464-469). During
alphavirus RNA replication, a subgenomic RNA is generated that normally
encodes the viral capsid
proteins. This subgenomic RNA replicates to higher levels than the full length
genomic RNA,
resulting in the overproduction of capsid proteins relative to the viral
proteins with enzymatic activity
(e.g., protease and polymerase). Similarly, inserting the coding sequence for
ECMCAD into the
alphavirus genome in place of the capsid-coding region results in the
production of a large number of
ECMCAD-coding RNAs and the synthesis of high levels of ECMCAD in vector
transduced cells.
While alphavirus infection is typically associated with cell lysis within a
few days, the ability to
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
establish a persistent infection in hamster normal kidney cells (BHK-21) with
a variant of Sindbis virus
(SIN) indicates that the lytic replication of alphaviruses can be altered to
suit the needs of the gene
therapy application (Dryga, S.A. et al. (1997) Virology 228:74-83). The wide
host range of
alphaviruses will allow the introduction of ECMCAD into a variety of cell
types. The specific
transduction of a subset of cells in a population may require the sorting of
cells prior to transduction.
The methods of manipulating infectious cDNA clones of alphaviruses, performing
alphavirus cDNA
and RNA transfections, and performing alphavirus infections, axe well known to
those with ordinary
skill in the art.
Oligonucleotides derived from the transcription initiation site, e.g., between
about positions -10
1o and +10 from the start site, may also be employed to inhibit gene
expression. Similarly, inhibition can
be achieved using triple helix base-pairing methodology. Triple helix pairing
is useful because it causes
inhibition of the ability of the double helix to open sufficiently for the
binding of polymerases,
transcription factors, or regulatory molecules. Recent therapeutic advances
using triplex DNA have
been described in the literature. (See, e.g., Gee, J.E. et al. (1994) in
Huber, B.E. and B.I. Carr,
Molecular and Immunolo~ic Approaches, Futura Publishing, Mt. Kisco NY, pp. 163-
177.) A
complementary sequence or antisense molecule may also be designed to block
translation of mRNA
by preventing the transcript from binding to ribosomes.
Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific
cleavage of .
RNA. The mechanism of ribozyme action involves sequence-specific hybridization
of the ribozyme
molecule to complementary target RNA, followed by endonucleolytic cleavage.
For example,
engineered hammerhead motif ribozyme molecules may specifically and
efficiently catalyze
endonucleolytic cleavage of sequences encoding ECMCAD.
Specific ribozyme cleavage sites within any potential RNA target are initially
identified by
scanning the target molecule for ribozyme cleavage sites, including the
following sequences: GUA,
GUU, and GUC. Once identified, short RNA sequences of between 15 and 20
ribonucleotides,
corresponding to the region of the target gene containing the cleavage site,
may be evaluated for
secondary structural features which may render the oligonucleotide inoperable.
The suitability of
candidate targets may also be evaluated by testing accessibility to
hybridization with complementary
oligonucleotides using ribonuclease protection assays.
Complementary ribonucleic acid molecules and ribozymes of the invention may be
prepared
by any method known in the art for the synthesis of nucleic acid molecules.
These include techniques
for chemically synthesizing oligonucleotides such as solid phase
phosphoramidite chemical synthesis.
Alternatively, RNA molecules may be generated by in vitro and in vivo
transcription of DNA
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CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
sequences encoding ECMCAD. Such DNA sequences may be incorporated into a wide
variety of
vectors with suitable RNA polymerase promoters such as T7 or SP6.
Alternatively, these cDNA
constructs that synthesize complementary RNA, constitutively or inducibly, can
be introduced into cell
lines, cells, or tissues.
RNA molecules may be modified to increase intracellular stability and half
life. Possible
modifications include, but are not limited to, the addition of flanking
sequences at the 5' and/or 3' ends
of the molecule, or the use of phosphorothioate or 2' O-methyl rather than
phosphodiesterase linkages
within the backbone of the molecule. This concept is inherent in the
production of PNAs and can be
extended in all of these molecules by the inclusion of nontraditional bases
such as inosine, queosine,
and wybutosine, as well as acetyl-, methyl-, thio-, and similarly modified
forms of adenine, cytidine,
guanine, thymine, and uridine which are not as easily recognized by endogenous
endonucleases.
An additional embodiment of the invention encompasses a method for screening
for a
compound which is effective in altering expression of a polynucleotide
encoding ECMCAD.
Compounds which may be effective in altering expression of a specific
polynucleotide may include, but
are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-
forming oligonucleotides,
transcription factors and other polypeptide transcriptional regulators, and
non-macromolecular
chemical entities which are capable of interacting with specific
polynucleotide sequences. Effective
compounds may alter polynucleotide expression by acting as either inhibitors
or promoters of
polynucleotide expression. Thus, in the treatment of disorders associated with
increased ECMCAD
expression or activity, a compound which specifically inhibits expression of
the polynucleotide
encoding ECMCAD may be therapeutically useful, and in the treatment of
disorders associated with
decreased ECMCAD expression or activity, a compound which specifically
promotes expression of
the polynucleotide encoding ECMCAD may be therapeutically useful.
At least one, and up to a plurality, of test compounds may be screened for
effectiveness in
altering expression of a specific polynucleotide. A test compound may be
obtained by any method
commonly known in the art, including chemical modification of a compound known
to be effective in
altering polynucleotide expression; selection from an existing, commercially-
available or proprietary
library of naturally-occurring or non-natural chemical compounds; rational
design of a compound
based on chemical and/or structural properties of the target polynucleotide;
and selection from a
library of chemical compounds created combinatorially or randomly. A sample
comprising a
polynucleotide encoding ECMCAD is exposed to at least one test compound thus
obtained. The
sample may comprise, for example, an intact or permeabilized cell, or an in
vitro cell-free'or
reconstituted biochemical system. Alterations in the expression of a
polynucleotide encoding
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CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ECMCAD are assayed by any method commonly known in the art. Typically, the
expression of a
specific nucleotide is detected by hybridization with a probe having a
nucleotide sequence
complementary to the sequence of the polynucleotide encoding ECMCAD. The
amount of
hybridization may be quantified, thus forming the basis for a comparison of
the expression of the
polynucleotide both with and without exposure to one or more test compounds.
Detection of a change
in the expression of a polynucleotide exposed to a test compound indicates
that the test compound is
effective in altering the expression of the polynucleotide. A screen for a
compound effective in
altering expression of a specific polynucleotide can be carried out, fox
example, using a
Schizosacchaxomvces pombe gene expression system (Atkins, D. et al. (1999)
U.S. Patent No.
5,932,435; Arndt, G.M. et al. (2000) Nucleic Acids Res. 28:E15) or a human
cell line such as HeLa
cell (Clarke, M.L. et al. (2000) Biochem. Biophys. Res. Common. 268:8-13). A
particular
embodiment of the present invention involves screening a combinatorial library
of oligonucleotides
(such as deoxyribonucleotides; ribonucleotides, peptide nucleic acids, and
modified oligonucleotides)
for antisense activity against a specific polynucleotide sequence (Bruice,
T.W, et al. (1997) U.S.
Patent No. 5,686,242; Bruice, T.W. et al. (2000) U.S. Patent No. 6,022,691).
Many methods for introducing vectors into cells or tissues are available and
equally suitable
fox use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be
introduced into stem cells
taken from the patient and clonally propagated for autologous transplant back
into that same patient.
Delivery by transfection, by liposome injections, or by polycationic amino
polymers may be achieved
using methods which are well known in the art. (See, e.g., Goldman, C.K. et
al. (1997) Nat.
Biotechnol. 15:462-466.)
Any of the therapeutic methods described above may be applied to any subject
in need of
such therapy, including, for example, mammals such as humans, dogs, cats,
cows, horses, rabbits, and
monkeys.
An additional embodiment of the invention relates to the administration of a
composition which
generally comprises an active ingredient formulated with a pharmaceutically
acceptable excipient.
Excipients may include, for example, sugars, starches, celluloses, gums, and
proteins. Various
formulations are commonly known and are thoroughly discussed in the latest
edition of Remin on's
Pharmaceutical Sciences (Maack Publishing, Easton PA). Such compositions may
consist of
ECMCAD, antibodies to ECMCAD, and mimetics, agonists, antagonists, or
inhibitors of ECMCAD.
The compositions utilized in this invention may be administered by any number
of routes
including, but not limited to, oral, intravenous, intramuscular, infra-
arterial, intramedullary, intrathecal,
intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal,
intranasal, enteral, topical,
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WO 02/02634 PCT/USO1/21067
sublingual, or rectal means.
Compositions for pulmonary administration may be prepared in liquid or dry
powder form.
These compositions are generally aerosolized immediately prior to inhalation
by the patient. In the
case of small molecules (e.g. traditional low molecular weight organic drugs),
aerosol delivery of fast-
s acting formulations is well-known in the art. In the case of macromolecules
(e.g. larger peptides and
proteins), recent developments in the field of pulmonary delivery via the
alveolar region of the lung
have enabled the practical delivery of drugs such as insulin to blood
circulation (see, e.g., Patton, J.S.
et al., U.S. Patent No. 5,997,848). Pulmonary delivery has the advantage of
administration without
needle injection, and obviates the need for potentially toxic penetration
enhancers.
Compositions suitable for use in the invention include compositions wherein
the active
ingredients are contained in an effective amount to achieve the intended
purpose. The determination
of an effective dose is well within the capability of those skilled in the
art.
Specialized forms of compositions may be prepared for direct intracellular
delivery of
macromolecules comprising ECMCAD or fragments thereof. For example, liposome
preparations
containing a cell-impermeable macromolecule may promote cell fusion and
intracellular delivery of the
macromolecule. Alternatively, ECMCAD or a fragment thereof may be joined to a
short cationic N-
terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated
have been found to
transduce into the cells of all tissues, including the brain, in a mouse model
system (Schwarze, S.R. et
al. (1999) Science 285:1569-1572).
For any compound, the therapeutically effective dose can be estimated
initially either in cell
culture assays, e.g., of neoplastic cells, or in animal models such as mice,
rats, rabbits, dogs, monkeys,
or pigs. An animal model may also be used to determine the appropriate
concentration range and
route of administration. Such information can then be used to determine useful
doses and routes for
administration in humans.
A therapeutically effective dose refers to that amount of active ingredient,
for example
ECMCAD or fragments thereof, antibodies of ECMCAD, and agonists, antagonists
or inhibitors of
ECMCAD, which ameliorates the symptoms or condition. Therapeutic efficacy and
toxicity may be
determined by standard pharmaceutical procedures in cell cultures or with
experimental animals, such
as by calculating the EDso (the dose therapeutically effective in 50% of the
population) or LDSO (the
dose lethal to 50% of the population) statistics. The dose ratio of toxic to
therapeutic effects is the
therapeutic index, which can be expressed as the LDSO/EDSO ratio. Compositions
which exhibit large
therapeutic indices are preferred. The data obtained from cell culture assays
and animal studies are
used to formulate a range of dosage for human use. The dosage contained in
such compositions is
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CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
preferably within a range of circulating concentrations that includes the EDso
with little or no toxicity.
The dosage varies within this range depending upon the dosage form
employed,,the sensitivity of the
patient, and the route of administration.
The exact dosage will be determined by the practitioner, in light of factors
related to the
subject requiring treatment. Dosage and administration are adjusted to provide
sufficient levels of the
active moiety or to maintain the desired effect. Factors which may be taken
into account include the
severity of the disease state, the general health of the subject, the age,
weight, and gender of the
subject, time and frequency of administration, drug combination(s), reaction
sensitivities, and response
to therapy. Long-acting compositions may be.administered every 3 to 4 days,
every week, or
biweekly depending on the half life and clearance rate of the particular
formulation.
Normal dosage amounts may vary from about 0.1 ,ug to 100,000 fig, up to a
total dose of
about 1 gram, depending upon the route of administration. Guidance as to
particular dosages and
methods of delivery is provided in the literature and generally available to
practitioners in the art.
Those skilled in the art will employ different formulations for nucleotides
than for proteins or their
inhibitors. Similarly, delivery of polynucleotides or polypeptides will be
specific to particular cells,
conditions, locations, etc.
DIAGNOSTICS
In another embodiment, antibodies which specifically bind ECMCAD may be used
for fine
diagnosis of disorders characterized by expression of ECMCAD, or in assays to
monitor patients being
treated with ECMCAD or agonists, antagonists, or inhibitors of ECMCAD.
Antibodies useful for
diagnostic purposes may be prepared in the same manner as described above for
therapeutics.
Diagnostic assays for ECMCAD include methods which utilize the antibody and a
label to detect
ECMCAD in human body fluids or in extracts of cells or tissues. The antibodies
may be used with or
without modification, and may be labeled by covalent or non-covalent
attachment of a reporter
molecule. A wide variety of reporter molecules, several of which are described
above, are known in
the art and may be used.
A variety of protocols for measuring ECMCAD, including ELISAs, RTAs, and FACS,
are
known in the art and provide a basis for diagnosing altered or abnormal levels
of ECMCAD
expression. Normal or standard values for ECMCAD expression are established by
combining body
fluids or cell extracts taken from normal mammalian subjects, for example,
human subjects, with
antibodies to ECMCAD under conditions suitable for complex formation. The
amount of standard
complex formation may be quantitated by various methods, such as photometric
means. Quantities of
ECMCAD expressed in subject, control, and disease samples from biopsied
tissues are compared with
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the standard values. Deviation between standard and subject values establishes
the parameters for
diagnosing disease.
In another embodiment of the invention, the polynucleotides encoding ECMCAD
may be used
for diagnostic purposes. The polynucleotides which may be used include
oligonucleotide sequences,
complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used
to detect
and quantify gene expression in biopsied tissues in which expression of ECMCAD
may be correlated
with disease. The diagnostic assay may be used to determine absence, presence,
and excess
expression of ECMCAD, and to monitor regulation of ECMCAD levels during
therapeutic
intervention.
In one aspect, hybridization with PCR probes which are capable of detecting
polynucleotide
sequences, including genomic sequences, encoding ECMCAD or closely related
molecules may be
used to identify nucleic acid sequences which encode ECMCAD. The specificity
of the probe,
whether it is made from a highly specific region, e.g., the 5' regulatory
region, or from a less specific
region, e.g., a conserved motif, and the stringency of the hybridization or
amplification will determine
whether the probe identifies only naturally occurring sequences encoding
ECMCAD, allelic variants,
or related sequences.
Probes may also be used for the detection of related sequences, and may have
at least 50%
sequence identity to any of the ECMCAD encoding sequences. The hybridization
probes of the
subject invention may be DNA or RNA and may be derived from the sequence of
SEQ 1D N0:37-72
or from genomic sequences including promoters, enhancers, and introns of the
ECMCAD gene.
Means for producing specific hybridization probes for DNAs encoding ECMCAD
include the
cloning of polynucleotide sequences encoding ECMCAD or ECMCAD derivatives into
vectors for the
production of mRNA probes. Such vectors are known in the art, are commercially
available, and may
be used to synthesize RNA probes~in vitro by means of the addition of the
appropriate RNA
polymerases and the appropriate labeled nucleotides. Hybridization probes may
be labeled by a
variety of reporter groups, for example, by radionuclides such as 32P or 355,
or by enzymatic labels,
such as alkaline phosphatase coupled to the probe via avidin/biotin coupling
systems, and the like.
Polynucleotide sequences encoding ECMCAD may be used for the diagnosis of
disorders
associated with expression of ECMCAD. Examples of such disorders include, but
are not limited to, a
genetic disorder such as adrenoleukodystrophy, Alport's syndrome,
choroideremia, Duchenne and
Becker muscular dystrophy, D'own's syndrome, cystic fibrosis, chronic
granulomatous disease,
Gaucher's disease, Huntington's chorea, Marfan's syndrome, muscular dystrophy,
myotonic
dystrophy, pycnodysostosis, Refsum's syndrome, retinoblastoma, sickle cell
anemia, thalassemia,
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Werner syndrome, von Willebrand's disease, Wilms' tumor, Zellweger syndrome,
peroxisomal acyl-
CoA oxidase deficiency, peroxisomal thiolase deficiency, peroxisomal
bifunctional protein deficiency,
mitochondria) carnitine palmitoyl transferase and carnitine deficiency,
mitochondriaI very-Iong-chain
acyl-CoA dehydrogenase deficiency, mitochondria) medium-chain acyl-CoA
dehydrogenase
deficiency, mitochondria) short-chain acyl-CoA dehydrogenase deficiency,
mitochondria) electron
transport flavoprotein and electron transport flavoprotein:ubiquinone
oxidoreductase deficiency,
mitochondria) trifunctional protein deficiency, and mitochondria) short-chain
3-hydroxyacyl-CoA
dehydrogenase deficiency; an immune/inflammatory disorder such as acquired
immunodeficiency
syndrome (AIDS), X-linked agammaglobinemia of Bruton, common variable
immunodeficiency (CV)),
DiGeorge's syndrome (thymic hypoplasia), thymic dysplasia, isolated IgA
deficiency, severe combined
immunodeficiency disease (SCID), immunodeficiency with thrombocytopenia and
eczema (Wiskott-
Aldrich syndrome), Chediak-Higashi syndrome, chronic granulomatous diseases,
hereditary
angioneurotic edema, immunodeficiency associated with Cushing's disease,
Addison's disease, adult
respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis,
anemia, asthma,
atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis,
autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis,
cholecystitis, contact
dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes
mellitus, emphysema, episodic
lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum,
atrophic gastritis,
glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's
thyroiditis,
hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia
gravis, myocardial or
pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis,
polymyositis, psoriasis, Reiter's
syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic
anaphylaxis, systemic
lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative
colitis, uveitis, Werner
syndrome, complications of cancer, hemodialysis, and extracoiporeal
circulation, viral, bacterial,
fungal, parasitic, protozoa), and helminthic infections, and trauma; a
developmental disorder such as
renal tubular acidosis, anemia, Cushing's syndrome, achondroplastic dwarfism,
Duchenne and Becker
muscular dystrophy, epilepsy, gonadal dysgenesis, WAGR syndrome (Wilms' tumor,
aniridia,
genitourinary abnormalities, and mental retardation), Smith-Magenis syndrome,
myelodysplastic
syndrome, hereditary mucoepithelial dysplasia, hereditary keratodermas,
hereditary neuropathies such '
as Charcot-Marie-Tooth disease and neurofibromatosis, hypothyroidism,
hydrocephalus, seizure
disorders such as Syndenham's chorea and cerebral palsy, spina bifida,
anencephaly,
craniorachischisis, congenital glaucoma, cataract, and sensorineural hearing
loss; a neurological
disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral
neoplasms, Alzheimer's
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disease, Pick's disease, Huntington's disease, dementia> Parkinson's disease
and other extrapyramidal
disorders, amyotrophic lateral sclerosis and other motor neuron disorders,
progressive neural muscular
atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and
other demyelinating diseases,
bacterial and viral meningitis, brain abscess, subdural empyema, epidural
abscess, suppurative
intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous
system disease, prion
diseases including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Sixaussler-
Scheinker syndrome,
fatal familial insomnia, nutritional and metabolic diseases of the nervous
system, neurofibromatosis,
tuberous sclerosis, cerebelloretinal hemangioblastomatosis,
encephalotrigeminal syndrome, mental
retardation and other developmental disorders of the centt~al nervous system
including Down
syndrome, cerebral palsy, neuroskeletal disorders, autonomic nervous system
disorders, cranial nerve
disorders, spinal cord diseases, muscular dystrophy and other neuromuscular
disorders, peripheral
nervous system disorders, dermatomyositis and polymyositis, inherited,
metabolic, endocrine, and toxic
myopathies, myasthenia gravis, periodic paralysis, mental disorders including
mood, anxiety, and
schizophrenic disorders, seasonal affective disorder (SAD), akathesia,
amnesia, catatonia, diabetic
neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postheipetic
neuralgia, Tourette's
disorder, progressive supranuclear palsy, corticobasal degeneration, and
familial frontotemporal
dementia; a connective tissue disorder such as osteogenesis imperfecta, Ehlers-
Danlos syndrome,
chondrodysplasias, Marfan syndrome, Alport syndrome, familial aortic aneurysm,
achondroplasia,
mucopolysaccharidoses, osteoporosis, osteopetrosis, Paget's disease, rickets,
osteomalacia,
hypeiparathyroidism, renal osteodystrophy, osteonecrosis, osteomyelitis,
osteoma, osteoid osteoma,
osteoblastoma, osteosarcoma, osteochondroma, chondroma, chondroblastoma,
chondromyxoid fibroma,
chondrosarcoriia, fibrous cortical defect, nonossifying fibroma, fibrous
dysplasia, fibrosarcoma,
malignant fibrous histiocytoma, Ewing's sarcoma, primitive neuroectodermal
tumor, giant cell tumor,
osteoarthritis, rheumatoid arthritis, ankylosing spondyloarthritis, Reiter's
syndrome, psoriatic arthritis,
enteropathic arthritis, infectious arthritis, gout, gouty arthritis, calcium
pyrophosphate crystal deposition
disease, ganglion, synovial cyst, villonodulax synovitis, systemic sclerosis,
Dupuytren's contracture,
hepatic fibrosis, lupus erythematosus, mixed connective tissue disease,
epidermolysis bullosa simplex,
bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis),
non-epidermolytic and
epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens,
pachyonychia congenita, and
white sponge nevus; and a cell proliferative disorder such as actinic
keratosis, arteriosclerosis,
atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue
disease (MCTD), myelofibrosis,
paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary
thrombocythemia, and
cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma,
sarcoma,
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teratocarcinoma, and, in particular, cancers of the adrenal gland, bladder,
bone, bone marrow, brain,
breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney,
liver, lung, muscle, ovary,
pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis,
thymus, thyroid, and uterus.
The polynucleotide sequences encoding ECMCAD may be used in Southern or
northern analysis, dot
blot, or other membrane-based technologies; in PCR technologies; in dipstick,
pin, and multiformat
ELISA-like assays; and in microarrays utilizing fluids or tissues from
patients to detect altered
ECMCAD expression. Such qualitative or quantitative methods are well known in
the art.
In a particular aspect, the nucleotide sequences encoding ECMCAD may be useful
in assays
that detect the presence of associated disorders, particularly those mentioned
above. The nucleotide
sequences encoding ECMCAD may be labeled by standard methods and added to a
fluid or tissue
sample from a patient under conditions suitable for the formation of
hybridization complexes. After a
suitable incubation period, the sample is washed and the signal is quantified
and compaxed with a
standard value. If the amount of signal in the patient sample is significantly
altered in comparison to a
control sample then the presence of altered levels of nucleotide sequences
encoding ECMCAD in the
sample indicates the presence of the associated disorder. Such assays may also
be used to evaluate
the efficacy of a particular therapeutic treatment regimen in animal studies,
in clinical trials, or to
monitor the treatment of an individual patient.
In order to provide a basis for the diagnosis of a disorder associated with
expression of
ECMCAD, a normal or standard profile for expression is established. This may
be accomplished by
combining body fluids or cell extracts taken from normal subjects, either
animal or human, with a
sequence, or a fragment thereof, encoding ECMCAD, under conditions suitable
for hybridization or
amplification. Standard hybridization may be quantified by comparing the
values obtained from normal
subjects with values from an experiment in which a known amount of a
substantially purified
polynucleotide is used. Standard values obtained in this manner may be
compared with values
obtained from samples from patients who are symptomatic for a disorder.
Deviation from standard
values is used to establish the presence of a disorder.
Once the presence of a disorder is established and a treatment protocol is
initiated,
hybridization assays may be repeated on a regular basis to determine if the
level of expression in the
patient begins to approximate that which is observed in the normal subject.
The results obtained from
successive assays may be used to show the efficacy of treatment over a period
ranging from several
days to months.
With respect to cancer, the presence of an abnormal amount of transcript
(either under- or
overexpressed) in biopsied tissue from an individual may indicate a
predisposition for the development
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of the disease, or may provide a means for detecting the disease prior to the
appearance of actual
clinical symptoms. A more definitive diagnosis of this type may allow health
professionals to employ
preventative measures or aggressive treatment earlier thereby preventing the
development or further
progression of the cancer.
Additional diagnostic uses for oligonucleotides designed from the sequences
encoding
ECMCAD may involve the use of PCR. These oligomers may be chemically
synthesized, generated
enzymatically, or produced in vitro. Oligomers will preferably contain a
fragment of a polynucleotide
encoding ECMCAD, or a fragment of a polynucleotide complementary to the
polynucleotide encoding
ECMCAD, and will be employed under optimized conditions for identification of
a specific gene or
to condition. Oligomers may also be employed under less stringent conditions
for detection or
quantification of closely related DNA or RNA sequences.
In a particular aspect, oligonucleotide primers derived from the
polynucleotide sequences
encoding ECMCAD may be used to detect single nucleotide polymorphisms (SNPs).
SNPs are
substitutions, insertions and deletions that are a frequent cause of inherited
or acquired genetic disease
in humans. Methods of SNP detection include, but are not limited to, single-
stranded conformation
polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP,
oligonucleotide primers
derived from the polynucleotide sequences encoding ECMCAD are used to amplify
DNA using the
polymerase chain reaction (PCR). The DNA may be derived, for example, from
diseased or normal
tissue, biopsy samples, bodily fluids, and the like. SNPs in the DNA cause
differences in the
secondary and tertiary structures of PCR products in single-stranded form, and
these differences are
detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the
oligonucleotide primers are
fluorescently labeled, which allows detection of the amplimers in high-
throughput equipment such as
DNA sequencing machines. Additionally, sequence database analysis methods,
termed in silico SNP
(isSNP), are capable of identifying polymorphisms by comparing the sequence of
individual
overlapping DNA fragments which assemble into a common consensus sequence.
These computer-
based methods filter out sequence variations due to laboratory preparation of
DNA and sequencing
errors using statistical models and automated analyses of DNA sequence
chromatograms. In the
alternative, SNPs may be detected and characterized by mass spectrometry
using, for example, the
high throughput MASSARRAY system (Sequenom, Inc., San Diego CA).
Methods which may also be used to quantify the expression of ECMCAD include
radiolabeling or biotinylating nucleotides, coamplification of a control
nucleic acid, and interpolating
results from standard curves. (See, e.g., Melby, P.C. et al. (1993) J.
Immunol. Methods 159:235-244;
Duplaa, C. et al. (1993) Anal. Biochem. 212:229-236.) The speed of
quantitation of multiple samples
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may be accelerated by running the assay in a high-throughput format where the
oligomer or
polynucleotide of interest is presented in various dilutions and a
spectrophotometric or colorimetric
response gives rapid quantitation.
In further embodiments, oligonucleotides or longer fragments derived from any
of the
polynucleotide sequences described herein may be used as elements on a
microarray. The microarray
can be used in transcript imaging techniques which monitor the relative
expression levels of large
numbers of genes simultaneously as described below. The microarray may also be
used to identify
genetic variants, mutations, and polymorphisms. This information may be used
to determine gene
function, to understand the genetic basis of a disorder, to diagnose a
disorder, to monitor
progression/regression of disease as a function of gene expression, and to
develop and monitor the
activities of therapeutic agents in the treatment of disease. In particular,
this information may be used
to develop a pharmacogenomic profile of a patient in order to select the most
appropriate and effective
treatment regimen for that patient. For example, therapeutic agents which are
highly effective and
display the fewest side effects may be selected for a patient based on his/her
pharmacogenomic
profile.
In another embodiment, ECMCAD, fragments of ECMCAD, or antibodies specific for
ECMCAD may be used as elements on a microarray. The microarray may be used to
monitor or
measure protein-protein interactions, drug-target interactions, and gene
expression profiles, as
described above.
A particular embodiment relates to the use of the polynucleotides of the
present invention to
generate a transcript image of a tissue or cell type. A transcript image
represents the global pattern of
gene expression by a particular tissue or cell type. Global gene expression
patterns are analyzed by
quantifying the number of expressed genes and their relative abundance under
given conditions and at
a given time. (See Seilhamer et al., "Comparative Gene Transcript Analysis,"
U.S. Patent Number
5,840,484, expressly incorporated by reference herein.) Thus a transcript
image may be generated by
hybridizing the polynucleotides of the present invention or their complements
to the totality of
transcripts or reverse transcripts of a particular tissue or cell type. In one
embodiment, the
hybridization takes place in high-throughput format, wherein the
polynucleotides of the present
invention or their complements comprise a subset of a plurality of elements on
a microarray. The
resultant transcript image would provide a profile of gene activity.
Transcript images may be generated using transcripts isolated from tissues,
cell lines, biopsies,
or other biological samples. The transcript image may thus reflect gene
expression in vivo, as in the
case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.
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Transcript images which profile the expression of the polynucleotides of the
present invention
may also be used in conjunction with in vitro model systems and preclinical
evaluation of
pharmaceuticals, as well as toxicological testing of industrial and naturally-
occurring environmental
compounds. All compounds induce characteristic gene expression patterns,
frequently termed
molecular fingerprints or toxicant signatures, which are indicative of
mechanisms of action and toxicity
(Nuwaysir, E.F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S. and N.L.
Anderson (2000)
Toxicol. Lett. 112-113:467-471, expressly incorporated by reference herein).
If a test compound has a
signature similar to that of a compound with known toxicity, it is likely to
share those toxic properties.
These fingerprints or signatures are most useful and refined when they contain
expression information
from a large number of genes and gene families. Ideally, a genome-wide
measurement of expression
provides the highest quality signature. Even genes whose expression is not
altered by any tested
compounds are important as well, as the levels of expression of these genes
are used to normalize the
rest of the expression data. The normalization procedure is useful for
comparison of expression data
after treatment with different compounds. While the assignment of gene
function to elements of a
toxicant signature aids in interpretation of toxicity mechanisms, knowledge of
gene function is not
necessary for the statistical matching of signatures which leads to prediction
of toxicity. (See, for
example, Press Release 00-02 from the National Institute of Environmental
Health Sciences, released
February 29, 2000, available at http://www.niehs.nih.gov/oc/news/toxchip.htm.)
Therefore, it is
important and desirable in toxicological screening using toxicant signatures
to include all expressed
gene sequences.
In one embodiment, the toxicity of a test compound is assessed by treating a
biological sample
containing nucleic acids with the test compound. Nucleic acids that are
expressed in the treated
biological sample are hybridized with one or more probes specific to the
polynucleotides of the present
invention, so that transcript levels corresponding to the polynucleotides of
the present invention may be
quantified. The transcript levels in the treated biological sample are
compared with levels in an
untreated biological sample. Differences in the transcript levels between the
two samples axe
indicative of a toxic response caused by the test compound in the treated
sample.
Another particular embodiment relates to the use of the polypeptide sequences
of the present
invention to analyze the proteome of a tissue or cell type. The term proteome
refers to the global
pattern of protein expression in a particular tissue or cell type. Each
protein component of a proteome
can be subjected individually to further analysis. Proteome expression
patterns, or profiles, are
analyzed by quantifying the number of expressed proteins and their relative
abundance under given
conditions and at a given time. A profile of a cell's proteome may thus be
generated by separating
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and analyzing the polypeptides of a particular tissue or cell type. In one
embodiment, the separation is
achieved using two-dimensional gel electrophoresis, in which proteins from a
sample are separated by
isoelectric focusing in the first dimension, and then according to molecular
weight by sodium dodecyl
sulfate slab gel electrophoresis in the second dimension (Steiner and
Anderson, supra). The proteins
are visualized in the gel as discrete and uniquely positioned spots, typically
by staining the gel with an
agent such as Coomassie Blue or silver or fluorescent stains. The optical
density of each protein spot
is generally proportional to the level of the protein in the sample. The
optical densities of equivalently
positioned protein spots from different samples, for example, from biological
samples either treated or
untreated with a test compound or therapeutic agent, are compared to identify
any changes in protein
spot density related to the treatment. The proteins in the spots are partially
sequenced using, for
example, standard methods employing chemical or enzymatic cleavage followed by
mass
spectrometry. The identity of the protein in a spot may be determined by
comparing its partial
sequence, preferably of at least 5 contiguous amino acid residues, to the
polypeptide sequences of the
present invention. In some cases, further sequence data may be obtained for
definitive protein
identification.
A proteomic profile may also be generated using antibodies specific for ECMCAD
to quantify
the levels of ECMCAD expression. In one embodiment, the antibodies are used as
elements on a
microarray, and protein expression levels are quantified by exposing the
microarray to the sample and
detecting the levels of protein bound to each array element (Lueking, A. et
al. ( 1999) Anal. Biochem.
270:103-111; Mendoze, L.G. et al. (1999) Biotechniques 27:778-788). Detection
may be performed by
a variety of methods known in the art, for example, by reacting the proteins
in the sample with a thiol-
or amino-reactive fluorescent compound and detecting the amount of
fluorescence bound at each
array element.
Toxicant signatures at the proteome level are also useful for toxicological
screening, and
should be analyzed in parallel with toxicant signatures at the transcript
level. There is a poor
correlation between transcript and protein abundances for some proteins in
some tissues (Anderson,
N.L. and J. Seilhamer (1997) Electrophoresis 18:533-537), so proteome toxicant
signatures may be
useful in the analysis of compounds which do not significantly affect the
transcript image, but which
alter the proteomic profile. In addition, the analysis of transcripts in body
fluids is difficult, due to rapid
degradation of mRNA, so proteomic profiling may be more reliable and
informative in such cases.
In another embodiment, the toxicity of a test compound is assessed by treating
a biological
sample containing proteins with the test compound. Proteins that are expressed
in the treated
biological sample are separated so that the amount of each protein can be
quantified. The amount of
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each protein is compared to the amount of the corresponding protein in an
untreated biological sample.
A difference in the amount of protein between the two samples is indicative of
a toxic response to the
test compound in the treated sample. Individual proteins are identified by
sequencing the amino acid
residues of the individual proteins and comparing these partial sequences to
the polypeptides of the
present invention.
In another embodiment, the toxicity of a test compound is assessed by treating
a biological
sample containing proteins with the test compound. Proteins from the
biological sample are incubated
with antibodies specific to the polypeptides of the present invention. The
amount of protein recognized
by the antibodies is quantified. The amount of protein in the treated
biological sample is compared
z0 with the amount in an untreated biological sample. A difference in the
amount of protein between the
two samples is indicative of a toxic response to the test compound in the
treated sample.
Microarrays may be prepared, used, and analyzed using methods known in the
art. (See, e.g.,
Brennan, T.M. et al. (1995) U.S. Patent No. 5,474,796; Schena, M. et al.
(1996) Proc. Natl. Acad.
Sci. USA 93:10614-10619; Baldeschweiler et al. (1995) PCT application
W095/251116; Shalom D. et
al. (1995) PCT application W095/35505; Heller, R.A. et al. (1997) Proc. Natl.
Acad. Sci. USA
94:2150-2155; and Heller, M.J. et al. (1997) U.S. Patent No. 5,605,662.)
Various types of
microarrays are well known and thoroughly described in DNA Microarravs: A
Practical Approach,
M, Schena, ed. (1999) Oxford University Press, London, hereby expressly
incorporated by reference.
In another embodiment of the invention, nucleic acid sequences encoding ECMCAD
may be
z0 used to generate hybridization probes useful in mapping the naturally
occurring genomic sequence.
Either coding or noncoding sequences may be used, and in some instances,
noncoding sequences may
be preferable over coding sequences. For example, conservation of a coding
sequence among
members of a mufti-gene family may potentially cause undesired cross
hybridization during
chromosomal mapping. The sequences may be mapped to a particular chromosome,
to a specific
region of a chromosome, or to artificial chromosome constructions, e.g., human
artificial chromosomes
(HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes
(BACs), bacterial P1
constructions, or single chromosome cDNA libraries. (See, e.g., Harnngton,
J.J. et aI. (1997) Nat.
Genet. 15:345-355; Price, C.M. (1993) Blood Rev. 7:127-134; and Trask, B.J.
(1991) Trends Genet.
7:149-154.) Once mapped, the nucleic acid sequences of the invention may be
used to develop
genetic linkage maps, for example, which correlate the inheritance of a
disease state with the
inheritance of a particular chromosome region or restriction fragment length
polymorphism (RFLP).
(See, for example, Lander, E.S. and D. Botstein (1956) Proc. Natl. Acad. Sci.
USA 53:7353-7357.)
Fluorescent in situ hybridization (FISH) may be correlated with other physical
and genetic
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map data. (See, e.g., Heinz-Utrich, et al. (1995) in Meyers, supra, pp. 965-
968.) Examples of genetic
map data can be found in various scientific journals or at the Online
Mendelian Inheritance in Man
(OM1M) World Wide Web site. Correlation between the location of the gene
encoding ECMCAD on
a physical map and a specific disorder, or a predisposition to a specific
disorder, may help define the
region of DNA associated with that disorder and thus may further positional
cloning efforts.
In situ hybridization of chromosomal preparations and physical mapping
techniques, such as
linkage analysis using established chromosomal markers, may be used for
extending genetic maps.
Often the placement of a gene on the chromosome of another mammalian species,
such as mouse,
may reveal associated markers even if the exact chromosomal locus is not
known. This information is
l0 valuable to investigators searching for disease genes using positional
cloning or other gene discovery
techniques. Once the gene or genes responsible for a disease or syndrome have
been crudely
localized by genetic linkage to a particular genomic region, e.g., ataxia-
telangiectasia to 11 q22-23, any
sequences mapping to that area may represent associated or regulatory genes
for further investigation.
(See, e.g., Gatti, R.A. et al. (1988) Nature 336:577-580.) The nucleotide
sequence of the instant
invention may also be used to detect differences in the chromosomal location
due to translocation,
inversion, etc., among normal, carrier, or affected individuals.
In another embodiment of the invention, ECMCAD, its catalytic or immunogenic
fragments, or
oligopeptides thereof can be used for screening libraries of compounds in any
of a variety of drug
screening techniques. The fragment employed in such screening may be free in
solution, affixed to a
solid support, borne on a cell surface, or located intracellularly. The
formation of binding complexes
between ECMCAD and the agent being tested may be measured.
Another technique for drug screening provides for high throughput screening of
compounds
having suitable binding affinity to the protein of interest. (See, e.g.,
Geysen, et al. (1984) PCT
application W084/03564.) In this method, large numbers of different small test
compounds are
synthesized on a solid substrate. The test compounds are reacted with ECMCAD,
or fragments
thereof, and washed. Bound ECMCAD is then detected by methods well known in
the art. Purified
ECMCAD can also be coated directly onto plates for use in the aforementioned
drug screening
techniques. Alternatively, non-neutralizing antibodies can be used to capture
the peptide and
immobilize it on a solid support.
In another embodiment, one may use competitive drug screening assays in which
neutralizing
antibodies capable of binding ECMCAD specifically compete with a test compound
for binding
ECMCAD. In this manner, antibodies can be used to detect the presence of any
peptide which
shares one or more antigenic determinants with ECMCAD.
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In additional embodiments, the nucleotide sequences which encode ECMCAD may be
used in
any molecular biology techniques that have yet to be developed, provided the
new techniques rely on
properties of nucleotide sequences that are currently known, including, but
not limited to, such
properties as the triplet genetic code and specific base pair interactions.
Without further elaboration, it is believed that one skilled in the art can,
using the preceding
description, utilize the present invention to its fullest extent. The
following embodiments are, therefore,
to be construed as merely illustrative, and not limitative of the remainder of
the disclosure in any way
whatsoever.
The disclosures of all patents, applications, and publications mentioned above
and below,
1o including U.S. Ser. No. 60/215,454, U.S. Sex. No. 601219,462, U.S. Ser. No.
60/240,111, U.S. Ser.
No. 60/240,106, U.S. Ser. No. 601244,021, U.S. Ser. No. 60/248,887, and U.S.
Ser. No. 60/249,570
are hereby expressly incorporated by reference.
EXAMPLES
I. Construction of cDNA Libraries
Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD
database (Incyte Genomics, Palo Alto CA) and shown in Table 4, column 5. Some
tissues were
homogenized and lysed in guanidinium isothiocyanate, while others were
homogenized and lysed in
phenol or in a suitable mixture of denaturants, such as TRIZOL (Life
Technologies), a monophasic
solution of phenol and guanidine isothiocyanate. The resulting lysates were
centrifuged over CsCI
cushions or extracted with chloroform. RNA was precipitated from the lysates
with either isopropanol
or sodium acetate and ethanol, or by other routine methods.
Phenol extraction and precipitation of RNA were repeated as necessary to
increase RNA
purity. In some cases, RNA was treated with DNase. For most libraries,
poly(A)+ RNA was
isolated using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX
latex particles
(QIAGEN, Chatsworth CA), or an OLIGOTEX mRNA purification kit (QIAGEN).
Alternatively,
RNA was isolated directly from tissue lysates using other,RNA isolation kits,
e.g., the
POLY(A)PURE mRNA purification kit (Ambion, Austin TX).
In some cases, Stratagene was provided with RNA and constructed the
corresponding cDNA
libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed
with the
UNIZAP vector system (Stratagene) or SUPERSCRIPT plasmid system (Life
Technologies), using
the recommended procedures or similar methods known in the art. (See, e.g.,
Ausubel, 1997, supra,
units 5.1-6.6.) Reverse transcription was initiated using oligo d(T) or random
primers. Synthetic
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oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA
was digested with the
appropriate restriction enzyme or enzymes. For most libraries, the cDNA was
size-selected (300-
1000 bp) using SEPHACRYL S 1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column
chromatography (Amersham Pharmacia Biotech) or preparative agarose gel
electrophoresis. cDNAs
were ligated into compatible restriction enzyme sites of the polylinker of a
suitable plasmid, e.g.,
PBLUESCRIPT plasmid (Stratagene), PSPORTl plasmid (Life Technologies),
PCDNA2.1 plasmid
(Invitrogen, Carlsbad CA), PBK-CMV plasmid (Stxatagene), or pINCY (Incyte
Genomics, Palo Alto
CA), or derivatives thereof. Recombinant plasmids were transformed into
competent E. coli cells
including XL1-Blue, XLl-BlueMRF, or SOLR from Stratagene or DHSa, DHlOB, or
ElectroMAX
l0 DH10B from Life Technologies.
II. Isolation of cDNA Clones
Plasmids obtained as described in Example I were recovered from host cells by
in vivo
excision using the UNIZAP vector system (Stratagene) or by cell lysis.
Plasmids were purified using
at least one of the following: a Magic or WIZARD Minipreps DNA purification
system (Promega); an
AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg MD); and QIAWELL
8 Plasmid,
QIAWELL 8 Plus Plasmid, QIAWELL 8 Ultra Plasmid purification systems or the
R.E.A.L. PREP
96 plasmid purification kit from QIAGEN. Following precipitation, plasmids
were resuspended in 0.1
ml of distilled water and stored, with or without lyophilization, at
4°C.
Alternatively, plasmid DNA was amplified from host cell lysates using direct
link PCR in a
high-throughput format (Rao, V.B. (1994) Anal. Biochem. 216:1-14). Host cell
lysis and thermal
cycling steps were carried out in a single reaction mixture. Samples were
processed and stored in
384-well plates, and the concentration of amplified plasmid DNA was quantified
fluorometrically using
PICOGREEN dye (Molecular Probes, Eugene OR) and a FLUOROSKAN II fluorescence
scanner
(Labsystems Oy, Helsinki, Finland).
III. Sequencing and Analysis
Incyte cDNA recovered in plasmids as described in Example II were sequenced as
follows.
Sequencing reactions were processed using standaxd methods or high-throughput
instrumentation such
as the ABI CATALYST 800 (Applied Biosystems) thermal cycler or the PTC-200
thermal cycler
(MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientifc)
or the
MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions
were prepared
using reagents provided by Amersham Pharmacia Biotech or supplied in ABI
sequencing kits such as
the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied
Biosystems).
Electrophoretic separation of cDNA sequencing reactions and detection of
labeled polynucleotides
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were carried out using the MEGABACE 1000 DNA sequencing system (Molecular
Dynamics); the
ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction
with standard ABI
protocols and base calling software; or other sequence analysis systems known
in the art. Reading
frames within the cDNA sequences were identified using standard methods
(reviewed in Ausubel,
1997, supra, unit 7.7). Some of the cDNA sequences were selected for extension
using the
techniques disclosed in Example VIII.
The polynucleotide sequences derived from Incyte cDNAs were validated by
removing
vector, linker, and poly(A) sequences and by masking ambiguous bases, using
algorithms and
programs based on BLAST, dynamic programming, and dinucleotide nearest
neighbor analysis. The
l0 Incyte cDNA sequences or translations thereof were then queried against a
selection of public
databases such as the GenBankprimate, rodent, mammalian, vertebrate, and
eukaryote databases, and
BLOCKS, PRINTS, DOMO, PRODOM, and hidden Markov model (HMM)-based protein
family
databases such as PFAM. (HMM is a probabilistic approach which analyzes
consensus primary
structures of gene families. See, for example, Eddy, S.R. (1996) Curr. Opin.
Struct. Biol. 6:361-365.)
The queries were performed using programs based on BLAST, FASTA, BLIMPS, and
HMMER.
The Incyte cDNA sequences were assembled to produce full length polynucleotide
sequences.
Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched
sequences, or
Genscan-predicted coding sequences (see Examples IV and V) were used to extend
Incyte cDNA
assemblages to full length. Assembly was performed using programs based on
Phred, Phrap, and
Consed, and cDNA assemblages were screened for open reading frames using
programs based on
GeneMark, BLAST, and FASTA. The full length polynucleotide sequences were
translated to derive
the corresponding full length polypeptide sequences. Alternatively, a
polypeptide of the invention may
begin at any of the methionine residues of the full length translated
polypeptide. Full length polypeptide
sequences were subsequently analyzed by querying against databases such as the
GenBankprotein
databases (genpept), SwissProt, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, and
hidden
Markov model (HMM)-based protein family databases such as PFAM. Full length
polynucleotide
sequences are also analyzed using MACDNASIS PRO software (Hitachi Software
Engineering,
South San Francisco CA) and LASERGENE software (DNASTAR). Polynucleotide and
polypeptide
sequence alignments are generated using default parameters specified by the
CLUSTAL algorithm as
incorporated into the MEGALIGN multisequence alignment program (DNASTAR),
which also
calculates the percent identity between aligned sequences.
Table 7 summarizes the tools, programs, and algorithms used for the analysis
and assembly of
Incyte cDNA and full length sequences and provides applicable descriptions,
references, and threshold
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parameters. The first column of Table 7 shows the tools, programs, and
algorithms used, the second
column provides brief descriptions thereof, the third column presents
appropriate references, all of
which are incorporated by reference herein in their entirety, and the fourth
column presents, where
applicable, the scores, probability values, and other parameters used to
evaluate the strength of a
match between two sequences (the higher the score or the lower the probability
value, the greater the
identity between two sequences).
The programs described above for the assembly and analysis of full length
polynucleotide and
polypeptide sequences were also used to identify polynucleotide sequence
fragments from SEQ ID
N0:37-72. Fragments from about 20 to about 4000 nucleotides which are useful
in hybridization and
1o amplification technologies are described in Table 4, column 4.
IV. Identification and Editing of Coding Sequences from Genomic DNA
Putative extracellular matrix and cell adhesion molecules were initially
identified by running
the Genscan gene identification program against public genomic sequence
databases (e.g., gbpri and
gbhtg). Genscan is a general-purpose gene identification program which
analyzes genomic DNA
sequences from a variety of organisms (See Burge, C. and S. Karlin (1997) J.
Mol. Biol. 268:78-94,
and Burge, C. and S. Karlin (1998) Curr. Opin. Struct. Biol. 8:346-354). The
program concatenates
predicted exons to form an assembled cDNA sequence extending from a methionine
to a stop codon.
The output of Genscan is a FASTA database of polynucleotide and polypeptide
sequences. The
maximum range of sequence for Genscan to analyze at once was set to 30 kb. To
determine which of
these Genscan predicted cDNA sequences encode extracellular matrix and cell
adhesion molecules,
the encoded polypeptides were analyzed by querying against PFAM models for
extracellulax matrix
and cell adhesion molecules. Potential extracellular matrix and cell adhesion
molecules were also
identified by homology to Incyte cDNA sequences that had been annotated as
extracellular matrix and
cell adhesion molecules. These selected Genscan-predicted sequences were then
compared by
BLAST analysis to the genpept and gbpri public databases. Where necessary, the
Genscan-predicted
sequences were then edited by comparison to the top BLAST hit from genpept to
correct errors in the
sequence predicted by Genscan, such as extra or omitted exons. BLAST analysis
was also used to
fmd any Incyte cDNA or public cDNA coverage of the Genscan-predicted
sequences, thus providing
evidence for transcription. When Incyte cDNA coverage was available, this
information was used to
correct or confirm the Genscan predicted sequence. Full length polynucleotide
sequences were
obtained by assembling Genscan-predicted coding sequences with Incyte cDNA
sequences and/or
public cDNA sequences using the assembly process described in Example III.
Alternatively, full
length polynucleotide sequences were derived entirely from edited or unedited
Genscan-predicted
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coding sequences.
V. Assembly of Genomic Sequence Data with cDNA Sequence Data
"Stitched" Sequences .
Partial cDNA sequences were extended with exons predicted by the Genscan gene
identification program described in Example IV. Partial cDNAs assembled as
described in Example
IIT were mapped to genomic DNA and parsed into clusters containing related
cDNAs and Genscan
exon predictions from one or more genomic sequences. Each cluster was analyzed
using an algorithm
based on graph theory and dynamic programming to integrate cDNA and genomic
information,
generating possible splice variants that were subsequently confirmed, edited,
or extended to create a
full length sequence. Sequence intervals in which the entire length of the
interval was present on
more than one sequence in the cluster were identified, and intervals thus
identified were considered to
be equivalent by transitivity. For example, if an interval was present on a
cDNA and two genomic
sequences, then all three intervals were considered to be equivalent. This
process allows unrelated
but consecutive genomic sequences to be brought together, bridged by cDNA
sequence. Intervals
thus identified were then "stitched" together by the stitching algorithm in
the order that they appear
along their parent sequences to generate the longest possible sequence, as
well as sequence variants.
Linkages between intervals which proceed along one type of parent sequence
(cDNA to cDNA or
genomic sequence to genomic sequence) were given preference over linkages
which change parent
type (cDNA to genomic sequence). The resultant stitched sequences were
translated and compared
2o by BLAST analysis to the genpept and gbpri public databases. Incorrect
exons predicted by Genscan
were corrected by comparison to the top BLAST hit from genpept. Sequences were
further extended
with additional cDNA sequences, or by inspection of genomic DNA, when
necessary.
"Stretched" Sequences
Partial DNA sequences were extended to full length with an algorithm based on
BLAST
analysis. First, partial cDNAs assembled as described in Example DI were
queued against public
databases such as the GenBank primate, rodent, mammalian, vertebrate, and
eukaryote databases
using the BLAST program. The nearest GenBank protein homolog was then compared
by BLAST
analysis to either Incyte cDNA sequences or GenScan exon predicted sequences
described in
Example IV. A chimeric protein was generated by using the resultant high-
scoring segment pairs
(HSPs) to map the translated sequences onto the GenB auk protein homolog.
Insertions or deletions
may occur in the chimeric protein with respect to the original GenB auk
protein homolog. The
GenBank protein homolog, the chimeric protein, or both were used as probes to
search for homologous
genomic sequences from the public human genome databases. Partial DNA
sequences were
CA 02413186 2002-12-27
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therefore "stretched" or extended by the addition of homologous genomic
sequences. The resultant
stretched sequences were examined to determine whether it contained a complete
gene.
VI. Chromosomal Mapping of ECMCAD Encoding Polynucleotides
The sequences which were used to assemble SEQ ID N0:37-72 were compared with
sequences from the Incyte LIFESEQ database and public domain databases using
BLAST and other
implementations of the Smith-Waterman algorithm. Sequences from these
databases that matched
SEQ ID N0:37-72 were assembled into clusters of contiguous and overlapping
sequences using
assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic
mapping data available
from public resources such as the Stanford Human Genome Center (SHGC),
Whitehead Institute for
1o Genome Research (WIGR), and Genethon were used to determine if any of the
clustered sequences
had been previously mapped. Inclusion of a mapped sequence in a cluster
resulted in the assignment
of all sequences of that cluster, including its particular SEQ ID NO:, to that
map location.
Map locations are represented by ranges, or intervals, of human chromosomes.
The map
position of an interval, in centiMorgans; is measured relative to the terminus
of the chromosome's p-
arm. (The centiMorgan (cM) is a unit of measurement based on recombination
frequencies between
chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb)
of DNA in
humans, although this can vary widely due to hot and cold spots of
recombination.) The cM distances
are based on genetic markers mapped by G6n~thon which provide boundaries for
radiation hybrid
markers whose sequences were included in each of the clusters. Human genome
maps and other
resources available to the public, such as the NCBI "GeneMap' 99" World Wide
Web site
(http:Jlwww.ncbi.nlm.nih.govJgenemap!), can be employed to determine if
previously identified disease
genes map within or in proximity to the intervals indicated above.
In this manner, SEQ )D N0:47 was mapped to chromosome 3 within the interval
from 162.00
to 168.30 centiMorgans. SEQ 1D N0:49 was mapped to chromosome 4 within the
interval from
63.90 to 88.50 centiMorgans.
VII. Analysis of Polynucleotide Expression
Northern analysis is a laboratory technique used to detect the presence of a
transcript of a
gene and involves the hybridization of a labeled nucleotide sequence to a
membrane on which RNAs
from a particular cell type or tissue have been bound. (See, e.g., Sambrook,
supra, ch. 7; Ausubel
(1995) supra, ch. 4 and 16.)
Analogous computer techniques applying BLAST were used to search for identical
or related
molecules in cDNA databases such as GenBank or LIFESEQ (Incyte Genomics). This
analysis is
much faster than multiple membrane-based hybridizations. In addition, the
sensitivity of the computer
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search can be modified to determine whether any particular match is
categorized as exact or similar.
The basis of the search is the product score, which is defined as:
BLAST Score x Percent Identity
x minimum {length(Seq. 1), length(Seq. 2) }
The product score takes into account both the degree of similarity between two
sequences and the
length of the sequence match. The product score is a normalized value between
0 and 100, and is
calculated as follows: the BLAST score is multiplied by the percent nucleotide
identity and the
product is divided by (5 times the length of the shorter of the two
sequences). The BLAST score is
calculated by assigning a score of +5 for every base that matches in a high-
scoring segment pair
(HSP), and -4 for every mismatch. Two sequences may share more than one HSP
(separated by
gaps). If there is more than one HSP, then the pair with the highest BLAST
score is used to calculate
the product score. The product score represents a balance between fractional
overlap and quality in a
BLAST alignment. For example, a product score of 100 is produced only for 100%
identity over the
entire length of the shorter of the two sequences being compared. A product
score of 70 is produced
either by 100% identity and 70% overlap at one end, or by 88% identity and
100% overlap at the
other. A product score of SO is produced either by 100% identity and 50%
overlap at one end, or 79%
identity and 100% overlap.
2o Alternatively, polynucleotide sequences encoding ECMCAD are analyzed with
respect to the
tissue sources from which they were derived. For example, some full length
sequences are
assembled, at least in part, with overlapping Incyte cDNA sequences (see
Example III). Each cDNA
sequence is derived from a cDNA library constructed from a human tissue. Each
human tissue is
classified into one of the following organltissue categories: cardiovascular
system; connective tissue;
digestive system; embryonic structures; endocrine system; exocrine glands;
genitalia, female; genitalia,
male; germ cells; heroic and immune system; liver; musculoskeletal system;
nervous system;
pancreas; respiratory system; sense organs; skin; stomatognathic system;
unclassified/mixed; or
urinary tract. The number of libraries in each category is counted and divided
by the total number of
libraries across all categories. Similarly, each human tissue is classified
into one of the following
disease/condition categories: cancer, cell line, developmental, inflammation,
neurological, trauma,
cardiovascular, pooled, and other, and the number of libraries in each
category is counted and divided
by the total number of libraries across all categories. The resulting
percentages reflect the tissue- and
disease-specific expression of cDNA encoding ECMCAD, cDNA sequences and cDNA
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library/tissue information are found in the LIFESEQ GOLD database (Incyte
Genomics, Palo Alto
CA).
VIII. Extension of ECMCAD Encoding Polynucleotides
Full length polynucleotide sequences were also produced by extension of an
appropriate
fragment of the full length molecule using oligonucleotide primers designed
from this fragment. One
primer was synthesized to initiate 5' extension of the known fragment, and the
other primer was
synthesized to initiate 3' extension of the known fragment. The initial
primers were designed using
OLIGO 4.06 software (National Biosciences), or another appropriate program, to
be about 22 to 30
nucleotides in length, to have a GC content of about 50% or more, and to
anneal to the target
sequence at temperatures of about 68 °C to about 72°C. Any
stretch of nucleotides which would
result in hairpin structures and primer-primer dimerizations was avoided.
Selected human cDNA libraries were used to extend the sequence. If more than
one
extension was necessary or desired, additional or nested sets of primers were
designed.
high fidelity amplification was obtained by PCR using methods well known in
the art. PCR
was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research,
Inc.). The reaction
mix contained DNA template, 200 nmol of each primer, reaction buffer
containing Mg2+, (NH4)2504,
and 2-mercaptoethanol, Taq DNA polymerase (Amersham Pharmacia Biotech),
ELONGASE
enzyme (Life Technologies), and Pfu DNA polymerase (Stratagene), with the
following parameters
for primer pair PCI A and PCI B: Step 1: 94°C, 3 min; Step 2:
94°C, 15 sec; Step 3: 60°C, 1 min;
Step 4: 68°C, 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step
6: 68°C, 5 min; Step 7: storage
at 4°C. In the alternative, the parameters for primer pair T7 and SK.+
were as follows: Step 1: 94°C,
3 min; Step 2: 94°C, 15 sec; Step 3: 57°C, 1 min; Step 4:
68°C, 2 min; Step 5: Steps 2, 3, and 4
repeated 20 times; Step 6: 68 °C, 5 min; Step 7: storage at 4
°C.
The concentration of DNA in each well was determined by dispensing 100 ~1
PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR)
dissolved in 1X TE
and 0.5 ~1 of undiluted PCR product into each well of an opaque fluorimeter
plate (Corning Costar,
Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a
Fluoroskan II
(Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample
and to quantify the
concentration of DNA. A 5 ,u1 to 10 ~l aliquot of the reaction mixture was
analyzed by
electrophoresis on a 1 % agarose gel to determine which reactions were
successful in extending the
sequence.
The extended nucleotides were desalted and concentrated, transferred to 384-
well plates,
digested with CviJI cholera virus endonuclease (Molecular Biology Research,
Madison WI), and
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sonicated or sheared prior to relegation into pUC 18 vector (Amersham
Pharmacia Biotech). For
shotgun sequencing, the digested nucleotides were separated on low
concentration (0.6 to 0.8%)
agarose gels, fragments were excised, and agar digested with Agar ACE
(Promega). Extended
clones were relegated using T4 ligase (New England Biolabs, Beverly MA) into
pUC 18 vector
(Amersham Pharmacia Biotech), treated with Pfu DNA polymerase (Stratagene) to
fill-in restriction
site overhangs, and transfected into competent E. coli cells. Transformed
cells were selected on
antibiotic-containing media, and individual colonies were picked and cultured
overnight at 37 °C in 384-
well plates in LB/2x carb liquid media.
The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase
l0 (Amersham Pharmacia Biotech) and Pfu DNA polymerase (Stratagene) with the
following
parameters: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3;
60°C, 1 min; Step 4: 72°C, 2 min; Step
5: steps 2, 3, and 4 repeated 29 times; Step 6: 72°C, 5 min; Step 7:
storage at 4°C. DNA was
quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples
with low DNA
recoveries were reamplified using the same conditions as described above.
Samples were diluted with
20% dimethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer
sequencing
primers and the DYENAMIC DIRECT kit (Amersham Pharmacia Biotech) or the ABI
PRISM
BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).
In like manner, full length polynucleotide sequences are verified using the
above procedure or
are used to obtain 5' regulatory sequences using the above procedure along
with oligonucleotides
designed for such extension,' and an appropriate genomic library.
IX. Labeling and Use of Individual Hybridization Probes
Hybridization probes derived from SEQ ID NO:37-72 are employed to screen
cDNAs,
genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting
of about 20 base
pairs, is specifically described, essentially the same procedure is used with
larger nucleotide
fragments. Oligonucleotides are designed using state-of-the-art software such
as OLIGO 4,06
software (National Biosciences) and labeled by combining 50 pmol of each
oligomer, 250 ~Ci of
~,~ 32P1 adenosine- triphosphate (Amersham Pharmacia Biotech), and T4
polynucleotide kinase
(DuPont NEN, Boston MA). The labeled oligonucleotides are substantially
purifted using a
SEPHADEX G-25 supexfine size exclusion dextran bead column (Amersham Pharmacia
Biotech).
An aliquot containing 10' counts per minute of the labeled probe is used in a
typical membrane-based
hybridization analysis of human genomic DNA digested with one of the following
endonucleases: Ase
I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).
The DNA from each digest is fractionated on a 0.7% agarose gel and transferred
to nylon
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membranes (Nytran Plus, Schleicher & SchueIl, Durham NH). Hybridization is
carried out for 16
hours at 40°C. To remove nonspecific signals, blots are sequentially
washed at room temperature
under conditions of up to, for example, 0.1 x saline sodium citrate and 0.5%
sodium dodecyl sulfate.
Hybridization patterns are visualized using autoradiography or an alternative
imaging means and
compared.
X. Microarrays
The linkage or synthesis of array elements upon a microarray can be achieved
utilizing
photolithography, piezoelectric printing (ink jet printing, See, e.g.,
Baldeschweiler, su ra.), mechanical
microspotting technologies, and derivatives thereof. The substrate in each of
the aforementioned
technologies should be uniform and solid with a non-porous surface (Schena
(1999), supra).
Suggested substrates include silicon, silica, glass slides, glass chips, and
silicon wafers. Alternatively, a
procedure analogous to a dot or slot blot may also be used to arrange and link
elements to the surface
of a substrate using thermal, LTV, chemical, or mechanical bonding procedures.
A typical array may
be produced using available methods arid machines well known to those of
ordinary skill in the art and
may contain any appropriate number of elements. (See, e.g., Schena, M. et al.
(1995) Science
270:467-470; Shalom D. et al. (1996) Genome Res. 6:639-645; Marshall, A. and
J. Hodgson (1998)
Nat. Biotechnol. 16:27-31.)
Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers
thereof may
comprise the elements of the microarray. Fragments or oligomers suitable for
hybridization can be
selected using software well known in the art such as LASERGENE software
(DNASTAR). The
array elements are hybridized with polynucleotides in a biological sample. The
polynucleotides in the
biological sample are conjugated to a fluorescent label or other molecular tag
for ease of detection.
After hybridization, nonhybridized nucleotides from the biological sample are
removed, and a
fluorescence scanner is used to detect hybridization at each array element.
Alternatively, laser
desorbtion and mass spectrometry may be used for detection of hybridization.
The degree of
complementaxity and the relative abundance of each polynucleotide which
hybridizes to an element on
the microarray may be assessed. In one embodiment, microarray preparation and
usage is described
in detail below.
Tissue or Cell Sample Preparation
Total RNA is isolated from tissue samples using the guanidinium thiocyanate
method and
poly(A)* RNA is purified using the oligo-(dT) cellulose method. Each poly(A)+
RNA sample is
reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/~1 oligo-(dT)
primer (2lmer), 1X first
strand buffer, 0.03 units/~1 RNase inhibitor, 500 pM dATP, 5001tM dGTP, 500 ~M
dTTP, 40 pM
CA 02413186 2002-12-27
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dCTP, 40 ~M dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Pharmacia Biotech). The
reverse
transcription reaction is performed in a 25 ml volume containing 200 ng
poly(A)+ RNA with
GEMBRIGHT kits (Incyte). Specific control poly(A)+ RNAs are synthesized by in
vitro transcription
from non-coding yeast genomic DNA. After incubation at 37° C for 2 hr,
each reaction sample (one
with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of O.SM sodium
hydroxide and
incubated for 20 minutes at 85° C to the stop the reaction and degrade
the RNA. Samples are purified
using two successive CHROMA SPIN 30 gel filtration spin columns (CLONTECH
Laboratories, Inc.
(CLONTECH), Palo Alto CA) and after combining, both reaction samples are
ethanol precipitated
using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100%
ethanol. The sample is
then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook
NY) and resuspended
in 14 ~l SX SSC/0.2% SDS.
Microarray Preparation
Sequences of the present invention are used to generate array elements. Each
array element
is amplified from bacterial cells containing vectors with cloned cDNA inserts.
PCR amplification uses
primers complementary to the vector sequences flanking the cDNA insert. Array
elements are
amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a
final quantity greater than 5 dug.
Amplified array elements are then purified using SEPHACRYL-400 (Amersham
Pharmacia Biotech).
Purified array elements are immobilized on polymer-coated glass slides. Glass
microscope
slides (Corning) are cleaned by ultrasound in 0.1 %o SDS and acetone, with
extensive distilled water
washes between and after treatments. Glass slides are etched in 4%
hydrofluoric acid (VWR
Scientific Products Corporation (VWR), West Chester PA), washed extensively in
distilled water, and
coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are
cured in a 110°C
oven.
Array elements are applied to the coated glass substrate using a procedure
described in US
Patent No. 5,807,522, incorporated herein by reference. 1 ~1 of the array
element DNA, at an average
concentration of 100 ng/~1, is loaded into the open capillary printing element
by a high-speed robotic
apparatus. The apparatus then deposits about 5 n1 of array element sample per
slide.
Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker
(Stratagene).
Microarrays are washed at room temperature once in 0.2% SDS and three times in
distilled water.
Non-specific binding sites are blocked by incubation of microarrays in 0.2%
casein in phosphate
buffered saline (PBS) (Tropix, Inc., Bedford MA) for 30 minutes at 60°
C followed by washes in 0.2%
SDS and distilled water as before.
Hybridization
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WO 02/02634 PCT/USO1/21067
Hybridization reactions contain 9 ~ l of sample mixture consisting of 0.2 p g
each of Cy3 and
Cy5 labeled cDNA synthesis products in 5X SSC, 0.2% SDS hybridization buffer.
The sample
mixture is heated to 65° C for S minutes and is aliquoted onto the
microarray surface and covered with
an 1.8 cm2 coverslip. The arrays are transferred to a waterproof chamber
having a cavity just slightly
larger than a microscope slide. The chamber is kept at 100% humidity
internally by the addition of 140
p1 of 5X SSC in a corner of the chamber. The chamber containing the arrays is
incubated for about
6.5 hours at 60° C. The arrays are washed for 10 min at 45° C in
a first wash buffer (1X SSC, 0.1%
SDS), three times for 10 minutes each at 45° C in a second wash buffer
(0.1X SSC), and dried.
Detection
Reporter-labeled hybridization complexes are detected with a microscope
equipped with an
Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara CA) capable of
generating spectral lines
at 488 nm for excitation of Cy3 and at 632 nm for excitation of CyS. The
excitation laser light is
focused on the array using a 20X microscope objective (Nikon, Inc., Melville
NY). The slide
containing the array is placed on a computer-controlled X-Y stage on the
microscope and raster-
scanned past the objective. The 1.8 cm x 1.8 em array used in the present
example is scanned with a
resolution of 20 micrometers.
In two separate scans, a mixed gas multiline laser excites the two
fluorophores sequentially. ,
Emitted light is split, based on wavelength, into two photomultiplier tube
detectors (PMT 81477,
Hamamatsu Photonics Systems, Bridgewater NJ) corresponding to the two
fluorophores. Appropriate,
filters positioned between the array and the photomultiplier tubes are used to
filter the signals. The
emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for
CyS. Each array is
typically scanned twice, one scan per fluorophore using the appropriate
filters at the laser source,
although the apparatus is capable of recording the spectra from both
fluorophores simultaneously.
The sensitivity of the scans is typically calibrated using the signal
intensity generated by a
cDNA control species added to the sample mixture at a known concentration. A
specific location on
the array contains a complementary DNA sequence, allowing the intensity of the
signal at that location
to be correlated with a weight ratio of hybridizing species of 1:100,000. When
two samples from
different sources (e.g., representing test and control cells), each labeled
with a different fluorophore,
are hybridized to a single array for the purpose of identifying genes that are
differentially expressed,
the calibration is done by labeling samples of the calibrating cDNA with the
two fluorophores and
adding identical amounts of each to the hybridization mixture.
The output of the photomultiplier tube is digitized using a 12-bit RTI-835H
analog-to-digital
(A/D) conversion board (Analog Devices, Inc., Norwood MA) installed in an IBM-
compatible PC
82
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
computer. The digitized data are displayed as an image where the signal
intensity is mapped using a
linear 20-color transformation to a pseudocolor scale ranging from blue (low
signal) to red (high
signal). The data is also analyzed quantitatively. Where two different
fluorophores are excited and
measured simultaneously, the data are first corrected for optical crosstalk
(due to overlapping emission
S spectra) between the fluorophores using each fluorophore's emission
spectrum.
A grid is superimposed over the fluorescence signal image such that the signal
from each spot
is centered in each element of the grid. The fluorescence signal within each
element is then integrated
to obtain a numerical value corresponding to the average intensity of the
signal. The software used
for signal analysis is the GEMTOOLS gene expression analysis program (Incyte).
l0 XI. Complementary Polynucleotides
Sequences complementary to the ECMCAD-encoding sequences, or any parts
thereof, are
used to detect, decrease, or inhibit expression of naturally occurring ECMCAD.
Although use of
oligonucleotides comprising from about 15 to 30 base pairs is described,
essentially the same
procedure is used with smaller or with larger sequence fragments. Appropriate
oligonucleotides are
15 designed using OLIGO 4.06 software (National Biosciences) and the coding
sequence of ECMCAD.
To inhibit transcription, a complementary oligonucleotide is designed from the
most unique 5' sequence
and used to prevent promoter binding to the coding sequence. To inhibit
translation, a complementary
oligonucleotide is designed to prevent ribosomal binding to the ECMCAD-
encoding transcript.
XII. Expression of ECMCAD
20 Expression and purification of ECMCAD is achieved using bacterial or virus-
based expression
systems. For expression of ECMCAD in bacteria, cDNA is subcloned into an
appropriate vector
containing an antibiotic resistance gene and an inducible promoter that
directs high levels of cDNA
transcription. Examples of such promoters include, but are not limited to, the
trp-lac (tac) hybrid
promoter and the TS or T7 bacteizophage promoter in conjunction with the lac
operator regulatory
25 element. Recombinant vectors are transformed into suitable bacterial hosts,
e.g., BL21 (DE3).
Antibiotic resistant bacteria express ECMCAD upon induction with isopropyl
beta-D-
thiogalactopyranoside (IPTG). Expression of ECMCAD in eukaryotic cells is
achieved by infecting
insect or mammalian cell lines with recombinant Auto~raphica californica
nuclear polyhedrosis virus
(AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of
baculovirus is
30 replaced with cDNA encoding ECMCAD by either homologous recombination or
bacterial-mediated
transposition involving transfer plasmid intermediates. Viral infectivity is
maintained and the strong
polyhedrin promoter drives high levels of cDNA transcription. Recombinant
baculovirus is used to
infect Spodoptera fru~iperda (Sf9) insect cells in most cases, or human
hepatocytes, in some cases.
83
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Infection of the latter requires additional genetic modifications to
baculovirus. (See Engelhard, E.K. et
al. (1994) Proc. Natl. Acad. Sci. USA 91:3224-3227; Sandig, V. et al. (1996)
Hum. Gene Ther.
7:1937-1945.)
In most expression systems, ECMCAD is synthesized as a fusion protein with,
e.g.,
glutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-
His, permitting rapid,
single-step, affinity-based purification of recombinant fusion protein from
crude cell lysates. GST, a
26-kilodalton enzyme from Schistosoma japonicum, enables the purification of
fusion proteins on
immobilized glutathione under conditions that maintain protein activity and
antigenicity (Amersham
Pharmacia Biotech). Following purification, the GST moiety can be
proteolytically cleaved from
1o ECMCAD at specifically engineered sites. FLAG, an 8-amino acid peptide,
enables immunoaffinity
purification using commercially available monoclonal and polyclonal anti-FLAG
antibodies (Eastman
Kodak). 6-His, a stretch of six consecutive histidine residues, enables
purification on metal-chelate
resins (QIAGEN). Methods for protein expression and purification are discussed
in Ausubel (1995,
supra, ch. 10 and 16). Purified ECMCAD obtained by these methods can be used
directly in the
assays shown in Examples XVI and XVII where applicable.
XIII. Functional Assays
ECMCAD function is assessed by expressing the sequences encoding ECMCAD at
physiologically elevated levels in mammalian cell culture systems. cDNA is
subcloned into a
mammalian expression vector containing a strong promoter that drives high
levels of cDNA
expression. Vectors of choice include PCMV SPORT (Life Technologies) and
PCR3.1 (Invitrogen,
Carlsbad CA), both of which contain the cytomegalovirus promoter. 5-10 ,ug of
recombinant vector
are transiently transfected into a human cell line, for example, an
endothelial or hematopoietic cell Line,
using either liposome formulations or electroporation. 1-2 ~cg of an
additional plasmid containing
sequences encoding a marker protein are co-transfected. Expression of a marker
protein provides a
means to distinguish transfected cells from nontransfected cells and is a
reliable predictor of cDNA
expression from the recombinant vector. Maxker proteins of choice include,
e.g., Green Fluorescent
Protein (GFP; Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry
(FCM), an
automated, laser optics-based technique, is used to identify transfected cells
expressing GFP or CD64-
GFP and to evaluate the apoptotic state of the cells and other cellular
properties. FCM detects and
quantifies the uptake of fluorescent molecules that diagnose events preceding
or coincident with cell
death. These events include changes in nuclear DNA content as measured by
staining of DNA with
propidium iodide; changes in cell size and granularity as measured by forward
light scatter and 90
degree side light scatter; down-regulation of DNA synthesis as measured by
decrease in
84
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
bromodeoxyuridine uptake; alterations in expression of cell surface and
intracellular proteins as
measured by reactivity with specific antibodies; and alterations in plasma
membrane composition as
measured by the binding of fluorescein-conjugated Annexin V protein to the
cell surface. Methods in
flow cytometry are discussed in Ormerod, M.G. (1994) Flow C, ometry, Oxford,
New York NY.
The influence of ECMCAD on gene expression can be assessed using highly
purified
populations of cells transfected with sequences encoding ECMCAD and either
CD64 or CD64-GFP.
CD64 and CD64-GFP are expressed on the surface of transfected cells and bind
to conserved regions
of human immunoglobulin G (IgG). Transfected cells are efficiently separated
from nontransfected
cells using magnetic beads coated with either human IgG or antibody against
CD64 (DYNAL, Lake
l0 Success NY). mRNA can be purified from the cells using methods well known
by those of skill in the
art. Expression of mRNA encoding ECMCAD and other genes of interest can be
analyzed by
northern analysis or microarray techniques.
XIV. Production of ECMCAD Specific Antibodies
ECMCAD substantially purified using polyacrylamide gel electrophoresis (PAGE;
see, e.g.,
Harrington, M.G. (1990) Methods Enzymol. 182:488-495), or other purification
techniques, is used to
immunize rabbits and to produce antibodies using standard protocols.
Alternatively, the ECMCAD amino acid sequence is analyzed using LASERGENE
software
(DNASTAR) to determine regions of high immunogenicity, and a corresponding
oligopeptide is
synthesized and used to raise antibodies by means known to those of skill in
the art. Methods for
selection of appropriate epitopes, such as those near the C-terminus or in
hydrophilic regions are well
described in the art. (See, e.g., Ausubel, 1995, supra, ch. 11.) '
Typically, oligopeptides of about 15 residues in length are synthesized using
an ABI 431A
peptide synthesizer (Applied Biosystems) using FMOC chemistry and coupled to
KLH (Sigma-
Aldrich, St. Louis MO) by reaction with N-maleimidobenzoyl-N-
hydroxysuccinimide ester (MBS) to
increase immunogenicity. (See, e.g., Ausubel, 1995, su ra.) Rabbits are
immunized with the
oligopeptide-KI,H complex in complete Freund's adjuvant. Resulting antisera
are tested for
antipeptide and anti-ECMCAD activity by, for example, binding the peptide or
ECMCAD to a
substrate, blocking with 1 % BSA, reacting with rabbit antisera, washing, and
reacting with radio-
iodinated goat anti-rabbit IgG.
XV. Purification of Naturally Occurring ECMCAD Using Specific Antibodies
Naturally occurring or recombinant ECMCAD is substantially purified by
immunoa~nity
chromatography using antibodies specific for ECMCAD. An immunoaffinity column
is constructed by
covalently coupling anti-ECMCAD antibody to an activated chromatographic
resin, such as
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the
resin is
blocked and washed according to the manufacturer's instructions.
Media containing ECMCAD are passed over the immunoaffnity column, and the
column is
washed under conditions that allow the preferential absorbance of ECMCAD
(e.g., high ionic strength
buffers in the presence of detergent). The column is eluted under conditions
that disrupt
antibody/ECMCAD binding (e.g., a buffer of pH 2 to pH 3, or a high
concentration,of a chaotrope,
such as urea or thiocyanate ion), and ECMCAD is collected.
XVI. Identification of Molecules Which Interact with ECMCAD
ECMCAD, or biologically active fragments thereof, are labeled with 12s1 Bolton-
Hunter
l0 reagent. (See, e.g., Bolton A.E. and W.M. Hunter (1973) Biochem. J. 133:529-
539.) Candidate
molecules previously arrayed in the wells of a mufti-well plate are incubated
with the labeled
ECMCAD, washed, and any wells with labeled ECMCAD complex are assayed. Data
obtained using
different concentrations of ECMCAD are used to calculate values for the
number, affinity, and
association of ECMCAD with the candidate molecules.
Alternatively, molecules interacting with ECMCAD are analyzed using the yeast
two-hybrid
system as described in Fields, S. and O. Song (1989) Nature 340:245-246, or
using commercially
available kits based on the two-hybrid system, such as the MATCHMAKER system
(Clontech).
ECMCAD may also be used in the PATHCALLING process (CuraGen Corp., New Haven
CT) which employs the yeast two-hybrid system in a high-throughput manner to
determine all
interactions between the proteins encoded by two large libraries of genes
(Nandabalan, K. et al.
(2000) U.S. Patent No. 6,057,101).
XVII. Demonstration of ECMCAD Activity
An assay for ECMCAD activity measures the expression of ECMCAD on the cell
surface.
cDNA encoding ECMCAD is transfected into a non-leukocytic cell line. Cell
surface proteins are
labeled with biotin (de la Fuente, M.A. et al. (1997) Blood 90:2398-2405).
Irnmunoprecipitations are
performed using ECMCAD-speciftc antibodies, and immunoprecipitated samples are
analyzed using
SDS-PAGE and immunoblotting techniques. The ratio of labeled immunoprecipitant
to unlabeled
immunoprecipitant is proportional to the amount of ECMCAD expressed on the
cell surface.
Alternatively, an assay for ECMCAD activity measures the amount of cell
aggregation
induced by overexpression of ECMCAD. In this assay, cultured cells such as
NIH3T3 are
transfected with cDNA encoding ECMCAD contained within a suitable mammalian
expression vector
under control of a strong promoter. Cotransfection with cDNA encoding a
fluorescent marker
protein, such as Green Fluorescent Protein (CLONTECH), is useful for
identifying stable
86
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
transfectants. The amount of cell agglutination, or clumping, associated with
transfected cells is
compared with that associated with untransfected cells. The amount of cell
agglutination is a direct
measure of ECMCAD activity.
Alternatively, an assay for ECMCAD activity measures the disruption of
cytoskeletal filament
networks upon overexpression of ECMCAD in cultured cell lines (Rezniczek, G.
A. et al. (1998) J.
Cell Biol. 141:209-225). cDNA encoding ECMCAD is subcloned into a mammalian
expression vector
that drives high levels of cDNA expression. This construct is transfected into
cultured cells, such as
rat kangaroo PtK2 or rat bladder carcinoma 8046 cells. Actin filaments and
intermediate filaments
such as keratin and vimentin are visualized by immunofluorescence microscopy
using antibodies and
techniques well known in the art. The configuration and abundance of
cyoskeletal filaments can be
assessed and quantified using confocal imaging techniques. In particular, the
bundling and collapse of
cytoskeletal filament networks is indicative of ECMCAD activity.
Alternatively, cell adhesion activity in ECMCAD is measured in a 96-well
microtiter assay in
which wells are first coated with ECMCAD by adding solutions of ECMCAD of
varying
concentrations to the wells. Excess ECMCAD is washed off with saline, and the
wells incubated with
a solution of 1 % bovine serum albumin to block non-specific cell binding.
Aliquots of a cell suspension
of a suitable cell type are then added to the micortiter wells and incubated
for a period of time at 37
°C. Non-adhered cells are washed off with saline and the cells stained
with a suitable cell stain such
as Coomassie blue. The intensity of staining is measured using a variable
wavelength microtiter plate
reader and compared to a standard curve to determine the number of cells
adhering to the ECMCAD
coated plates. The degree of cell staining is proportional to the cell
adhesion activity of ECMCAD in
the sample.
Various. modifications and variations of the described methods and systems of
the invention
will be apparent to those skilled in the art without departing from the scope
and spirit of the invention.
Although the invention has been described in connection with certain
embodiments, it should be
understood that the invention as claimed should not be unduly limited to such
specific embodiments.
Indeed, various modifications of the described modes for carrying out the
invention which are obvious
to those skilled in molecular biology or related fields are intended to be
within the scope of the
following claims.
87
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
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CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<110> INCYTE GENOMICS, INC.
TANG, Y. Tom
YUE, Henry
AZIMZAI, Yalda
HE, Ann
BATRA, Sajeev
L0, Terence P.
NGUYEN, Danniel B.
BURRILL, John D.
MARCUS, Gregory A.
ZINGLER, Kurt A.
GANDHI, Ameena R.
LAL, Preeti
KEARNEY, Liam
BURFORD, Neil
YAO, Monique G.
WALIA, Narinder K.
ELLIOT, Vicki S.
PATTERSON, Chandra
KHAN, Farrah A.
BAUGHN, Mariah R.
HAFALIA, April, J.A.
POLICKY, Jennifer L.
AU-YOUNG, Janice
LU, Yan
BOROWSKY, Mark L.
LU, Dyung Aina M.
RAMKUMAR, JayalaHIni
YANG, Junming
GURURAJAN, Rajagopal
WARREN, Bridget A.
GIETZEN, Kimberly
XU, Yuming
KALLICK, Deborah A.
LEE, Ernestine A.
THANGAVELU, Kavitha
DELEGEANE, Angelo M.
LEE, Sally
<120> EXTRACELLULAR MATRIX AND CELL ADHESION MOLECULES
<130> PF-0794 PCT
<140> To Be Assigned
<141> Herewith
<150> 60/215,454; 60/219,462; 60/240,111; 60/240,106; 60/244,021;
60/248,887; 60/249,570
<151> 2000-06-30; 2000-07-18; 2000-10-12; 2000-10-12; 2000-10-27;
2000-11-14; 2000-11-16
<160> 72
<170> PERL Program
<210> 1
1/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<211> 234
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1888682CD1
<400> 1
Met Pro Ser Gly Cys His Ser Ser Pro Pro Ser Gly Leu Arg Gly
1 5 10 15
Asp Met Ala Ser Leu Val Pro Leu Ser Pro Tyr Leu Ser Pro Thr
20 25 30
Val Leu Leu Leu Val Ser Cys Asp Leu Gly Phe Val Arg Ala Asp
35 40 45
Arg Pro Pro Ser Pro Val Asn Val Thr Val Thr His Leu Arg Ala
50 55 60
Asn Ser Ala Thr Val Ser Trp Asp Val Pro Glu Gly Asn Ile Va1
65 70 75
Ile Gly Tyr Ser Ile Ser Gln Gln Arg Gln Asn Gly Pro Gly Gln
80 85 90
Arg Val Ile Arg Glu Val Asn Thr Thr Thr Arg Ala Cys Ala Leu
95 100 105
Trp Gly Leu Ala G1u Asp Ser Asp Tyr Thr Val Gln Val Arg Ser
110 115 120
Ile Gly Leu Arg Gly Glu Ser Pro Pro Gly Pro Arg Val His Phe
125 130 135
Arg Thr Leu Lys Gly Ser Asp Arg Leu Pro Ser Asn Ser Ser Ser
140 145 150
Pro Gly Asp Ile Thr Val Glu G1y Leu Asp Gly Glu Arg Pro Leu
155 160 165
Gln Thr Gly Glu Val Val Ile Ile Val Val Val Leu Leu Met Trp
170 175 180
Ala Ala Val Ile Gly Leu Phe Cys Arg Gln Tyr Asp Ile Ile Lys
185 190 195
Asp Asn Asp Ser Asn Asn Asn Pro Lys Glu Lys Gly Lys Gly Pro
200 205 210
Glu Gln Ser Pro Gln Gly Arg Pro Val Gly Thr Arg Gln Lys Lys
215 220 225
Ser Pro Ser Ile Asn Thr Ile Asp Val
230
<210> 2
<211> 443
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> 2ncyte ID No: 1794980CD1
<400> 2
Met Gly Gly Pro Arg Ala Trp Ala Leu Leu Cys Leu Gly Leu Leu
1 5 10 15
Leu Pro Gly Gly Gly Ala Ala Trp Ser Ile Gly Ala Ala Pro Phe
20 25 30
2/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Ser Gly Arg Arg Asn Trp Cys Ser Tyr Val Val Thr Arg Thr Ile
35 40 45
Ser Cys His Val Gln Asn Gly Thr Tyr Leu Gln Arg Val Leu Gln
50 . 55 60
Asn Cys Pro Trp Pro Met Ser Cys Pro Gly Ser Ser Tyr Arg Thr
65 70 75
Val Val Arg Pro Thr Tyr Lys Val Met Tyr Lys Ile Val Thr Ala
80 85 90
Arg Glu Trp Arg Cys Cys Pro Gly His Ser Gly Val Ser Cys Glu
95 100 105
Glu Val Ala Ala Ser Ser Ala Ser Leu Glu Pro Met Trp Ser Gly
110 1l5 120
Ser Thr Met Arg Arg Met Ala Leu Arg Pro Thr Ala Phe Ser Gly
125 130 135
Cys Leu Asn Cys Ser Lys Val Ser Glu Leu Thr Glu Arg Leu Lys
140 145 150
Val Leu Glu Ala Lys Met Thr Met Leu Thr Val Ile Glu Gln Pro
155 160 165
Val Pro Pro Thr Pro Ala Thr Pro Glu Asp Pro Ala Pro Leu Trp
170 175 180
Gly Pro Pro Pro Ala Gln Gly Ser Pro Gly Asp Gly Gly Leu Gln
185 190 195
Asp Gln Val Gly Ala Trp Gly Leu Pro Gly Pro Thr Gly Pro Lys
200 205 210
Gly Asp Ala Gly Ser Arg Gly Pro Met Gly Met Arg Gly Pro Pro
215 220 225
Gly Pro Gln Gly Pro Pro Gly Ser Pro Gly Arg Ala Gly Ala Val
230 235 240
Gly Thr Pro Gly Glu Arg Gly Pro Pro Gly Pro Pro Gly Pro Pro
245 250 255
Gly Pro Pro Gly Pro Pro Ala Pro Val Gly Pro Pro His Ala Arg
260 265 270
Ile Ser Gln His Gly Asp Pro Leu Leu Ser Asn Thr Phe Thr Glu
275 280 285
Thr Asn Asn His Trp Pro Gln Gly Pro Thr Gly Pro Pro Gly Pro
290 295 300
Pro Gly Pro Met Gly Pro Pro Gly Pro Pro Gly Pro Thr Gly Val
305 310 315
Pro Gly Ser Pro Gly His Ile Gly Pro Pro Gly Pro Thr Gly Pro
320 325 330
Lys Gly Ile Ser Gly His Pro Gly Glu Lys Gly Glu Arg Gly Leu
335 340 345
Arg Gly Glu Pro Gly Pro Gln Gly Ser Ala Gly Gln Arg Gly Glu
350 355 360
Pro Gly Pro Lys Gly Asp Pro Gly Glu Lys Ser His Trp Gly Glu
365 370 375
Gly Leu His Gln Leu Arg Glu Ala Leu Lys Ile Leu Ala Glu Arg
380 385 390
Val Leu Ile Leu Glu Thr Met Ile Gly Leu Tyr Glu Pro Glu Leu
395 400 405
Gly Ser Gly Ala Gly Pro Ala Gly Thr G1y Thr Pro Ser Leu Leu
410 415 420
Arg Gly Lys Arg Gly Gly His Ala Thr Asn Tyr Arg Ile Val Ala
425 430 435
Pro Arg Ser Arg Asp Glu Arg Gly
440
3/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 3
<211> 261
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 5533958CD1
<400> 3
Met Gly Gly Ala Gly Ile Leu Leu Leu Leu Leu Ala Gly Ala Gly
1 5 10 15
Val Val Val Ala Trp Arg Pro Pro Lys Gly Lys Cys Pro Leu Arg
20 25 30
Cys Ser Cys Ser Lys Asp Ser Ala Leu Cys Glu Gly Ser Pro Asp
35 40 45
Leu Pro Val Ser Phe Ser Pro Thr Leu Leu Ser Leu Ser Leu Val
50 55 60
Arg Thr Gly Val Thr Gln Leu Lys Ala Gly Ser Phe Leu Arg Ile
65 70 75
Pro Ser Leu His Leu Leu Leu Phe Thr Ser Asn Ser Phe Ser Val
80 85 90
Ile Glu Asp Asp Ala Phe Ala Gly Leu Ser His Leu Gln Tyr Leu
95 100 105
Phe Ile Glu Asp Asn Glu Ile Gly Ser Ile Ser Lys Asn Ala Leu
110 115 120
Arg Gly Leu Arg Ser Leu Thr His Leu Ser Leu Ala Asn Asn His
125 130 135
Leu Glu Thr Leu Pro Arg Phe Leu Phe Arg Gly Leu Asp Thr Leu
140 145 150
Thr His Val Asp Leu Arg Gly Asn Pro Phe Gln Cys Asp Cys Arg
155 160 165
Val Leu Trp Leu Leu Gln Trp Met Pro Thr Val Asn Ala Ser Val
170 175 180
Gly Thr Gly Ala Cys Ala Gly Pro Ala Ser Leu Ser His Met Gln
185 190 195
Leu His His Leu Asp Pro Lys Thr Phe Lys Cys Arg Ala Ile Gly
200 205 210
Gly Gly Leu Ser Arg Trp Gly Gly Arg Arg Glu Ile Trp Gly Lys
215 220 225
Gly Cys G1n Gly Gln Glu Ala Arg Leu Thr Pro Cys Pro Ala Ile
230 235 240
Ser Arg Ser Gly Lys Thr Leu Ser Lys Gln His Cys Leu Pro Glu
245 250 255
Pro Gln Phe Ser His Leu
260
<210> 4
<211> 643
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 60210196CD1
4/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<400> 4
Met Glu Pro Val Pro Leu Gln Asp Phe Val Arg Ala Leu Asp Pro
1 5 10 15
Ala Ser Leu Pro Arg Val Leu Arg Val Cys Ser Gly Val Tyr Phe
20 25 30
Glu Gly Ser Ile Tyr Glu Ile Ser Gly Asn Glu Cys Cys Leu Ser
35 40 45
Thr Gly Asp Leu Ile Lys Val Thr Gln Val Arg Leu Gln Lys Val
50 55 60
Val Cys Glu Asn Pro Lys Thr Ser Gln Thr Met Glu Leu Ala Pro
65 70 75
Asn Phe Gln Gly Tyr Phe Thr Pro Leu Asn Thr Pro Gln Ser Tyr
80 85 90
Glu Thr Leu Glu Glu Leu Val Ser Ala Thr Thr Gln Ser Ser Lys
95 100 105
Gln Leu Pro Thr Cys Phe Met Ser Thr His Arg Ile Val Thr Glu
110 115 120
Gly Arg Val Val Thr Glu Asp Gl.n Leu Leu Met Leu Glu Ala Val
125 130 135
Val Met His Leu Gly Ile Arg Ser Ala Arg Cys Val Leu Gly Met
140 145 150
Glu G1y G1n Gln Val Ile Leu His Leu Pro Leu Ser Gln Lys Gly
155 ~ 160 165
Pro Phe Trp Thr Trp Glu,Pro Ser Ala Pro Arg Thr Leu Leu Gln
170 175 180
Val Leu Gln Asp Pro Ala Leu Lys Asp Leu Val Leu Thr Cys Pro
185 190 195
Thr Leu Pro Trp His Ser Leu Ile Leu Arg Pro G1n Tyr Glu Ile
200 205 210
GIn Ala I1e Met His Met Arg Arg Thr Ile Val Lys Ile Pro Ser
215 220 225
Thr Leu Glu Val Asp Val Glu Asp Val Thr Ala Ser Sex Arg His
230 235 240
Val His Phe Ile Lys Pro Leu Leu Leu Ser Glu Val Leu Ala Trp
245 250 255
Glu Gly Pro Phe Pro Leu Ser Met G1u Ile Leu Glu Val Pro Glu
260 265 270
Gly Arg Pro Ile Phe Leu Ser Pro Trp Val Gly Ser Leu Gln Lys
275 280 285
Gly Gln Arg Leu Cys Val Tyr Gly Leu Ala Ser Pro Pro Trp Arg
290 295 300
Val Leu Ala Ser Ser Lys Gly Arg Lys Val Pro Arg His Phe Leu
305 310 315
Val Ser Gly Gly Tyr Gln Gly Lys Leu Arg Arg Arg Pro Arg Glu
320 325 330
Phe Pro Thr Ala Tyr Asp Leu Leu Gly Ala Phe Gln Pro Gly Arg
335 340 ' 345
Pro Leu Arg Val Val Ala Thr Lys Asp Cys Glu Gly Glu Arg Glu
350 355 360
y
Glu Asn Pro Glu Phe Thr Ser Leu Ala Val Gly Asp Arg Leu Glu
365 370 375
Val Leu Gly Pro Gly Gln Ala His Gly Ala Gln Gly Ser Asp Val
380 385 390
Asp Val Leu Val Cys Gln Arg Leu Ser Asp Gln Ala Gly Glu Asp
395 400 405
Glu Glu G1u Glu Cys Lys Glu Glu Ala G1u Ser Pro Glu Arg Val
5/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
410 415 420
Leu Leu Pro Phe His Phe Pro Gly Ser Phe Val Glu Glu Met Ser
425 430 435
Asp Ser Arg Arg Tyr Ser Leu Ala Asp Leu Thr Ala Gln Phe Ser
440 445 450
Leu Pro Cys Glu Val Lys Val Val Ala Lys Asp Thr Ser His Pro
455 460 465
Thr Asp Pro Leu Thr Ser Phe Leu Gly Leu Arg Leu Glu Glu Lys
470 475 480
Ile Thr Glu Pro Phe Leu Val Val Ser Leu Asp Ser G1u Pro Gly
485 490 495
Met Cys Phe Glu Ile Pro Pro Arg Trp Leu Asp Leu Thr Val Val
500 505 510
Lys Ala Lys Gly Gln Pro Asp Leu Pro Glu Gly Ser Leu Pro Ile
515 520 525
Ala Thr Val Glu Glu Leu Thr Asp Thr Phe Tyr Tyr Arg Leu Arg
530 535 540
Lys Leu Pro Ala Cys Glu Ile Gln Ala Pro Pro Pro Arg Pro Pro
545 550 555
Lys Asn Gln Gly Leu Ser Lys Gln Arg Arg His Ser Ser Glu Gly
560 565 570
Gly Val Lys Ser Ser Gln Va1 Leu Gly Leu Gln Gln His Ala Arg
575 580 585
Leu Pro Lys Pro Lys Ala Lys Thr Leu Pro Glu Phe Ile Lys Asp
590 595 600
Gly Ser Ser Thr Tyr Ser Lys Ile Pro Ala His Arg Lys Gly His
605 610 615
Arg Pro Ala Lys Pro Gln Arg Gln Asp Leu Asp Asp Asp Glu His
620 625 630
Asp Tyr Glu Glu Ile Leu Glu Gln Phe Gln Lys Thr Ile
635 640
<210> 5
<211> 628
<212> PRT
<213> Homo sapiens
<220>
<221> misc feature
<223> Incyte ID No: 815125CD1
<400> 5
Met Gly Ser Cys Ala Arg Leu Leu Leu Leu Trp Gly Cys Thr Val
1 ~ 5 10 15
Val Ala Ala Gly Leu Ser Gly Val Ala Gly Val Ser Ser Arg Cys
20 25 30
Glu Lys Ala Cys Asn Pro Arg Met Gly Asn Leu Ala Leu Gly Arg
35 40 . 45
Lys Leu Trp Ala Asp Thr Thr Cys Gly Gln Asn Ala Thr Glu Leu
50 55 60
Tyr Cys Phe Tyr Ser Glu Asn Thr Asp Leu Thr Cys Arg Gln Pro
65 70 75
Lys Cys Asp Lys Cys Asn Ala Ala Tyr Pro His Leu Ala His Leu
80 85 90
Pro Ser Ala Met Ala Asp Ser Ser Phe Arg Phe Pro Arg Thr Trp
95 100 105
6/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Trp Gln Ser Ala Glu Asp Val His Arg Glu Lys Val Gln Leu Asp
110 115 120
Leu Glu Ala Glu Phe Tyr Phe Thr His Leu Ile Val Met Phe Lys
125 130 135
Ser Pro Arg Pro Ala Ala Met Va1 Leu Asp Arg Ser Gln Asp Phe
140 145 150
Gly Lys Thr Trp Lys Pro Tyr Lys Tyr Phe Ala Thr Asn Cys Ser
155 160 165
Ala Thr Phe Gly Leu Glu Asp Asp Val Val Lys Lys Gly Ala Ile
170 175 180
Cys Thr Ser Lys Tyr Ser Ser Pro Phe Pro Cys Thr Gly Gly Glu
185 190 195
Va1 Ile Phe Lys Ala Leu Ser Pro Pro Tyr Asp Thr Glu Asn Pro
200 205 210
Tyr Ser Ala Lys Val Gln Glu Gln Leu Lys Ile Thr Asn Leu Arg
215 220 225
Val Gln Leu Leu Lys Arg Gln Ser Cys Pro Cys Gln Arg Asn Asp
230 235 240
Leu Asn Glu Glu Pro Gln His Phe Thr His Tyr Ala Ile Tyr Asp
245 250 255
Phe Ile Va1 Lys Gly Ser Cys Phe Cys Asn Gly His Ala Asp Gln
260 265 270
Cys Ile Pro Va1 His Gly Phe Arg Pro Val Lys Ala Pro Gly Thr
275 280 285
Phe His Met Val His Gly Lys Cys Met Cys Lys His Asn Thr Ala
290 295 300
Gly Ser His Cys Gln His Cys Ala Pro Leu Tyr Asn Asp Arg Pro
305 310 315
Trp Glu Ala Ala Asp Gly Lys Thr Gly Ala Pro Asn Glu Cys Arg
320 325 330
Thr Cys Lys Cys Asn Gly His Ala Asp Thr Cys His Phe Asp Val
335 340 , 345
Asn Val Trp Glu Ala Ser Gly Asn Arg Ser Gly Gly Val Cys Asp
350 355 360
Asp Cys Gln His Asn Thr Glu Gly Gln Tyr Cys Gln Arg Cys Lys
365 370 375
Pro Gly Phe Tyr Arg Asp Leu Arg Arg Pro Phe Ser Ala Pro Asp
380 385 390
Ala Cys Lys Pro Cys Ser Cys His Pro Val Gly Ser Ala.Val Leu
395 400 405
Pro Ala Asn Ser Val Thr Phe Cys Asp Pro Ser Asn Gly Asp Cys
410 415 420
Pro Cys Lys Pro Gly Val Ala G1y Arg Arg Cys Asp Arg Cys Met
425 430 435
Val Gly Tyr Trp Gly Phe Gly Asp Tyr Gly Cys Arg Pro Cys Asp
440 445 450
Cys Ala Gly Ser Cys Asp Pro I1e Thr Gly Asp Cys Ile Ser Ser
455 460 465
His Thr Asp Ile Asp Trp Tyr His Glu Val Pro Asp Phe Arg Pro
470 475 480
Val His Asn Lys Ser Glu Pro Ala Trp G1u Trp Glu Asp Ala Gln
485 490 495
Gly Phe Ser Ala Leu Leu His Ser Gly Lys Cys Glu Cys Lys Glu
500 505 510
Gln Thr Leu Gly Asn Ala Lys Ala Phe Cys Gly Met Lys Tyr Ser
515 520 525
7/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Tyr Val Leu Lys Ile Lys Ile Leu Ser Ala His Asp Lys Gly Thr
530 535 540
His Val Glu Val Asn Val Lys Ile Lys Lys Val Leu Lys Ser Thr
545 550 555
Lys Leu Lys Ile Phe Arg Gly Lys Arg Thr Leu Tyr Pro Glu Ser
560 565 570
Trp Thr Asp Arg Gly Cys Thr Cys Pro Ile Leu Asn Pro Gly Leu
575 580 585
Glu Tyr Leu Val Ala Gly His Glu Asp Ile Arg Thr Gly Lys Leu
590 595 600
Ile Val Asn Met Lys Ser Phe Val G1n His Trp Lys Pro Ser Leu
605 610 615
Gly Arg Lys Val Met Asp Ile Leu Lys Arg Glu Cys Lys
620 625
<210> 6
<211> 686
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1386915CD1
<400> 6
Met Leu Leu Arg Gly Val Leu Leu Ala Leu Gln Ala Leu Gln Leu
1 5 10 15
Ala Gly Ala Leu Asp Leu Pro Ala Gly Ser Cys Ala Phe Glu Glu
20 25 30
Ser Thr Cys Gly Phe Asp Ser VaI Leu Ala Ser Leu Pro Trp Ile
35 40 ~ 45
Leu Asn Glu Glu Gly His Tyr.Ile Tyr Val Asp Thr Ser Phe Gly
50 55 60
Lys Gln Gly Glu Lys Ala Val Leu Leu Ser Pro Asp Leu Gln Ala
65 70 75
Glu Gl.u Trp Ser Cys Leu Arg Leu Val Tyr Gln Ile Thr Thr Ser
80 85 90
Ser Glu Ser Leu Ser Asp Pro Ser Gln Leu Asn Leu Tyr Met Arg
95 l00 105
Phe Glu Asp Glu Ser Phe Asp Arg Leu Leu Trp Ser Ala Lys Glu
110 115 120
Pro Ser Asp Ser Trp Leu Ile Ala Ser Leu Asp Leu Gln Asn Ser
125 130 135
Ser Lys Lys Phe Lys Ile Leu Ile Glu Gly Val Leu Gly Gln Gly
140 145 150
Asn Thr Ala Ser Ile Ala Leu Phe Glu Ile Lys Met Thr Thr Gly
155 160 165
Tyr Cys Ile Glu Cys Asp Phe Glu Glu Asn His Leu Cys Gly Phe
170 175 180
Val Asn Arg Trp Asn Pro Asn Val Asn Trp Phe Val Gly Gly Gly
185 190 195
Ser Ile Arg Asn Val His Ser Ile Leu Pro Gln Asp His Thr Phe
200 205 210
Lys Ser Glu Leu G1y His Tyr Met Tyr Val Asp Ser Val Tyr Val
215 220 225
Lys His Phe Gln Glu Val Ala Gln Leu Ile Ser Pro Leu Thr Thr
8/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
230 235 240
Ala Pro Met Ala Gly Cys Leu Ser Phe Tyr Tyr Gln Ile Gln Gln
245 250 255
Gly Asn Asp Asn Val Phe Ser Leu Tyr Thr Arg Asp Val Ala Gly
260 265 270
Leu Tyr Glu Glu Ile Trp Lys Ala Asp Arg Pro Gly Asn Ala Ala
275 280 285
Trp Asn Leu Ala Glu Val Glu Phe Asn Ala Pro Tyr Pro Met Glu
290 295 300
Val Ile Phe Glu Val Ala Phe Asn Gly Pro Lys Gly Gly Tyr Val
305 310 315
Ala Leu Asp Asp Ile Ser Phe Ser Pro Val His Cys Gln Asn Gln
320 325 330
Thr Glu Leu Leu Phe Ser Ala Val Glu Ala Ser Cys Asn Phe Glu
335 340 345
Gln Asp Leu Cys Asn Phe Tyr Gln Asp Lys Glu Gly Pro Gly Trp
350 355 360
Thr Arg Val Lys Val Lys Pro Asn Met Tyr Arg Ala Gly Asp His
365 370 375
Thr Thr Gly Leu G1y Tyr Tyr Leu Leu Ala Asn Thr Lys Phe Thr
380 ~ 385 390
Ser Gln Pro Gly Tyr Ile Gly Arg Leu Tyr Gly Pro Ser Leu Pro
395 400 405
Gly Asn Leu Gln Tyr Cys Leu Arg Phe His Tyr Ala Ile Tyr Gly
410 415 420
Phe Leu Lys Met Ser Asp Thr Leu Ala Val Tyr Ile Phe Glu Glu
425 430 435
Asn His Val Val Gln Glu Lys Ile Trp Ser Val Leu Glu Ser Pro
440 445 450
Arg G1y Val Trp Met Gln Ala G1u Ile Thr Phe Lys Lys Pro Met
455 460 465
Pro Thr Lys Val Val Phe Met Ser Leu Cys Lys Ser Phe Trp Asp
470 475 480
Cys Gly Leu Val Ala Leu Asp Asp Ile Thr Ile Gln Leu Gly Ser
485 490 495
Cys Ser Ser Ser Glu Lys Leu Pro Pro Pro Pro Gly Glu Cys Thr
500 505 510
Phe Glu Gln Asp G1u Cys Thr Phe Thr Gln Glu Lys Arg Asn Arg
515 520 525
Ser Ser Trp His Arg Arg Arg Gly Glu Thr Pro Thr Ser Tyr Thr
530 535, 540
Gly Pro Lys Gly Asp His Thr Thr Gly Val Gly Tyr Tyr Met Tyr
545 550 555
Ile Glu A1a Ser His Met Val Tyr Gly Gln Lys Ala Arg Leu Leu
560 565 570
Ser Arg Pro Leu Arg Gly Val Ser Gly Lys His Cys Leu Thr Phe
575 580 585
Phe Tyr His Met Tyr Gly Gly Gly Thr Gly Leu Leu Sex Val Tyr
590 595 600
Leu Lys Lys Glu Glu Asp Ser Glu Glu Ser Leu Leu Trp Arg Arg
605 610 615
Arg Gly Glu Gln Ser Ile Ser Trp Leu Arg Ala Leu I1e Glu Tyr
620 625 630
Ser Cys Glu Arg Gln His Gln Ile Ile Phe Glu Ala Ile Arg Gly
635 640 645
Val Ser Ile Arg Ser Asp Ile Ala Ile Asp Asp Val Lys Phe Gln
9/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
650 655 660
Ala Gly Pro Cys Gly Glu Met Glu Asp Thr Thr Gln Gln Ser Ser
665 670 675
Gly Tyr Ser Glu Asp Leu Asn Glu Ile Glu Tyr
680 685
<210> 7
<211> 296
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1344495CD1
<400> 7
Met Arg His Glu Glu Leu Leu Thr Lys Thr Phe Gln Gly Pro~Ala
1 5 10 15
Val Val Cys Gly Thr Pro Thr Ser His Val Tyr Met Phe Lys Asn
20 25 30
Gly Ser Gly Asp Ser Gly Asp Ser Ser Glu Glu Glu Ser His Arg
35 40 45
Val Val Leu Arg Pro Arg Gly Lys Glu Arg His Lys Ser Gly Val
50 55 60
His Gln Pro Pro Gln Ala Gly Ala Gly Asp Val Val Leu Leu Gln
65 70 75
Arg Glu Leu Ala Gln Glu Asp Ser Leu Asn Lys Leu Ala Leu Gln
80 ' 85 90
Tyr Gly Cys Lys Val Ala Asp Tle Lys Lys Val Asn Asn Phe Ile
95 100 ~ 105
Arg Glu Gln Asp Leu Tyr Ala Leu Lys Ser Val Lys Ile Pro Val
110 115 120
Arg Asn His Gly Ile Leu Met G1u Thr His Lys Glu Leu Lys Pro
125 130 ' 135
Leu Leu Ser Pro Ser Ser Glu Thr Thr Val Thr Val Glu Leu Pro
140 145 150
Glu Ala Asp Arg Ala G1y Ala Gly Thr Gly Ala G1n Ala Gly Gln
155 160 165
Leu Met Gly Phe Phe Lys Gly Ile Asp Gln Asp Ile Glu Arg Ala
170 175 180
Va1 GIn Ser Glu Ile Phe Leu His Glu Ser Tyr Cys Met Asp Thr
185 190 195
Ser His Gln Pro Leu Leu Pro Ala Pro Pro Lys Thr Pro Met Asp
200 205 210
Gly Ala Asp Cys Gly Ile Gln Trp Trp Asn Ala Val Phe Ile Met
215 220 225
Leu Leu Ile Gly Ile Val Leu Pro Val Phe Tyr Leu Val Tyr Phe
230 235 240
Lys Ile Gln Ala Ser Gly Glu Thr Pro Asn Ser Leu Asn Thr Thr
245 250 255
Val Ile Pro Asn Gly Ser Met Ala Met Gly Thr Val Pro Gly Gln
260 265 270
Ala Pro Arg Leu Ala Val Ala Val Pro Ala Val Thr Ser Ala Asp
275 280 285
Ser Gln Phe Ser Gln Thr Thr Gln Ala Gly Ser
290 295
10/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 8
<211> 575
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1485774CD1
<400> 8
Met Ala Lys Pro Phe Phe Arg Leu Gln Lys Phe Leu Arg Arg Thr
1 5 10 15
Gln Phe Leu Leu Phe Phe Leu Thr Ala Ala Tyr Leu Met Thr Gly
20 25 30
Ser Leu Leu Leu Leu Gln Arg Val Arg Val Ala Leu Pro Gln Gly
35 40 45
Pro Arg Ala Pro Gly Pro Leu Gln Thr Leu Pro Val Ala Ala Val
50 55 60
Ala Leu Gly Val Gly Leu Leu Asp Ser Arg Ala Lieu His Asp Pro
65 70 75
Arg Val Ser Pro Glu Leu Leu Leu Gly Val Asp Met Leu Gln Ser
80 85 90
Pro Leu Thr Arg Pro Arg Pro G1y Pro Arg Trp Leu Arg Ser Arg
95 100 105
Asn Ser Glu Leu Arg Gln Leu Arg Arg Arg Trp Phe His His Phe
110 115 120
Met Ser Asp Ser Gln Gly Pro Pro Ala Leu Gly Pro Glu Ala Ala
125 130 135
Arg Pro Ala Ile His Ser Arg Gly Thr Tyr Ile Gly Cys Phe Ser
140 145 150
Asp Asp Gly His Glu Arg Thr Leu Lys G1y Ala Val Phe Tyr Asp
155 160 165
Leu Arg Lys Met Thr Val Ser His Cys Gln Asp Ala Cys Ala Glu
170 175 180
Arg Ser Tyr Val Tyr Ala Gly Leu Glu Ala Gly Ala Glu Cys Tyr
185 190 195
Cys Gly Asn Arg Leu Pro Ala Val Ser Val Gly Leu Glu Glu Cys
200 205 210
Asn His Glu Cys Lys Gly Glu Lys Gly Ser Val Cys Gly Ala Va1
215 220 225
Asp Arg Leu Ser Val Tyr Arg Val Asp Glu Leu Gln Pro Gly Ser
230 235 240
Arg Lys Arg Arg Thr Ala Thr Tyr Arg Gly Cys Phe Arg Leu Pro
245 250 255
Glu Asn Ile Thr His Ala Phe Pro Ser Ser Leu Ile Gln Ala Asn
260 265 270
Val Thr Va1 Gly Thr Cys Ser Gly Phe Cys Ser Gln Lys Glu Phe
275 280 285
Pro Leu Ala Ile Leu Arg Gly Trp Glu Cys Tyr Cys Ala Tyr Pro
290 295 300
Thr Pro Arg Phe Asn Leu Arg Asp Ala Met Asp Ser Ser Va1 Cys
305 310 315
Gly Gln Asp Pro Glu Ala Gln Arg Leu Ala Glu Tyr Cys Glu Val
320 ,325 330
Tyr Gln Thr Pro Val Gln Asp Thr Arg Cys Thr Asp Arg Arg Phe
335 340 345
11/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Leu Pro Asn Lys Ser Lys Val Phe Val Ala Leu Ser Ser Phe Pro
350 355 360
Gly Ala Gly Asn Thr Trp Ala Arg His Leu Ile Glu His Ala Thr
365 370 375
Gly Phe Tyr Thr Gly Ser Tyr Tyr Phe Asp Gly Thr Leu Tyr Asn
380 385 390
Lys Gly Phe Lys Gly Glu Lys Asp His Trp Arg Ser Arg Arg Thr
395 400 405
Ile Cys Val Lys Thr His Glu Ser Gly Arg Arg Glu Ile Glu Met
410 415 420
Ser Asp Ser Ala Ile Leu Leu Ile Arg Asn Pro Tyr Arg Ser Leu
425 430 435
Val Ala Glu Phe Asn Arg Lys Cys Ala Gly His Leu Gly Tyr Ala
440 445 450
Ala Asp Arg Asn Trp Lys Ser Lys Glu Trp Pro Asp Phe Val Asn
455 460 465
Ser Tyr Ala Ser Trp Trp Ser Ser His Val Leu Asp Trp Leu Lys
470 475 480
Tyr Gly Lys Arg Leu Leu Val Val His Tyr Glu Glu Leu Arg Arg
485 490 495
Ser Leu Val Pro Thr Leu Arg Glu Met Val Ala Phe Leu Asn Val
500 505 510
Ser Val Ser Glu Glu Arg Leu Leu Cys Val Glu Asn Asn Lys Glu
515 520 525
Gly Ser Phe Arg Arg Arg Gly Arg Arg Ser His Asp Pro Glu Pro
530 535 540
Phe Thr Pro Glu Met Lys Asp Leu Ile Asn Gly Tyr Ile Arg Thr
545 550 555
Val Asp Gln Ala Leu Arg Asp His Asn Trp Thr Gly Leu Pro Arg
560 565 570
Glu Tyr Val Pro Arg
575
<210> 9
<211> 592
<212> PRT
<2l3> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 7289372CD1
<400> 9
Met Phe Pro Leu Arg Ala Leu Trp Leu Val Trp Ala Leu Leu Gly
1 5 10 15
Val Ala Gly Ser Cys Pro Glu Pro Cys Ala Cys Val Asp Lys Tyr
20 25 30
Ala His Gln Phe Ala Asp Cys Ala Tyr Lys Glu Leu Arg Glu Val
35 40 45
Pro Glu Gly Leu Pro Ala Asn Val Thr Thr Leu Ser Leu Ser Ala
50 ~ 55 60
Asn Lys Ile Thr Val Leu Arg Arg Gly Ala Phe Ala Asp Val Thr
65 70 75
Gln Val Thr Ser Leu Trp Leu Ala His Asn Glu Val Arg Thr Val
80 85 90
Glu Pro Gly Ala Leu Ala Val Leu Ser Gln Leu Lys Asn Leu Asp
12/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
95 100 105
Leu Ser His Asn Phe Ile Ser Ser Phe Pro Trp Ser Asp Leu Arg
110 115 120
Asn Leu Ser Ala Leu Gln Leu Leu Lys Met Asn His Asn Arg Leu
125 130 135
Gly Ser Leu Pro Arg Asp Ala Leu Gly Ala Leu Pro Asp Leu Arg
140 145 150
Ser Leu Arg Ile Asn Asn Asn Arg Leu Arg Thr Leu A1a Pro Gly
155 160 165
Thr Phe Asp Ala Leu Ser Ala Leu Ser His Leu Gln Leu Tyr His
170 175 180
Asn Pro Phe His Cys Gly Cys Gly Leu Va1 Trp Leu Gln Ala Trp
185 190 195
Ala Ala Ser Thr Arg Val Ser Leu Pro Glu Pro Asp Ser Ile Ala
200 205 210
Cys Ala Ser Pro Pro Ala Leu Gln Gly Va1 Pro Val Tyr Arg Leu
215 220 225
Pro Ala Leu Pro Cys Ala Pro Pro Ser Val His Leu Ser Ala Glu
230 235 240
Pro Pro Leu Glu Ala Pro Gly Thr Pro Leu Arg Ala Gly Leu Ala
245 250 255
Phe Val Leu His Cys Ile Ala Asp Gly His Pro Thr Pro Arg Leu
260 265 270
Gln Trp Gln Leu Gln Ile Pro Gly Gly Thr Val Val Leu Glu Pro
275 280 285
Pro Val Leu Ser Gly Glu Asp Asp Gly Val Gly Ala Glu Glu Gly
290 295 300
Glu Gly Glu Gly Asp Gly Asp Leu Leu Thr Gln Thr Gln Ala Gln
305 310 315
Thr Pro Thr Pro Ala Pro Ala Trp Pro Ala Pro Pro Ala Thr Pro
320 325 330
Arg Phe Leu Ala Leu Ala Asn Gly Ser Leu Leu Val Pro Leu Leu
335 340 345
Ser Ala Lys Glu Ala Gly Val Tyr Thr Cys Arg Ala His Asn Glu
350 355 360
Leu Gly Ala Asn Ser Thr Ser Ile Arg Val Ala Val Ala Ala Thr
365 370 375
Gly Pro Pro Lys His Ala Pro Gly Ala Gly Gly Glu Pro Asp Gly
380 385 390
Gln Ala Pro Thr Ser Glu Arg Lys Ser Thr Ala Lys Gly Arg Gly
395 400 405
Asn Ser Val Leu Pro Ser Lys Pro Glu Gly Lys Ile Lys Gly Gln
410 415 420
Gly Leu Ala Lys Val Ser Ile Leu G1y Glu Thr Glu Thr Glu Pro
425 430 435
Glu Glu Asp Thr Ser Glu Gly Glu Glu Ala Glu Asp Gln Ile Leu
440 445 450
Ala Asp Pro Ala Glu Glu Gln Arg Cys Gly Asn Gly Asp Pro Ser
455 460 465
Arg Tyr Val Ser Asn His Ala Phe Asn Gln Ser Ala Glu Leu Lys
470 475 480
Pro His Val Phe Glu Leu Gly Val Ile Ala Leu Asp Val Ala Glu
485 490 495
Arg Glu Ala Arg Val Gln Leu Thr Pro Leu Ala Ala Arg Trp Gly
500 505 510
Pro Gly Pro Gly Gly Ala Gly Gly Ala Pro Arg Pro Gly Arg Arg
13/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
515 520 525
Pro Leu Arg Leu Leu Tyr Leu Cys Pro Ala Gly Gly Gly Ala Ala
530 535 540
Val Gln Trp Ser Arg Val Glu Glu Gly Val Asn Ala Tyr Trp Phe
545 550 555
Arg G1y Leu Arg Pro Gly Thr Asn Tyr Ser Val Cys Leu Ala Leu
560 565 570
Ala Gly Glu Ala Cys His Va1 Gln Val Val Phe Pro Pro Arg Arg
575 580 585
Ser Ser His Arg Cys Trp Ser
590
<210> 10
<211> 255
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1672338CD1
<400> 10
Met Ala Leu Pro Ala Leu Gly Leu Asp Pro Trp Ser Leu Leu Gly
1 5 10 15
Leu Phe Leu Phe Gln Leu Leu Gln Leu Leu Leu Pro Thr Thr Thr
20 25 30
Ala Gly Gly Gly Gly Gln Gly Pro Met Pro Arg Val Arg Tyr Tyr
35 40 45
Ala Gly Asp Glu Arg Arg Ala Leu Ser Phe Phe His Gln Lys Gly
50 55 60
Leu Gln Asp Phe Asp Thr Leu Leu Leu Ser Gly Asp Gly Asn Thr
65 70 75
Leu Tyr Val Gly Ala Arg Glu Ala Ile Leu A1a Leu Asp Ile Gln
80 85 ' 90
Asp Pro Gly Val Pro Arg Leu Lys Asn Met Ile Pro Trp Pro Ala
95 100 105
Ser Asp Arg Lys Lys Ser Glu Cys Ala Phe Lys Lys Lys Ser Asn
110 115 120
Glu Thr Gln Cys Phe Asn Phe Ile Arg Va1 Leu Val Ser Tyr Asn
125 130 135
Val Thr His Leu Tyr Thr Cys Gly Thr Phe Ala Phe Ser Pro Ala
140 145 150
Cys Thr Phe Ile Val Ser Ser Leu Val Pro Ser Ala Gln Ala Pro
155 160 165
Lys His Pro Phe Ser His Leu Pro Thr Thr Phe Leu Cys Ser Ser
170 175 180
Gly Lys Leu Trp Pro Ser Arg Cys Arg Thr Leu Met Asn Phe Leu
185 190 195
Ala Pro Asp Gln Phe Pro Ser Met Ser Leu Ser Leu Pro Ser Ser
200 205 210
Ser Pro Ser Phe Pro Arg Cys Glu Thr Leu Ala Phe Trp Pro Pro
215 220 225
Ser Leu Ser Pro His Leu Gly Thr Ser Arg Phe Leu Pro Val Ala
230 235 240
His Leu Gly Gly Gln Gly His Gly Gly Lys Arg Pro Lys Pro Leu
245 250 255
14/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 11
<211> 641
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 184661CD1
<400> 11
Met Va1 Pro Gly Ala Arg Gly Gly Gly Ala Leu Ala Arg Ala Ala
1 5 10 15
Gly Arg Gly Leu Leu Ala Leu Leu Leu Ala Val Ser Ala Pro Leu
20 25 30
Arg Leu Gln Ala Glu Glu Leu Gly Asp Gly Cys Gly His Leu Val
35 40 45
Thr Tyr Gln Asp Ser Gly Thr Met Thr Ser Lys Asn Tyr Pro Gly
50 55 60
Thr Tyr Pro Asn His Thr Val Cys Glu Lys Thr Ile Thr Val Pro
65 70 75
Lys Gly Lys Arg Leu Ile Leu Arg Leu Gly Asp Leu Asp Ile Glu
80 85 90
Ser Gln Thr Cys Ala Ser Asp Tyr Leu Leu Phe Thr Ser Ser Ser
95 100 105
Asp G1n Tyr Gly Pro Tyr Cys Gly Ser Met Thr Val Pro Lys Glu
110 115 120
Leu Leu Leu Asn Thr Ser Glu Val Thr Val Arg Phe Glu Ser Gly
125 130 135
Ser His Ile Ser Gly Arg Gly Phe Leu Leu Thr Tyr AIa Ser Ser
140 145 150
Asp His Pro Asp Leu Ile Thr Cys Leu Glu Arg Ala Ser His Tyr
155 160 165
Leu Lys Thr Glu Tyr Ser Lys Phe Cys Pro Ala Gly Cys Arg Asp
170 175 180
Val Ala Gly Asp Ile Ser Gly Asn Met Val Asp Gly Tyr Arg Asp
185 190 195
Thr Ser Leu Leu Cys Lys Ala Ala Ile His Ala Gly Ile Ile Ala
200 205 210
Asp Glu Leu Gly Gly Gln Ile Ser Val Leu Gln Arg Lys Gly Ile
215 220 225
Ser Arg Tyr Glu Gly Ile Leu Ala Asn Gly Val Leu Ser Arg Asp
230 235 240
Gly Ser Leu Ser Asp Lys Arg Phe Leu Phe Thr Ser Asn Gly Cys
245 250 255
Ser Arg Ser Leu Ser Phe Glu Pro Asp Gly Gln Ile Arg Ala Ser
260 265 270
Ser Ser Trp Gln Ser Val Asn Glu Ser Gly Asp Gln Val His Trp
275 280 285
Ser Pro Gly Gln Ala Arg Leu Gln Asp Gln Gly Pro Ser Trp Ala
290 295 300
Ser Gly Asp Ser Ser Asn Asn His Lys Pro Arg Glu Trp Leu Glu
305 310 315
Ile Asp Leu Gly Glu Lys Lys Lys Ile Thr Gly Ile Arg Thr Thr
320 325 330
Gly Ser Thr Gln Ser Asn Phe Asn Phe Tyr Val Lys Ser Phe Val
15/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
335 340 345
Met Asn Phe Lys Asn Asn Asn Ser Lys Trp Lys Thr Tyr Lys GIy
350 355 360
Ile Va1 Asn Asri Glu Glu Lys Val Phe G1n Gly Asn Ser Asn Phe
365 370 375
Arg Asp Pro Val Gln Asn Asn Phe Ile Pro Pro Ile Val Ala Arg
380 385 390
Tyr Val Arg Val Val Pro Gln Thr Trp His Gln Arg Ile Ala Leu
395 400 405
Lys Val Glu Leu Ile Gly Cys Gln Ile Thr Gln Gly Asn Asp Ser
410 415 420
Leu Val Trp Arg Lys Thr Ser Gln Ser Thr Ser Val Ser Thr Lys
425 430 435
Lys Glu Asp Glu Thr Ile Thr Arg Pro Ile Pro Ser Glu Glu Thr
440 445 450
Ser Thr Gly Ile Asn Ile Thr Thr Val Ala Ile Pro Leu Val Leu
455 460 465
Leu Val Val Leu Val Phe Ala Gly Met Gly Ile Phe Ala A1a Phe
470 475 480
Arg Lys Lys Lys Lys Lys Gly Ser Pro Tyr Gly Ser Ala Glu Ala
485 490 495
Gln Lys Thr Asp Cys Trp Lys Gln Ile Lys Tyr Pro Phe Ala Arg
500 505 510
His Gln Ser Ala Glu Phe Thr Ile Ser Tyr Asp Asn Glu Lys Glu
515 520 525
Met Thr Gln Lys Leu Asp Leu Ile Thr Ser Asp Met Ala Asp Tyr
530 535 540
Gln Gln Pro Leu Met I1e Gly Thr Gly Thr Val Thr Arg Lys Gly
545 550 555
Ser Thr Phe Arg Pro Met Asp Thr Asp Ala Glu Glu Ala Gly Val
560 565 570
Ser Thr Asp Ala Gly Gly His Tyr Asp Cys Pro Gln Arg A1a Gly
575 580 585
Arg His Glu Tyr Ala Leu Pro Trp Arg Pro Arg Ser Pro Ser Thr
590 595 600
Pro Arg Pro Ser Trp Ser Gly Thr Cys Cys Ala Pro Thr Arg Ser
605 610 615
Leu Arg Arg Ala Ala Thr Ala Ser Gln Gly Pro Ser Pro Ala Thr
620 625 630
Asn Thr Pro Ser Pro Arg Ala Ala Ser Pro Pro
635 640 ,'
<210> 12
<211> 924
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 3719737CD1
<400> 12
Met Gly Arg Leu His Arg Pro Arg Ser Ser Thr Ser Tyr.Arg Asn
1 5 10 15
Leu Pro His Leu Phe Leu Phe Phe Leu Phe Val Gly Pro Phe Ser
20 25 30
16/123
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Cys Leu Gly Ser Tyr Ser Arg Ala Thr Glu Leu Leu Tyr Ser Leu
35 40 45
Asn Glu Gly Leu Pro A1a Gly Val Leu Ile Gly Ser Leu Ala Glu
50 55 60
Asp Leu Arg Leu Leu Pro Arg Ser Ala Gly Arg Pro Asp Pro Gln
65 70 75
Ser Gln Leu Pro Glu Arg Thr Gly Ala Glu Trp Asn Pro Pro Leu
80 85 90
Ser Phe Ser Leu Ala Ser Arg Gly Leu Ser Gly Gln Tyr Val Thr
95 l00 105
Leu Asp Asn Arg Ser Gly Glu Leu His Thr Ser Ala Gln Glu Ile
110 115 120
Asp Arg Glu Ala Leu Cys Val Glu Gly Gly Gly Gly Thr Ala Trp
125 130 135
Ser Gly Ser Val Ser Ile Ser Ser Ser Pro Ser Asp Ser Cys Leu
l40 145 150
Leu Leu Leu Asp Val Leu Val Leu Pro Gln Glu Tyr Phe Arg Phe
155 160 165
Val Lys Val Lys I1e Ala Ile Arg Asp Ile Asn Asp Asn Ala Pro
170 175 l80
Gln Phe Pro Val Ser Gln Ile Ser Val Trp Val Pro Glu Asn Ala
185 l90 195
Pro Val Asn Thr Arg Leu Ala Ile Glu His4Pro Ala Val Asp Pro
200 205 210
Asp Val Gly Ile Asn Gly Val Gln Thr Tyr Arg Leu Leu Asp Tyr
215 220 225
His Gly Met Phe Thr Leu Asp Val Glu Glu Asn Glu Asn Gly Glu
230 235 240
Arg Thr Pro Tyr Leu Ile Val Met Gly Ala Leu Asp Arg Glu Thr
245 250 255
Gln Asp Gln Tyr Val Ser Ile Ile I1e Ala Glu Asp Gly Gly Ser
260 265 270
Pro Pro Leu Leu Gly Ser Ala Thr Leu Thr Ile Gly Ile Ser Asp
275 280 285
Ile Asn Asp Asn Cys Pro Leu Phe Thr Asp Ser Gln Ile Asn Val
290 295 300
Thr Val Tyr Gly Asn Ala Thr Val G1y Thr Pro Ile Ala Ala 'Val
305 310 315
Gln Ala Val Asp Lys Asp Leu Gly Thr Asn A1a Gln Ile Thr Tyr
320 325 330
Ser Tyr Ser Gln Lys Val Pro Gln Ala Ser Lys Asp Leu Phe His
335 340 345
Leu Asp Glu Asn Thr Gly Val Ile Lys Leu Phe Ser Lys I1e Gly
350 355 360
Gly Ser Val Leu Glu Ser His Lys Leu Thr Ile Leu Ala Asn Gly
365 370 375
Pro Gly Cys Ile Pro Ala Va1 Ile Thr Ala Leu Val Ser Ile Ile
380 385 390
Lys Val Ile Phe Arg Pro Pro Glu Ile Val Pro Arg Tyr Ile Ala
395 400 405
Asn Glu Ile Asp Gly Val Val Tyr Leu Lys Glu Leu Glu Pro Val
420 415 420
Asn Thr Pro Ile Ala Phe Phe Thr Ile Arg Asp Pro Glu Gly Lys
425 430 435
Tyr Lys Val Asn Cys Tyr Leu Asp Gly Glu Gly Pro Phe Arg Leu
440 445 450
17/123
CA 02413186 2002-12-27
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Ser Pro Tyr Lys Pro Tyr Asn Asn Glu Tyr Leu Leu Glu Thr Thr
455 460 465
Lys Pro Met Asp Tyr Glu Leu Gln Gln Phe Tyr Glu Val Ala Val
470 475 480
Val Ala Trp Asn Ser Glu Gly Phe His Val Lys Arg Val Ile Lys
485 490 495
Val Gln Leu Leu Asp Asp Asn Asp Asn A1a Pro Ile Phe Leu Gln
500 505 510
Pro Leu Ile Glu Leu Thr Tle Glu Glu Asn Asn Ser Pro Asn Ala
515 520 525
Phe Leu Thr Lys Leu Tyr Ala Thr Asp Ala Asp Ser Glu Glu Arg
530 535 540
Gly Gln Val Ser Tyr Phe Leu Gly Pro Asp Ala Pro Ser Tyr Phe
545 550 555
Ser Leu Asp Ser Val Thr Gly Ile Leu Thr Val Ser Thr Gln Leu
560 565 570
Asp Arg Glu Glu Lys Glu Lys Tyr Arg Tyr Thr Val Arg A1a Val
575 580 585
Asp Cys Gly Lys Pro Pro Arg Glu Ser Va1 Ala Thr Val Ala Leu
590 595 600
Thr Val Leu Asp Lys Asn Asp Asn Ser Pro Arg Phe Ile Asn Lys
605 610 615
Asp Phe Ser Phe Phe Val Pro Glu Asn Phe Pro Gly Tyr Gly Glu
620 625 630
Ile Gly Val Ile Ser Val Thr Asp Ala Asp Ala Gly Arg Asn Gly
635 640 645
Trp Val Ala Leu Ser Val Val Asn Gln Ser Asp Ile Phe Val Ile
650 655 660
Asp Thr Gly Lys Gly Met Leu Arg Ala Lys Val Ser Leu Asp Arg
665 670 675
Glu Gln Gln Ser Ser Tyr Thr Leu Trp Val Glu Ala Val Asp Gly
680 685 690
Gly Glu Pro Ala Leu Ser Ser Thr Ala Lys Ile Thr Ile Leu Leu
695 700 705
Leu Asp Ile Asn Asp Asn Pro Pro Leu Val Leu Phe Pro Gln Ser
710 715 720
Asn Met Ser Tyr Leu Leu Val Leu Pro Ser Thr Leu Pro Gly Ser
725 730 735
Pro Val Thr Glu Val Tyr Ala Val Asp Lys Asp Thr Gly Met Asn
740 745 750
Ala Val Ile Ala Tyr Ser Ile I1e Gly Arg Arg Gly Pro Arg Pro
755 760 7,65
Glu Ser Phe Arg Ile Asp Pro Lys Thr Gly Asn Ile Thr Leu Glu
770 775 i 780
Glu Ala Leu Leu Gln Thr Asp Tyr Gly Leu His Arg Leu Leu Val
785 790 795
Lys Val Ser Asp His Gly Tyr Pro Glu Pro Leu His Ser Thr Val
800 805 810
Met Va1 Asn Leu Phe Val Asn Asp Thr Val Ser Asn Glu Ser Tyr
815 820 825
Ile Glu Ser Leu Leu Arg Lys Glu Pro Glu Ile Asn Ile Glu Glu
830 835 840
Lys Glu Pro Gln Ile Ser Tle Glu Pro Thr His Arg Lys Val Glu
845 850 855
Ser Val Ser Cys Met Pro Thr Leu Val Ala Leu Ser Val Ile Ser
860 865 870
28/123
CA 02413186 2002-12-27
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Leu G1y Ser Ile Thr Leu Val Thr Gly Met Gly Ile Tyr Ile Cys
875 880 885
Leu Arg Lys Gly Glu Lys His Pro Arg G1u Asp Glu Asn Leu Glu
890 895 900
Val Gln Ile Pro Leu Lys Gly Lys Ile Asp Leu His Met Arg Glu
905 910 915
Arg Lys Pro Met Asp Ile Ser Asn Ile
920
<210> 13
<211> 987
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 5773251CD1
<400> 13
Met Arg Ile Ser Ser Cys Ser Asp Glu Ser Ser Asn Ser Asn Ser
1 5 10 25
Ser Arg Lys Ser Asp Asn His Ser Pro Ala Val Val Thr Thr Thr
20 25 30
Val Ser Ser Lys Lys Gln Pro Ser Val Leu Val Thr Phe Pro Lys
35 40 45
Glu Glu Arg Lys Ser Val Ser Gly Lys Ala Ser Ile Lys Leu Ser
50 55 60
Glu Thr I1e Ser G1u Gly Thr Ser Asn Ser Leu Ser Thr Cys Thr
65 70 75
Lys Ser Gly Pro Ser Pro Leu Ser Ser Pro Asn Gly Lys Leu Thr
80 85 90
Val Ala Ser Pro Lys Arg Gly Gln Lys Arg Glu Glu Gly Trp Lys
95 100 105
Glu Val Val Arg Arg Ser Lys Lys Val Ser Val Pro Ser Thr Val
110 115 120
Ile Ser Arg Val Ile Gly Arg Gly Gly Cys Asn Ile Asn Ala Ile
125 130 135
Arg Glu Phe Thr Gly Ala His Ile Asp Ile Asp Lys Gln Lys Asp
140 145 150
Lys Thr Gly Asp Arg Ile Ile Thr Ile Arg Gly Gly Thr Glu Ser
155 160 165
Thr Arg Gln Ala Thr Gln Leu Ile Asn Ala Leu Ile Lys Asp Pro
170 175 180
Asp Lys Glu Ile Asp Glu Leu Ile Pro Lys Asn Arg Leu Lys Ser
185 190 195
Ser Ser Ala Asn Ser Lys Ile Gly Ser Ser Ala Pro Thr Thr Thr
200 205 210
Ala A1a Asn Thr Ser Leu Met Gly Ile Lys Met Thr Thr Val A1a
215 220 225
Leu Ser Ser Thr Ser Gln Thr Ala Thr Ala Leu Thr Val Pro Ala
230 235 240
Ile Ser Ser Ala Ser Thr His Lys Thr Ile Lys Asn Pro Val Asn
245 250 255
Asn Val Arg Pro Gly Phe Pro Val Ser Leu Pro Leu Ala Tyr Pro
260 265 270
Pro Pro Gln Phe Ala His Ala Leu Leu Ala Ala Gln Thr Phe Gln
19/123
CA 02413186 2002-12-27
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275 280 285
Gln Ile Arg Pro Pro Arg Leu Pro Met Thr His Phe Gly Gly Thr
290 295 300
Phe Pro Pro Ala Gln Ser Thr Trp Gly Pro Phe Pro Val Arg Pro
305 310 315
Leu Ser Pro Ala Arg Ala Thr Asn Ser Pro Lys Pro His Met Val
320 325 330
Pro Arg His Ser Asn Gln Asn Ser Ser Gly Ser Gln Val Asn Ser
335 340 345
Ala Gly Ser Leu Thr Ser Ser Pro Thr Thr Thr Thr Ser Ser Ser
350 355 360
Ala Ser Thr Val Pro Gly Thr Ser Thr Asn Gly Ser Pro Ser Ser
365 370 375
Pro Ser Val Arg Arg Gln Leu Phe Val Thr Val Val Lys Thr Ser
380 385 390
Asn Ala Thr Thr Thr Thr Val Thr Thr Thr Ala Ser Asn Asn Asn
395 400 405
Thr Ala Pro Thr Asn Ala Thr Tyr Pro Met Pro Thr Ala Lys Glu
410 415 420
His Tyr Pro Val Ser Ser Pro Ser Ser Pro Ser Pro Pro Ala Gln
425 430 435
Pro Gly Gly Val Ser Arg Asn Ser Pro Leu Asp Cys Gly Ser Ala
440 445 450
Ser Pro Asn Lys Val Ala Ser Ser Ser Glu Gln Glu Ala Gly Ser
455 460 465
Pro Pro Val Val Glu Thr Thr Asn Thr Arg Pro Pro Asn Ser Ser
470 475 480
Ser Ser Ser Gly Ser Ser Ser Ala His Ser Asn Gln Gln Gln Pro
485 490 495
Pro Gly Ser Val Ser Gln Glu Pro Arg Pro Pro Leu Gln Gln Ser
500 505 510
Gln Val Pro Pro Pro Glu Val Arg Met Thr Val Pro Pro Leu Ala
515 520 525
Thr Ser Ser Ala Pro Val Ala Val Pro Ser Thr Ala Pro Val Thr
530 535 540
Tyr Pro Met Pro Gln Thr Pro Met Gly Cys Pro Gln Pro Thr Pro
545 550 555
Lys Met Glu Thr Pro Ala Ile Arg Pro Pro Pro His Gly Thr Thr
560 565 570
Ala Pro His Lys Asn Ser Ala Ser Val Gln Asn Ser Ser Val Ala
575 580 585
Val Leu Ser Val Asn His Ile Lys Arg Pro His Ser Val Pro Ser
590 595 600
Ser Val Gln Leu Pro Ser Thr Leu Ser Thr Gln Ser Ala Cys Gln
605 610 615
Asn Ser Val His Pro Ala Asn Lys Pro Ile Ala Pro Asn Phe Ser
620 625 630
Ala Pro Leu Pro Phe Gly Pro Phe Ser Thr Leu Phe Glu Asn Ser
635 640 645
Pro Thr Ser Ala His Ala Phe Trp Gly Gly Ser Val Val Ser Ser
650 655 660
Gln Ser Thr Pro Glu Ser Met Leu Ser Gly Lys Ser Ser Tyr Leu
665 670 675
Pro Asn Ser Asp Pro Leu His Gln Ser Asp Thr Ser Lys A1a Pro
680 685 690
Gly Phe Arg Pro Pro Leu Gln Arg Pro Ala Pro Ser Pro Ser Gly
20/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
695 700 705
Ile Val Asn Met Asp Ser Pro Tyr Gly Ser Val Thr Pro Ser Ser
710 715 720
Thr His Leu Gly Asn Phe Ala Ser Asn Ile Ser Gly Gly Gln Met
725 730 735
Tyr Gly Pro Gly Ala Pro Leu Gly Gly Ala Pro Ala Ala Ala Asn
740 745 750
Phe Asn Arg Gln His Phe Ser Pro Leu Ser Leu Leu Thr Pro Cys
755 760 765
Ser Ser Ala Ser Asn Asp Ser Ser Ala Gln Ser Val Sex Ser Gly
770 775 780
Val Arg Ala Pro Ser Pro Ala Pro Ser Ser Val Pro Leu Gly Ser
785 790 795
Glu Lys Pro Ser Asn Val Ser Gln Asp Arg Lys Val Pro Val Pro
800 805 810
Ile Gly Thr Glu Arg Ser Ala Arg Ile Arg Gln Thr Gly Thr Ser
815 820 825
Ala Pro Ser Val Ile Gly Ser Asn Leu Ser Thr Ser Val Gly His
830 835 840
Ser Gly Ile Trp Ser Phe Glu Gly Ile Gly Gly Asn Gln Asp Lys
845 850 855
Val Asp Trp Cys Asn Pro Gly Met Gly Asn Pro Met Ile His Arg
860 865 870
Pro Met Ser Asp Pro Gly Val Phe Ser G1n His Gln Ala Met Glu
875 880 885
Arg Asp Ser Thr Gly Ile Val Thr Pro Ser Gly Thr Phe His Gln
890 895 900
His Val Pro Ala Gly Tyr Met Asp Phe Pro Lys Val Gly Gly Met
905 910 915
Pro Phe Ser Val Tyr Gly Asn Ala Met Ile Pro Pro Val Ala Pro
920 925 930
Ile Pro Asp Gly Ala Gly Gly Pro Ile Phe Asn Gly Pro His Ala
935 940 945
Ala Asp Pro Ser Trp Asn Ser Leu Ile Lys Met Val Ser Ser Ser
950 955 960
Thr Glu Asn Asn G1y Pro Gln Thr Val Trp Thr Gly Pro Trp Ala
965 970 975
Pro His Met Asn Ser Val His Met Asn G1n Leu Gly
980 985
<210> 14
<211> 1028
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature _.
<223> Incyte ID No: 5426470CD1
<400> 14
Met Met Phe Pro Trp Lys Gln Leu Ile Leu Leu Ser Phe Ile Gly
1 5 10 15
Cys Leu Gly Gly Glu Leu Leu Leu Gln Gly Pro Val Phe Ile Lys
20 25 30
Glu Pro Ser Asn Ser Ile Phe Pro Val Gly Ser Glu Asp Lys Lys
35 40 45
21/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Ile Thr Leu His Cys Glu Ala Arg Gly Asn Pro Ser Pro His Tyr
50 55 60
Arg Trp Gln Leu Asn Gly Ser Asp Ile Asp Met Ser Met Glu His
65 70 75
Arg Tyr Lys Leu Asn Gly Gly Asn Leu Val Val Ile Asn Pro Asn
80 , 85 90
Arg Asn Trp Asp Thr Gly Thr Tyr Gln Cys Phe Ala Thr Asn Ser
95 100 105
Leu G1y Thr Ile Val Ser Arg Glu Ala Lys Leu Gln Phe Ala Tyr
110 115 120
Leu Glu Asn Phe Lys Thr Lys Met Arg Ser Thr Val Ser Val Arg
125 130 135
Glu Gly Gln Gly Val Val Leu Leu Cys Gly Pro Pro Pro His Ser
140 145 150
Gly Glu Leu Ser Tyr Ala Trp Ile Phe Asn Glu Tyr Pro Ser Phe
155 160 165
Val Glu Glu Asp Ser Arg Arg Phe Val Ser Gln Glu Thr Gly His
170 175 180
Leu Tyr Ile Ser Lys Val Glu Pro Ser Asp Val Gly Asn Tyr Thr
185 190 195
Cys Val Val Thr Ser Met Val Thr Asn Ala Arg Val Leu Gly Ser
200 205 210
Pro Thr Pro Leu Val Leu Arg Ser Asp Gly Val Met Gly Glu Tyr
215 220 225
Glu Pro Lys Ile Glu Val Gln Phe Pro Glu Thr Leu Pro Ala Ala
230 235 240
Lys Gly Ser Thr Val Lys Leu Glu Cys Phe Ala Leu Gly Asn Pro
245 250 255
Ile Pro Gln Ile Asn Trp Arg Arg Ser Asp Gly Leu Pro Phe Ser
260 265 270
Ser Lys Ile Lys Leu Arg Lys Phe Ser Gly Val Leu Glu Ile Pro
275 280 285
Asn Phe Gln Gln Glu Asp Ala Gly Ser Tyr Glu Cys Ile Ala Glu
290 295 300
Asn Ser Arg Gly Lys Asn Val Ala Arg Gly Arg Leu Thr Tyr Tyr
305 310 315
Ala Lys Pro His Trp Val Gln Leu Ile Lys Asp Val Glu Ile Ala
320 325 330
Val Glu Asp Ser Leu Tyr Trp Glu Cys Arg Ala Ser Gly Lys Pro
335 340 345
Lys Pro Ser Tyr Arg Trp Leu Lys Asn Gly A1a Ala Leu Val Leu
350 355 360
Glu G1u Arg Thr G1n Ile Glu Asn Gly Ala Leu Thr Ile Ser Asn
365 370 375
Leu Ser Val Thr Asp Ser Gly Met Phe Gln Cys Ile Ala Glu Asn
380 385 390
Lys His Gly Leu Val Tyr Ser Ser Ala Glu Leu Lys Val Val AIa
395 400 405
Ser Ala Pro Asp Phe Ser Lys Asn Pro Met Lys Lys Leu Val Gln
410 415 420
Val Gln Val Gly Ser Leu Val Ser Leu Asp Cys Lys Pro Arg Ala
425 430 435
Ser Pro Arg Ala Leu Ser Ser Trp Lys Lys Gly Asp Val Ser Val
440 445 450
Gln Glu His Glu Arg Ile Ser Leu Leu Asn Asp Gly Gly Leu Lys
455 460 465
22/123
CA 02413186 2002-12-27
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Ile Ala Asn Val Thr Lys Ala Asp Ala Gly Thr Tyr Thr Cys Met
470 475 480
Ala Glu Asn Gln Phe Gly Lys Ala Asn Gly Thr Thr His Leu Val
485 490 495
Val Thr Glu Pro Thr Arg Ile Thr Leu Ala Pro Ser Asn Met Asp
500 505 510
Val Ser Val Gly Glu Ser Val Ile Leu Pro Cys Gln Val Gln His
515 520 525
Asp Pro Leu Leu Asp Ile Ile Phe Thr Trp Tyr Phe Asn Gly Ala
530 535 540
Leu Ala Asp Phe Lys Lys Asp G1y Ser His Phe Glu Lys Val Gly
545 550 555
Gly Ser Ser Ser Gly Asp Leu Met Ile Arg Asn Ile Gln Leu Lys
560 565 570
His Ser Gly Lys Tyr Val Cys Met Val Gln Thr Gly Val Asp Ser
575 580 585
Val Ser Ser Ala A1a Asp Leu Ile Val Arg Gly Ser Pro Gly Pro
590 595 600
Pro Glu Asn Val Lys Val Asp Glu Ile Thr Asp Thr Thr Ala Gln
605 610 615
Leu Ser Trp Lys Glu Gly Lys Asp Asn His Ser Pro Val Ile Ser
620 625 630
Tyr Ser Ile Gln Ala Arg Thr Pro Phe Ser Val Gly Trp Gln Thr
635 640 645
Val Thr Thr Val Pro Glu Val Ile Asp Gly Lys Thr His Thr Ala
650 655 660
Thr Val Val Glu Leu Asn Pro Trp Val Glu Tyr Glu Phe Arg Val
665 670 675
Val Ala Ser Asn Lys Ile Gly Gly Gly Glu Pro Ser Leu Pro Ser
680 685 690
Glu Lys Val Arg Thr Glu Glu Ala Val Pro Glu Val Pro Pro Ser
695 700 705
Glu Val Asn Gly Gly Gly Gly Ser Arg Ser Glu Leu Val Ile Thr
710 715 720
Trp Asp Pro Val Pro Glu Glu Leu Gln Asn Gly Glu Gly Phe Gly
725 730 735
Tyr Val Val Ala Phe Arg Pro Leu Gly Val Thr Thr Trp Ile Gln
740 745 750
Thr Val Val Thr Ser Pro Asp Thr Pro Arg Tyr Val Phe Arg Asn
755 760 765
Glu Ser Ile Val Pro Tyr Ser Pro Tyr Glu Val Lys Val Gly Val
770 775 780
Tyr Asn Asn Lys Gly Glu Gly Pro Phe Ser Pro Val Thr Thr Val
785 790 795
Phe Ser Ala Glu Glu Glu Pro Thr Val Ala Pro Ser Gln Val Ser
800 805 810
Ala Asn Ser Leu Ser Ser Ser Glu Ile Glu Val Ser Trp Asn Thr
815 820 ' 825
Ile Pro Trp Lys Leu Ser Asn Gly His Leu Leu Gly Tyr Glu Val
830 835 840
Arg Tyr Trp Asn Gly Gly Gly Lys Glu Glu Ser Ser Ser Lys Met
845 850 855
Lys Val Ala Gly Asn Glu Thr Ser Ala Arg Leu Arg Gly Leu Lys
860 865 870
Ser Asn Leu Ala Tyr Tyr Thr Ala Val Arg Ala Tyr Asn Ser Ala
875 880 885
23/123
CA 02413186 2002-12-27
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Gly Ala Gly Pro Phe Ser Ala Thr Val Asn Val Thr Thr Lys Lys
890 895 900
Thr Pro Pro Ser Gln Pro Pro Gly Asn Val Val Trp Asn Ala Thr
905 9l0 915
Asp Thr Lys Val Leu Leu Asn Trp Glu Gln Val Lys Ala Met Glu
920 925 930
Asn Glu Ser Glu Val Thr Gly Tyr Lys Val Phe Tyr Arg Thr Ser
935 940 945
Ser Gln Asn Asn Val Gln Val Leu Asn Thr Asn Lys Thr Ser Ala
950 955 960
Glu Leu Val Leu Pro Ile Lys Glu Asp Tyr Ile Ile Glu Val Lys
965 970 975
Ala Thr Thr Asp Gly Gly Asp Gly Thr Ser Ser Glu Gln Ile Arg
980 985 990
Ile Pro Arg Ile Thr Ser Met Asp Ala Arg Gly Ser Thr Ser Ala
995 1000 1005
Ile Ser Asn Va1 His Pro Met Ser Ser Tyr Met Pro Ile Val Leu
1010 1015 1020
Phe Leu Ile Val Tyr Val Leu Trp
1025
<210> 15
<211> 354
<2l2> PRT
<2l3> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 7087904CD1
<400> 15
Met Asp Met Met Leu Leu Val Gln Gly Ala Cys Cys Ser Asn Gln
1 5 l0 15
Trp Leu Ala Ala Val Leu Leu Ser Leu Cys Cys Leu Leu Pro Ser
20 25 30
Cys Leu Pro Ala Gly Gln Ser Val Asp Phe Pro Trp Ala Ala Val
35 40 45
Asp Asn Met Met Val Arg Lys Gly Asp Thr Ala Val Leu Arg Cys
50 55 60
Tyr Leu Glu Asp Gly Ala Ser Lys Gly Ala Trp Leu Asn Arg Ser
65 70 75
Ser Ile Ile Phe Ala Gly Gly Asp Lys Trp Ser Val Asp Pro Arg
80 85 90
Val Ser Ile Ser Thr Leu Asn Lys Arg Asp Tyr Ser Leu Gln Ile
95 100 105
Gln Asn Val Asp Val Thr Asp Asp Gly Pro Tyr Thr Cys Ser Val
110 115 120
Gln Thr Gln His Thr Pro Arg Thr Met Gln Val His Leu Thr Val
125 130 135
Gln Val Pro Pro Lys Ile Tyr Asp Ile Ser Asn Asp Met Thr Val
140 145 150
Asn Glu Gly Thr Asn Val Thr Leu Thr Cys Leu Ala Thr Gly Lys
155 160 165
Pro Glu Pro Ser Ile Ser Trp Arg His Ile Ser Pro Ser Ala Lys
170 175 180
Pro Phe Glu Asn Gly Gln Tyr Leu Asp Ile Tyr Gly Ile Thr Arg
24/123
CA 02413186 2002-12-27
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185 190 195
Asp Gln Ala Gly Glu Tyr Glu Cys Ser Ala Glu Asn Asp Val Ser
200 205 210
Phe Pro Asp Val Arg Lys Val Lys Val Val Val Asn Phe Ala Pro
215 220 225
Thr Ile Gln Glu Ile Lys Ser Gly Thr Val Thr Pro Gly Arg Ser
230 235 240
Gly Leu Ile Arg Cys Glu Gly Ala Gly Val Pro Pro Pro Ala Phe
245 250 255
Glu Trp Tyr Lys Gly Glu Lys Lys Leu Phe Asn Gly Gln Gln Gly
260 265 270
Ile Ile Ile Gln Asn Phe Ser Thr Arg Ser Ile Leu Thr Val Thr
275 280 285
Asn Val Thr Gln Glu His Phe Gly Asn Tyr Thr Cys Val Ala Ala
290 295 300
Asn Lys Leu Gly Thr Thr Asn Ala Ser Leu Pro Leu Asn Pro Pro
305 310 315
Ser Thr Ala G1n Tyr Gly Ile Thr Gly Ser Ala Asp Val Leu Phe
320 325 330
Ser Cys Trp Tyr Leu Val Leu Thr Leu Ser Ser Phe Thr Ser Ile
335 340 345
Phe Tyr Leu Lys Asn Ala Ile Leu Gln
350
<210> 16
<211> 1829
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7477312CD1
<400> 16
Met Gln Leu Ser Arg Ala Ala Ala Ala Ala Ala Ala Ala Pro Ala
1 5 10 15
Glu Pro Pro Glu Pro Leu Ser Pro Ala Pro Ala Pro Ala Pro Ala
20 25 30
Pro Pro Gly Pro Leu Pro Arg Ser Ala Ala Asp Gly Ala Pro Ala
35 40 45
Gly Gly Lys Gly Gly Pro Gly Arg Arg Ala Arg Ser Pro Arg Ala
50 55 60
Leu Arg Ser Pro Ala Arg Ala A1a Pro Ala Arg Ala Pro Ala Arg
65 70 75
Gly Trp Thr Ala Pro Gly Pro Gly Ala Ser Ala Val Val Val Arg
80 85 90
Val Gly Ile Pro Asp Leu Gln Gln Thr Lys Cys Leu Arg Leu Asp
95 100 105
Pro Ala Ala Pro Val Trp Ala Ala Lys Gln Arg Val Leu Cys Ala
110 115 120
Leu Asn His Ser Leu Gln Asp Ala Leu Asn Tyr Gly Leu Phe Gln
125 130 135
Pro Pro Ser Arg Gly Arg Ala Gly Lys Phe Leu Asp Glu Glu Arg
140 145 150
Leu Leu Gln Glu Tyr Pro Pro Asn Leu Asp Thr Pro Leu Pro Tyr
155 160 165
25/123
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Leu Glu Phe Arg Tyr Lys Arg Arg Val Tyr Ala Gln Asn Leu Ile
170 175 180
Asp Asp Lys Gln Phe Ala Lys Leu His Thr Lys Ala Asn Leu Lys
185 190 195
Lys Phe Met Asp Tyr Val Gln Leu His Ser Thr Asp Lys Val Ala
200 205 210
Arg Leu Leu Asp Lys Gly Leu Asp Pro Asn Phe His Asp Pro Asp
215 220 225
Ser Gly Glu Cys Pro Leu Ser Leu A1a Ala Gln Leu Asp Asn Ala
230 235 240
Thr Asp Leu Leu Lys Val Leu Lys Asn Gly Gly Ala His Leu Asp
245 250 255
Phe Arg Thr Arg Asp Gly Leu Thr Ala Val His Cys Ala Thr Arg
260 265 270
Gln Arg Asn Ala Ala Ala Leu Thr Thr Leu Leu Asp Leu Gly Ala
275 280 285
Ser Pro Asp Tyr Lys Asp Ser Arg Gly Leu Thr Pro Leu Tyr His
290 295 300
Ser Ala Leu Gly Gly Gly Asp Ala Leu Cys Cys Glu Leu Leu Leu
305 310 315
His Asp His Ala Gln Leu Gly Thr Thr Asp Glu Asn Gly Trp Gln
320 325 330
Glu Ile His Gln Ala Cys Arg Phe Gly His Val Gln His Leu Glu
335 340 345
His Leu Leu Phe Tyr Gly Ala Asp Met Gly Ala Gln Asn Ala Ser
350 355 360
G1y Asn Thr Ala Leu His Ile Cys Ala Leu Tyr Asn Gln Glu Ser
365 370 375
Cys Ala Arg Val Leu Leu Phe Arg Gly Ala Asn Arg Asp Val Arg
380 385 390
Asn Tyr Asn Ser Gln Thr A1a Phe Gln Val Ala Ile Ile Ala Gly
395 400 405
Asn Phe Glu Leu Ala Glu Val Ile Lys Thr His Lys Asp Ser Asp
410 415 420
Val Gly Gln Asp Ser His Asp Leu Leu His Pro Met Pro Thr Gly
425 430 435
Val Pro Glu Trp G1y Leu Tyr Thr Glu Glu Glu Leu Glu Gly Gly
440 445 450
Ala Ala Phe Ser Val Pro Phe Arg Glu Thr Pro Ser Tyr A1a Lys
455 460 465
Arg Arg Arg Leu Ala Gly Pro Ser Gly Leu Ala Ser Pro Arg Pro
470 475 480
Leu Gln Arg Ser Ala Ser Asp Ile Asn Leu Lys Gly Glu Ala Gln
485 490 495
Pro Ala Ala Ser Pro Gly Pro Ser Leu Arg Ser Leu Pro His Gln
500 505 510
Leu Leu Leu Gln Arg Leu Gln Glu Glu Lys Asp Arg Asp Arg Asp
515 520 525
Ala Asp Gln Glu Ser Asn Ile Ser Gly Pro Leu Ala Gly Arg Ala
530 . 535 540
Gly Gln Ser Lys I1e Arg Ser Cys Ile Arg Ile Arg Ala Arg Phe
545 550 555
Pro Ala Pro Pro Ala Pro Pro Ala Pro Pro Pro Arg Gly Pro Lys
560 565 570
Arg Lys Leu Tyr Ser Ala Val Pro Gly Arg Lys Phe Ile Ala Val
575 580 585
26/123
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Lys Ala His Ser Pro Gln Gly Glu Gly Glu Ile Pro Leu His Arg
590 595 600
Gly Glu Ala Val Lys Val Leu Ser Ile Gly Glu Gly Gly Phe Trp
605 610 615
Glu Gly Thr Val Lys Gly Arg Thr Gly Trp Phe Pro Ala Asp Cys
620 625 630
Val Glu Glu Val G1n Met Arg Gln His Asp Thr Arg Pro Glu Thr
635 640 645
Arg Glu Asp Arg Thr Lys Arg Leu Phe Arg His Tyr Thr Val Gly
650 655 660
Ser Tyr Asp Ser Leu Thr Ser His Ser Asp Tyr Val Ile Asp Asp
665 670 675
Lys Val Ala Val Leu Gln Lys Arg Asp His Glu Gly Phe Gly Phe
680 685 690
Val Leu Arg Gly Ala Lys Ala G1u Thr Pro Ile Glu Glu Phe Thr
695 700 705
Pro Thr Pro Ala Phe Pro Ala Leu Gln Tyr Leu Glu Ser Val Asp
710 715 720
Val Glu Gly Val Ala Trp Arg Ala Gly Leu Arg Thr Gly Asp Phe
725 730 735
Leu Ile Glu Val Asn Gly Val Asn Val Val Lys Val Gly His Lys
740 745 750
Gln Val Val Ala Leu Ile Arg Gln Gly Gly Asn Arg Leu Val Met
755 760 765
Lys Val Val Ser Val Thr Arg Lys Pro Glu Glu Asp Gly Ala Arg
770 775 780
Arg Arg Ala Pro Pro Pro Pro Lys Arg Ala Pro Ser Thr Thr Leu
785 790 795
Thr Leu Arg Ser Lys Ser Met Thr Ala Glu Leu Glu Glu Leu Glu
800 805 810
Lys Leu Asp Glu Met Leu Ala Ala Ala A1a Glu Pro Thr Leu Arg
815 820 825
Pro Asp Ile Ala Asp Ala Asp Ser Arg Ala Ala Thr Val Lys Gln
830 835 840
Arg Pro Thr Ser Arg Arg Ile Thr Pro~Ala Glu Ile Ser Ser Leu
845 850 855
Phe Glu Arg Gln Gly Leu Pro Gly Pro Glu Lys Leu Pro Gly Ser
860 865 870
Leu Arg Lys Gly Ile Pro Arg Thr Lys Ser Val Gly Glu Asp Glu
875 880 885
Lys Leu Ala Ser Leu Leu Glu Gly Arg Phe Pro Arg Ser Thr Ser
890 895 900
Met Gln Asp Pro Val Arg Glu Gly Arg Gly Ile Pro Pro Pro Pro
905 910 915
Gln Thr Ala Pro Pro Pro Pro Pro Ala Pro Tyr Tyr Phe Asp Ser
920 925 930
Gly Pro Pro Pro Ala Phe Ser Pro Pro Pro Pro Pro G1y Arg Ala
935 940 945
Tyr Asp Thr Val Arg Ser Ser Phe Lys Pro Gly Leu Glu Ala Arg
950 955 960
Leu Gly Ala Gly Ala Ala Gly Leu Tyr Glu Pro Gly Ala Ala Leu
965 970 975
Gly Pro Leu Pro Tyr Pro Glu Arg Gln Lys Arg Ala Arg Ser Met
980 985 990
Ile Ile Leu Gln Asp Ser Ala Pro Glu Ser Gly Asp Ala Pro Arg
995 1000 1005
27/l23
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Pro Pro Pro Ala Ala Thr Pro Pro Glu Arg Pro Lys Arg Arg Pro
1010 1015 1020
Arg Pro Pro Gly Pro Asp Ser Pro Tyr Ala Asn Leu Gly Ala Phe
1025 1030 1035
Ser Ala Ser Leu Phe Ala Pro Ser Lys Pro Gln Arg Arg Lys Ser
1040 1045 1050
Pro Leu Val Lys Gln Leu Gln Val Glu Asp Ala Gln GIu Arg Ala
1055 1060 1065
Ala Leu Ala Val Gly Ser Pro Gly Pro Gly Gly Gly Ser Phe Ala
1070 1075 1080
Arg Glu Pro Ser Pro Thr His Arg Gly Pro Arg Pro Gly Gly Leu
1085 1090 1095
Asp Tyr Gly Ala Gly Asp Gly Pro Gly Leu Ala Phe Gly Gly Pro
1100 1105 1110
Gly Pro Ala Lys Asp Arg Arg Leu Glu Glu Arg Arg Arg Ser Thr
1115 1120 1125
Val Phe Leu Ser Val Gly Ala Ile Glu Gly Ser Ala Pro Gly Ala
1130 1135 1140
Asp Leu Pro Ser Leu Gln Pro Ser Arg Ser Ile Asp Glu Arg Leu
1145 1150 1155
Leu Gly Thr Gly Pro Thr Ala Gly Arg Asp Leu Leu Leu Pro Ser
1160 1165 1170'
Pro Val Ser Ala Leu Lys Pro Leu Val Ser Gly Pro Ser Leu Gly
1175 1180 1185
Pro Ser Gly Ser Thr Phe Ile His Pro Leu Thr Gly Lys Pro Leu
1190 1195 1200
Asp Pro Ser Ser Pro Leu Ala Leu Ala Leu Ala Ala Arg Glu Arg
1205 1210 1215
Ala Leu Ala Ser Gln Ala Pro Ser Arg Ser Pro Thr Pro Val His
1220 1225 1230
Ser Pro Asp Ala Asp Arg Pro Gly Pro Leu Phe Val Asp Va1 Gln
1235 1240 1245
Ala Arg Asp Pro G1u Arg Gly Ser Leu Ala Ser Pro Ala Phe Ser
1250 1255 1260
Pro Arg Ser Pro Ala Trp Ile Pro Val Pro Ala Arg Arg Glu Ala
1265 1270 1275
G1u Lys Val Pro Arg Glu Glu Arg Lys Ser Pro Glu Asp Lys Lys
1280 1285 1290
Ser Met Ile Leu Ser Val Leu Asp Thr Ser Leu Gln Arg Pro Ala
1295 1300 1305
Gly Leu Ile Val Val His Ala Thr Ser Asn Gly Gln Glu Pro Ser
1310 1315 1320
Arg Leu Gly Gly Ala Glu Glu Glu Arg Pro Gly Thr Pro Glu Leu
1325 1330 1335
Ala Pro A1a Pro Met Gln Ser Ala Ala Val Ala Glu Pro Leu Pro
1340 1345 1350
Ser Pro Arg Ala Gln Pro Pro Gly Gly Thr Pro Ala Asp Ala Gly
1355 1360 1365
Pro Gly Gln Gly Ser Ser Glu~Glu Glu Pro Glu Leu Val Phe Ala
1370 1375 1380
Val Asn Leu Pro Pro Ala Gln Leu Ser Ser Ser Asp Glu Glu Thr
1385 1390 1395
Arg Glu Glu Leu Ala Arg Ile Gly Leu Val Pro Pro Pro Glu Glu
1400 1405 1410
Phe Ala Asn Gly Val Leu Leu Ala Thr Pro Leu Ala Gly Pro Gly
1415 1420 1425
28/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Pro Ser Pro Thr Thr Val Pro Ser Pro Ala Ser Gly Lys Pro Ser
1430 1435 1440
Ser Glu Pro Pro Pro Ala Pro Glu Ser Ala Ala Asp Ser Gly Val
1445 1450 1455
Glu Glu Ala Asp Thr Arg Ser Ser Ser Asp Pro His Leu Glu Thr
1460 1465 1470
Thr Ser Thr Ile Ser Thr Val Ser Ser Met Ser Thr Leu Ser Ser
1475 1480 1485
Glu Ser Gly Glu Leu Thr Asp Thr His Thr Ser Phe Ala Asp Gly
1490 1495 1500
His Thr Phe Leu Leu Glu Lys Pro Pro Val Pro Pro Lys Pro Lys
1505 1510 1515
Leu Lys Ser Pro Leu Gly Lys Gly Pro Val Thr Phe Arg Asp Pro
1520 1525 1530
Leu Leu Lys Gln Ser Ser Asp Ser Glu Leu Met Ala Gln Gln His
1535 1540 1545
His Ala Ala Ser Ala Gly Leu Ala Ser Ala Ala Gly Pro Ala Arg
1550 1555 1560
Pro Arg Tyr Leu Phe Gln Arg Arg Ser Lys Leu Trp Gly Asp Pro
1565 1570 1575
Val Glu Ser Arg Gly Leu Pro Gly Pro Glu Asp Asp Lys Pro Thr
1580 ' 1585 1590
Val Ile Ser Glu Leu Ser Ser Arg Leu Gln Gln Leu Asn Lys Asp
1595 1600 1605
Thr Arg Ser Leu Gly Glu Glu Pro Val Gly Gly Leu Gly Ser Leu
1610 1615 1620
Leu Asp Pro Ala Lys Lys Ser Pro Ile Ala Ala Ala Arg Leu Phe
1625 1630 1635
Ser Ser Leu Gly Glu Leu Ser Ser Ile Ser Ala Gln Arg Ser Pro
1640 1645 1650
Gly Gly Pro Gly Gly Gly Ala Ser Tyr Ser Val Arg Pro Ser Gly
1655 1660 1665
Arg Tyr Pro Val Ala Arg Arg Ala Pro Ser Pro Val Lys Pro Ala
1670 1675 1680
Ser Leu Glu Arg Val Glu GIy Leu Gly Ala Gly Ala Gly Gly Ala
1685 1690 1695
Gly Arg Pro Phe Gly Leu Thr Pro Pro Thr Ile Leu Lys Ser Ser
1700 1705 1710
Ser Leu Ser Ile Pro His Glu Pro Lys Glu Val Arg Phe Val Val
1715 1720 1725
Arg Ser Val Ser Ala Arg Ser Arg Ser Pro Ser Pro Ser Pro Leu
1730 1735 1740
Pr'o Ser Pro Ala Ser Gly Pro Gly Pro G1y Ala Pro G1y Pro Arg
1745 1750 1755
Arg Pro Phe Gln Gln Lys Pro Leu Gln Leu Trp Ser Lys Phe Asp
1760 1765 1770
Val Gly Asp Trp Leu Glu Ser Ile His Leu Gly Glu His Arg Asp
1775 1780 1785
Arg Phe Glu Asp His Glu Ile Glu Gly Ala His Leu Pro Ala Leu
1790 1795 1800
Thr Lys Asp Asp Phe Val Glu Leu G1y Val Thr Arg Val Gly His
1805 1810 1815
Arg Met Asn Ile Glu Arg Ala Leu Arg Gln Leu Asp Gly Ser
1820 1825
<210> 17
29/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<211> 323
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 2739431CD1
<400> 17
Met Met Ser Pro Ser Gln Ala Ser Leu Leu Phe Leu Asn Val Cys
1 5 10 15
Ile Phe Ile Cys Gly Glu Ala Val Gln Gly Asn Cys Val His His
20 25 30
Ser Thr Asp Ser Ser Va1 Val Asn Ile Val Glu Asp Gly Ser Asn
35 40 45
Ala Lys Asp Glu Ser Lys Ser Asn Asp Thr Val Cys Lys G1u Asp
50 55 60
Cys Glu Glu Ser Cys Asp Val Lys Thr Lys Ile Thr Arg Glu Glu
65 70 75
Lys His Phe Met Cys Arg Asn Leu Gln Asn Ser Ile Val Ser Tyr
80 85 90
Thr Arg Ser Thr Lys Lys Leu Leu Arg Asn Met Met Asp Glu Gln
95 . 100 105
Gln Ala Ser Leu Asp Tyr Leu Ser Asn Gln Val Met Cys Asp Met
110 115 120
Asp Tyr Arg Gly Gly Gly Trp Thr Val Ile Gln Lys Arg Ile Asp
125 130 135
Gly Ile Ile Asp Phe Gln Arg Leu Trp Cys Asp Tyr Leu Asp Gly
140 145 150
Phe Gly Asp Leu Leu Gly Glu Phe Trp Leu Gly Leu Lys Lys Ile
155 160 165
Phe Tyr Ile Val Asn Gln Lys Asn Thr Ser Phe Met Leu Tyr Val
170 175 180
Ala Leu Glu Ser Glu Asp Asp Thr Leu Ala Tyr Ala Ser Tyr Asp
185 190 195
Asn Phe Trp Leu Glu Asp Glu Thr Arg Phe Phe Lys Met His Leu
200 205 210
Gly Arg Tyr Ser Gly Asri A1a Gly Asp Ala Phe Arg Gly Leu Lys
215 220 225
Lys Glu Asp Asn Gln Asn Ala Met Pro Phe Ser Thr Ser Asp Val
230 235 240
Asp Asn Asp Gly Cys Arg Pro Ala Cys Leu Val Asn Gly Gln Ser ,
245 250 255
Val Lys Ser Cys Ser His Leu His Asn Lys Thr Gly Trp Trp Phe
260 265 270
Asn Glu Cys Gly Leu Ala Asn Leu Asn Gly I1e His His Phe Ser
275 280 285
Gly Lys Leu Leu Ala Thr Gly Ile Gln Trp Gly Thr Trp Thr Lys
290 295 300
Asn Asn Ser Pro Val Lys Ile Lys Ser Val Ser Met Lys Ile Arg
305 310 315
Arg Met Tyr Asn Pro Tyr Phe Lys
320
<210> l8
<211> 644
30/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 7473606CD1
<400> 18
Met Asp G1y Arg Gly A1a Phe Trp Thr Val Ala Ile Pro Arg Ala
1 5 10 15
Arg Gln Glu Gly Leu Gly Arg Leu Gly Leu Pro Phe Pro Val Lys
20 25 30
Arg Thr Pro Pro Ala Pro Gln Asn Pro Gly Gly Ser Thr Gln Ala
35 40 45
Pro Gln Arg Val Val Gly Lys Ser His Ser Gly Ile Arg Met Pro
50 55 60
Ala Lys Ser Arg Asn Leu Arg Leu Glu Ser Lys Leu Asn Arg Lys
65 70 75
Val Val Lys Tyr Lys Trp Gly Lys Gln Gly Ser Gly Ala Gly Arg
80 85 90
Glu Leu Val Pro Ala Phe Pro Thr Asn Ala Gly Leu G1y Arg Arg
95 100 105
Asp Arg Cys Arg Pro Pro Pro Ala Gly Gly Asp Val A1a Ser His
110 115 120
Gly Leu Pro Gly Ser Gly Val Gly Tyr Ser Cys Asn Gln Arg Glu
125 130 135
Glu Gly Leu Arg Gly Gly Cys Gly Gly Ile Pro His Val Pro Leu
140 145 150
Phe Leu Ser Pro Leu Pro Leu Asp Ala Ser Gly Gln Arg Pro Ser
155 160 165
Ser Thr Tyr Arg Gln Ser Leu Arg Arg Gly Leu Gly Thr Arg Ala
170 175 180
His Gln Ser Pro Ala Asn Glu Ile Pro Glu Leu Gly Asp Leu Arg
185 190 195
Gly Ser Arg Leu Ala Gln Glu Pro Ala Val Leu Phe Gly Leu Arg
200 205 210
Pro Ser Ile Ser Lys Arg Gly Leu Leu Ala Arg Arg Leu Trp Ala
215 220 225
Gln Pro Met Leu Leu Ser Gly Trp Val Val Ser Thr Thr Thr Thr
230 235 240
Ile Ile Thr Val Thr Val Thr Phe Thr Pro Thr Gly Leu Leu Cys
245 250 255
Val Lys His Ser Arg Gly Pro Leu Gln Pro Thr Cys Gln Glu Ser
260 265 270
Ala Pro Glu Asn Arg Val Gly Lys Ala Leu Ile Thr Phe Ser Lys
275 280 285
Gly Trp Arg Ala Ser Leu Arg Leu Ala Pro Pro Pro Ser Ala Leu
290 295 300
Leu Leu Arg Arg His Gly Pro Gly Gly Leu Pro Val Pro Gly Thr
305 310 ~ 315
Met Cys Asp Gly Ala Leu Leu Pro Pro Leu Val Leu Pro Val Leu
320 325 330
Leu Leu Leu Val Trp Gly Leu Asp Pro Gly Thr Gly Ser Ala Pro
335 340 345
Ser His Ser Pro Leu His Pro Ala Ser Cys Gly Tyr Leu Pro Ser
350 355 360
31/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Ala Phe Ser Arg Arg Pro Gly Gly Pro Gly Ala Ala Ala Gly Pro
365 370 375
Leu Thr Ala Pro Glu Arg Arg Arg Arg Gly Pro Arg Pro Glu Tyr
380 385 390
Gly Asn Arg Val Ala Pro Trp Gln Ala Arg Arg Arg Arg Val Ser
395 400 405
Ala Arg Arg Cys Ala Ala Pro Phe Arg Glu Val Leu Ala Arg Leu
410 415 420
Arg Arg Arg Pro Ser Pro Gly Gly Ala Gly Gln Arg Gly Ala Val
425 430 435
Gly Asp Ala Ala Ala Asp Val Glu Val Val Leu Pro Trp Arg Val
440 . 445 450
Arg Pro Asp Asp Val His Leu Pro Pro Leu Pro Ala Ala Pro Gly
455 460 465
Pro Arg Arg Arg Arg Arg Pro Arg Thr Pro Pro Ala Ala Pro Arg
470 475 480
Ala Arg Pro Gly Glu Arg Ala Leu Leu Leu His Leu Pro Ala Phe
485 490 495
Gly Arg Asp Leu Tyr Leu Gln Leu Arg Arg Asp Leu Arg Phe Leu
500 505 510
Ser Arg Gly Phe Glu Va1 Glu Glu Ala Gly Ala Ala Arg Arg Arg
515 520 525
Gly Arg Pro Ala Glu Leu Cys Phe Tyr Ser Gly Arg Val Leu Gly
530 535 540
His Pro Gly Ser Leu Val Ser Leu Ser Ala Cys Gly Ala Ala Gly
545 550 555
Gly Leu Val Gly Leu Ile Gln Leu Gly Gln Glu Gln Val Leu I1e
560 565 570
Gln Pro Leu Asn Asn Ser Gln Gly Pro Phe Ser G1y Arg Glu His
575 580 585
Leu Ile Arg Arg Lys Trp Ser Leu Thr Pro Ser Pro Ser Ala Glu
590 595 600
Ala Gln Arg Pro Glu Gln Leu Cys Lys Val Leu Thr Val Pro Gln
605 610 615
Cys Leu Gly Leu Thr Trp Glu Asp Leu Lys Ser Gly Gly Trp Ser
620 625 630
Asp Leu Glu Val Pro His Ser Cys Val Trp Pro Gly Gly Gly
635 640
<210> 19
<211> 881
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 3534918CD1
<400> 19
Met Glu His Gly Ala Leu Gly Ser Leu Gly Glu His Ala Ala Lys
1 ~ 5 10 15
Val Val Gly Lys Val Leu Arg Gln Glu Gln Asp Phe Val Ile Thr
20 25 30
His His Gln Arg Leu Val Gly Pro Thr Val Met Glu Gln Lys His
35 40 45
Arg Cys Lys Phe Ala Met Lys Glu Ile Val Gln Phe Met Ala Ser
32/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
50 55 60
Gly Arg Leu Gly Pro Val Gly Val Pro Val Leu Cys His Val Glu
65 70 75
Glu Val Pro Asp Arg Glu Gln Gly A1a Ala Pro Thr Leu Cys Pro
80 85 90
Ser Met Glu Glu Gly Asn Ala Lys Gly Val Met Ser Arg Val Ile
95 100 105
Phe Ala Thr Val Thr Leu Ala Gln Val Ser Val Gly Asn Thr His
110 115 120
Gly Asn Trp Ser Pro Trp Ser Gly Trp Gly Thr Cys Ser Arg Thr
125 130 135
Cys Asn Gly G1y Gln Met Arg Arg Tyr Arg Thr Cys Asp Asn Pro
140 145 150
Pro Pro Ser Asn Gly Gly Arg A1a Cys Gly Gly Pro Asp Ser Gln
l55 160 165
Ile Gln Arg Cys Asn Thr Asp Met Cys Pro Val Asp Gly Ser Trp
170 175 180
Gly Ser Trp His Ser Trp Ser Gln Cys Ser Ala Ser Cys Gly Gly
185 190 195
Gly Glu Lys Thr Arg Lys Arg Leu Cys Asp His Pro Val Pro Va1
200 205 210
Lys G1y Gly Arg Pro Cys Pro Gly Asp Thr Thr Gln Val Thr Arg
215 220 225
Cys Asn Val G1n Ala Cys Pro Gly Gly Pro Gln Arg A1a Arg Gly
230 235 240
Ser Val Ile Gly Asn Ile Asn Asp Val Glu Phe Gly Ile Ala Phe
245 250 255
Leu Asn Ala Thr Ile Thr Asp Ser Pro Asn Ser Asp Thr Arg Ile
260 265 270
Ile Arg Ala Lys Ile Thr Asn Va1 Pro Arg Ser Leu Gly Ser Ala
275 280 285
Met Arg Lys Ile Val Ser Ile Leu Asn Pro Ile Tyr Trp Thr Thr
290 295 300
Ala Lys Glu Ile Gly Glu Ala Val Asn Gly Phe Thr Leu Thr Asn
305 310 315
Ala Val Phe Lys Arg Glu Thr Gln Val Glu Phe Ala Thr Gly Glu
320 325 330
Ile Leu Gln Met Ser His Tle Ala Arg Gly Leu Asp Ser Asp Gly
335 340 345
Ser Leu Leu Leu Asp Ile Va1 Val Ser Gly Tyr Val Leu Gln Leu
350 355 360
Gln Ser Pro Ala Glu Val Thr Val Lys Asp Tyr Thr Glu Asp Tyr
365 370 375
Ile Gln Thr Gly Pro Gly Gln Leu Tyr Ala Tyr Ser Thr Arg Leu
380 385 390
Phe Thr Ile Asp Gly Ile Ser Ile Pro Tyr Thr Trp Asn His Thr
395 400 405
Val Phe Tyr Asp Gln Ala Gln Gly Arg Met Pro Phe Leu Val Glu
410 415 420
Thr Leu His Ala Ser Ser Val Glu Ser Asp Tyr Asn Gln Ile Glu
425 430 435
Glu Thr Leu Gly Phe Lys Ile His A1a Ser Ile Ser Lys Gly Asp
440 445 450
Arg Ser Asn Gln Cys Pro Ser Gly Phe Thr Leu Asp Ser Val Gly
455 460 465
Pro Phe Cys Ala Asp Glu Asp Glu Cys Ala Ala Gly Asn Pro Cys
33/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
470 475 480
Ser His Ser Cys His Asn Ala Met Gly Thr Tyr Tyr Cys Ser Cys
485 490 495
Pro Lys Gly Leu Thr Ile Ala Ala Asp Gly Arg Thr Cys Gln Asp
500 505 510
Ile Asp Glu Cys Ala Leu Gly Arg His Thr Cys His Ala Gly Gln
515 520 525
Asp Cys Asp Asn Thr Ile Gly Ser Tyr Arg Cys Val Val Arg Cys
530 535 540
Gly Ser Gly Phe Arg Arg Thr Ser Asp G1y Leu Ser Cys Gln Asp
545 550 555
Ile Asn Glu Cys Gln Glu Ser Ser Pro Cys His Gln Arg Cys Phe
560 565 570
Asn Ala Ile Gly Ser Phe His Cys Gly Cys Glu Pro G1y Tyr Gln
575 580 585
Leu Lys Gly Arg Lys Cys Met Asp Val Asn Glu Cys Arg Gln Asn
590 595 600
Val Cys Arg Pro Asp Gln His Cys Lys Asn Thr Arg Gly Gly Tyr
605 610 615
Lys Cys Ile Asp Leu Cys Pro Asn Gly Met Thr Lys Ala Glu Asn
620 625 630
Gly Thr Cys Ile Asp Ile Asp Glu Cys Lys Asp Gly Thr His Gln
635 640 645
Cys Arg Tyr Asn Gln Ile Cys Glu Asn Thr Arg Gly Ser Tyr Arg
650 655 660
Cys Val Cys Pro Arg Gly Tyr Arg Ser Gln Gly Val Gly Arg Pro
665 670 675
Cys Met Asp I1e Asp Glu Cys G1u Asn Thr Asp Ala Cys Gln His
680 685 690
Glu Cys Lys Asn Thr Phe Gly Ser Tyr Gln Cys Ile Cys Pro Pro
695 700 705
Gly Tyr Gln Leu Thr His Asn Gly Lys Thr Cys Gln Asp Ile Asp
710 715 720
Glu Cys Leu Glu Gln Asn Val His Cys Gly Pro Asn Arg Met Cys
725 730 735
Phe Asn Met Arg Gly Ser Tyr Gln Cys Ile Asp Thr Pro Cys Pro
740 745 750
Pro Asn Tyr Gln Arg Asp Pro Val Ser Gly Phe Cys Leu Lys Asn
755 760 765
Cys Pro Pro Asn Asp Leu Glu Cys Ala Leu Ser Pro Tyr Ala Leu
770 775 780
Glu Tyr Lys Leu Val Ser Leu Pro Phe Gly Ile Ala Thr Asn Gln
785 790 795
Asp Leu Ile Arg Leu Val Ala Tyr Thr Gln Asp Gly Val Met His
800 805 810
Pro Arg Thr Thr Phe Leu Met Val Asp Glu Glu Gln Thr Val Pro
815 820 825
Phe Ala Leu Arg Asp Glu Asn Leu Lys Gly Val Val Tyr Thr Thr
830 835 840
Arg Pro Leu Arg Glu Ala Glu Thr Tyr Arg Met Arg Val Arg Ala
845 850 855
Ser Ser Tyr Ser Ala Asn Gly Thr Ile Glu Tyr Gln Thr Thr Phe
860 865 870
Ile Val Tyr Ile Ala Val Ser Ala Tyr Pro Tyr
875 880
34/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 20
<211> 957
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Inoyte ID No: 2428715CD1
<400> 20
Met Gly Ala Ala Ala Val Arg Trp His Leu Cys Val Leu Leu Ala
1 5 10 15
Leu Gly Thr Arg Gly Arg Leu Ala Gly Gly Ser Gly Leu Pro Gly
20 25 30
Ser Val Asp Val Asp Glu Cys Ser Glu Gly Thr Asp Asp Cys His'
35 40 45
Ile Asp Ala Ile Cys Gln Asn Thr Pro Lys Ser Tyr Lys Cys Leu
50 55 60
Cys Lys Pro Gly Tyr Lys Gly Glu Gly Lys Gln Cys Glu Asp Ile
65 70 75
Asp Glu Cys Glu Asn Asp Tyr Tyr Asn Gly Gly Cys Val His Glu
80 85 90
Cys Ile Asn Ile Pro Gly Asn Tyr Arg Cys Thr Cys Phe Asp Gly
95 100 ~ 105
Phe Met Leu Ala His Asp Gly His Asn Cys Leu Asp Val Asp Glu
110 115 120
Cys Gln Asp Asn Asn Gly Gly Cys Gln Gln Ile Cys Val Asn Ala
125 130 135
Met Gly Ser Tyr Glu Cys Gln Cys His Ser Gly Phe Phe Leu Ser
140 145 150
Asp Asn GIn His Thr Cys Ile His Arg Ser Asn Glu Gly Met Asn
155 160 165
Cys Met Asn Lys Asp His Gly Cys Ala His Ile Cys Arg Glu Thr
170 175 180
Pro Lys Gly Gly Val Ala Cys Asp Cys Arg Pro Gly Phe Asp Leu
185 190 195
Ala Gln Asn Gln Lys Asp Cys Thr Leu Thr Cys Asn Tyr Gly Asn
200 205 210
Gly Gly Cys Gln His Ser Cys Glu Asp Thr Asp Thr Gly Pro Thr
215 220 225
Cys Gly Cys His Gln Lys Tyr Ala Leu His Ser Asp Gly Arg Thr
230 235 240
Cys Ile Glu Lys Asp Glu Ala Ala Ile Glu Arg Ser Gln Phe Asn
245 250 255
Ala Thr Ser Val Ala Asp Val Asp Lys Arg Val Lys Arg Arg Leu
260 265 270
Leu Met Glu Thr Cys Ala Val Asn Asn Gly Gly Cys Asp Arg Thr
275 280 285
Cys Lys Asp Thr Ala Thr Gly Val Arg Cys Ser Cys Pro Val Gly
290 295 300
Phe Thr Leu Gln Pro Asp Gly Lys Thr Cys Lys Asp 21e Asn Glu
305 310 315
Cys Leu Val Asn Asn Gly Gly Cys Asp His Phe Cys Arg Asn Thr
320 325 330
Val Gly Ser Phe Glu Cys Gly Cys Arg Lys Gly Tyr Lys Leu Leu
335 340 345
35/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Thr Asp Glu Arg Thr Cys Gln Asp Ile Asp Glu Cys Ser Phe Glu
350 355 360
Arg Thr Cys Asp His I1e Cys Ile Asn Ser Pro Gly Ser Phe Gln
365 ~ 370 375
Cys Leu Cys His Arg Gly Tyr Ile Leu Tyr Gly Thr Thr His Cys
380 385 390
Gly Asp Val Asp Glu Cys Ser Met Ser Asn Gly Ser Cys Asp Gln
395 ~ 400 405
Gly Cys Val Asn Thr Lys Gly Ser Tyr Glu Cys Val Cys Pro Pro
4l0 415 420
Gly Arg Arg Leu His Trp Asn Arg Lys Asp Cys Val Glu Thr Gly
425 430 435
Lys Cys Leu Ser Arg Ala Lys Thr Ser Pro Arg Ala Gln Leu Ser
440 445 450
Cys Ser Lys Ala Gly Gly Val Glu Ser Cys Phe Leu Ser Cys Pro
455 460 465
Ala His Thr Leu Phe Val Pro Asp Ala Pro Thr Thr Pro Ile Lys
470 475 480
Gln Lys Ala Arg Phe Lys Ile Arg Asp Ala Lys Cys His Leu Arg
485 490 495
Pro His Ser Gln Ala Arg Ala Lys Glu Thr Ala Arg Gln Pro Leu
500 505 510
Leu Asp His Cys His Va1 Thr Phe Val Thr Leu Lys Cys Asp Ser
515 520 525
Ser Lys Lys Arg Arg Arg Gly Arg Lys Ser Pro Ser Lys Glu Val
530 535 540
Ser His Ile Thr Ala Glu Phe Glu Ile Glu Thr Lys Met Glu Glu
545 550 555
A1a Ser Asp Thr Cys Glu Ala Asp Cys Leu Arg Lys Arg Ala Glu
560 565 570
Gln Ser Leu Gln Ala Ala Ile Lys Thr Leu Arg Lys Ser Ile Gly
575 580 585
Arg Gln Gln Phe Tyr Val Gln Val Ser Gly Thr Glu Tyr Glu Val
590 595 600
Ala Gln Arg Pro Ala Lys Ala Leu Glu Gly Gln Gly Ala Cys Gly
605 610 615
Ala Gly Gln Val Leu Gln Asp Ser Lys Cys Val Ala Cys Gly Pro
620 625 630
Gly Thr His Phe Gly Gly Glu Leu Gly Gln Cys Val Pro Cys Met
635 640 645
Pro Gly Thr Tyr Gln Asp Met Glu Gly Gln Leu Ser Cys Thr Pro
650 655 660
Cys Pro Ser Ser Asp Gly Leu Gly Leu Pro Gly Ala Arg Asn Val
665 670 675
Ser Glu Cys Gly Gly Gln Cys Ser Pro Gly Phe Phe Ser Ala Asp
680 685 690
Gly Phe Lys Pro Cys Gln Ala Cys Pro Val Gly Thr Tyr Gln Pro
695 700 705
Glu Pro Gly Arg Thr Gly Cys Phe Pro Cys Gly Gly Gly Leu Leu
710 715 720
Thr Lys His Glu Gly Thr Thr Ser Phe Gln Asp Cys Glu Ala Lys
725 730 735
Val His Cys Ser Pro Gly His His Tyr Asn Thr Thr Thr His Arg
740 745 750
Cys Ile Arg Cys Pro Val Gly Thr Tyr Gln Pro Glu Phe Gly Gln
755 760 765
36/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Asn His Cys Ile Thr Cys Pro Gly Asn Thr Ser Thr Asp Phe Asp
770 775 780
Gly Ser Thr Asn Val Thr His Cys Lys Asn Gln His Cys Gly Gly
785 790 795
Glu Leu Gly Asp Tyr Thr Gly Tyr Ile Glu Ser Pro Asn Tyr Pro
800 805 810
Gly Asp Tyr Pro Ala Asn Ala Glu Cys Val Trp His Ile Ala Pro
815 820 825
Pro Pro Lys Arg Arg Ile Leu Ile Val Val Pro Glu Ile Phe Leu
830 835 840
Pro Ile Glu Asp Glu Cys Gly Asp Val Leu Val Met Arg Lys Ser
845 850 855
Ala Ser Pro Thr Ser Ile Thr Thr Tyr Glu Thr Cys Gln Thr Tyr
860 865 870
Glu Arg Pro Ile Ala Phe Thr Ser Arg Ser Arg Lys Leu Trp Ile
875 880 885
Gln Phe Lys Ser Asri Glu Gly Asn Ser Gly Lys Gly Phe Gln VaI
890 895 900
Pro Tyr Val Thr Tyr Asp Glu Asp Tyr Gln Gln Leu Ile G1u Asp
905 910 915
Ile Val Arg Asp Gly Arg Leu Tyr Ala Ser Glu Asn His Gln Glu
920 925 930
Ile Leu Lys Asp Lys Lys Leu Ile Lys Ala Leu Phe Asp Val Leu
935 940 945
Ala His Pro Gln Asn Arg Gly Leu Val Ser Ser Cys
950 955
<2l0> 21
<211> 1393
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 3351332CD1
<400> 21 '
Met Gly Ala Ser Arg Asap Arg Gly Leu Ala Ala Leu Trp Cys Leu
1 5 10 15~
Gly Leu Leu Gly Gly Leu A1a Arg Val Ala Gly Thr His Tyr Arg
20 25 30
Tyr Leu Trp Arg Gly Cys Tyr Pro Cys His Leu Gly Gln A1a Gly
35 40 45
Tyr Pro Val Ser Ala Gly Asp Gln Arg Pro Asp Val Asp Glu Cys
50 55 60
Arg Thr His Asn Gly Gly Cys Gln His Arg Cys Val Asn Thr Pro
65 70 75
Gly Ser Tyr Leu Cys Glu Cys Lys Pro Gly Phe Arg Leu His Thr
80 85 90
Asp Ser Arg Thr Cys Leu Ala Ile Asn Ser Cys Ala Leu Gly Asn
95 100 105
Gly Gly Cys Gln His His Cys Val Gln Leu Thr Ile Thr Arg His
110 115 120
Arg Cys Gln Cys Arg Pro Gly Phe Gln Leu Gln Glu Asp Gly Arg
125 130 135
His Cys Val Arg Arg Ser Pro Cys Ala Asn Arg Asn Gly Ser Cys
37/l23
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
140 145 150
Met His Arg Cys Gln Val Val Arg Gly Leu Ala Arg Cys Glu Cys
155 160 165
His Val Gly Tyr Gln Leu Ala Ala Asp Gly Lys Ala Cys Pro Asp
170 ~ 175 180
Val Asp Glu Cys Ala Ala Gly Leu Ala Gln Cys Ala His Gly Cys
185 190 195
Leu Asn Thr Gln Gly Ser Phe Lys Cys Val Cys His Ala Gly Tyr
200 205 210
Glu Leu Gly Ala Asp Gly Arg Gln Cys Tyr Arg Ile Glu Met Glu
215 220 225
Ile Val Asn Ser Cys Glu Ala Asn Asn Gly Gly Cys Ser His Gly
230 235 240
Cys Ser His Thr Ser Ala Gly Pro Leu Cys Thr Cys Pro Arg Gly
245 250 255
Tyr Glu Leu Asp Thr Asp Gln Arg Thr Cys Ile Asp Val Asp Asp
260 265 270
Cys Ala Asp Ser Pro Cys Cys Gln Gln Val Cys Thr Asn Asn Pro
275 280 285
Gly Gly Tyr Glu Cys Gly Cys Tyr Ala Gly Tyr Arg Leu Ser Ala
290 295 300
Asp Gly Cys Gly Cys Glu Asp Val Asp Glu Cys Ala Ser Ser Arg
305 310 315
Gly Gly Cys Glu His His Cys Thr Asn Leu Ala Gly Ser Phe Gln
320 325 330
Cys Ser Cys Glu Ala G1y Tyr Arg Leu His Glu Asp Arg Arg Gly
335 340 345
Cys Ser Pro Leu Glu Glu Pro Met Val Asp Leu Asp G1y G1u Leu
350 355 360
Pro Phe Val Arg Pro Leu Pro His Ile Ala Val Leu Gln Asp Glu
365 370 375
Leu Pro Gln Leu Phe Gln Asp Asp Asp Val Gly Ala Asp Glu Glu
380 385 390
Glu Ala Glu Leu Arg Gly Glu His Thr Leu Thr Glu Lys Phe Val
395 400 405
Cys Leu Asp Asp Ser Phe Gly His Asp Cys Ser Leu Thr Cys Asp
410 415 420
Asp Cys Arg Asn Gly Gly Thr Cys Leu Leu Gly Leu Asp Gly Cys
425 430 435
Asp Cys Pro Glu Gly Trp Thr Gly Leu Ile Cys Asn Glu Thr Cys
440 445 450
Pro Pro Asp Thr Phe Gly Lys Asn Cys Ser Phe Ser Cys Ser Cys
455 460 465
Gln Asn Gly Gly Thr Cys Asp Ser Val Thr Gly Ala Cys Arg Cys
470 475 480
Pro Pro Gly Val Ser Gly Thr Asn Cys Glu Asp Gly Cys Pro Lys
485 490 495
Gly Tyr Tyr Gly Lys His Cys Arg Lys Lys Cys Asn Cys Ala Asn
500 505 510
Arg Gly Arg Cys His Arg Leu Tyr Gly Ala Cys Leu Cys Asp Pro
515 520 525
Gly Lei Tyr Gly Arg Phe Cys His Leu Thr Cys Pro Pro Trp Ala
530 535 540
Phe Gly Pro Gly Cys Ser Glu Glu Cys Gln Cys Val Gln Pro His
545 550 555
Thr Gln Ser Cys Asp Lys Arg Asp Gly Ser Cys Ser Cys Lys Ala
38/123
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560 565 570
Gly Phe Arg Gly Glu Arg Cys Gln Ala Glu Cys Glu Leu Gly Tyr
575 580 585
Phe Gly Pro Gly Cys Trp Gln Ala Cys Thr Cys Pro Val Gly Val
590 595 600
Ala Cys Asp Ser Val Ser Gly Glu Cys Gly Lys Arg Cys Pro Ala
605 610 615
Gly Phe Gln Gly Glu Asp Cys Gly Gln Glu Cys Pro Val Gly Thr
620 625 630
Phe Gly Val Asn Cys Ser Ser Ser Cys Ser Cys Gly Gly Ala Pro
635 640 645
Cys His Gly Val Thr Gly Gln Cys Arg Cys Pro Pro Gly Arg Thr
650 655 660
Gly Glu Asp Cys Glu Ala Asp Cys Pro Glu Gly Arg Trp Gly Leu
665 670 675
Gly Cys Gln Glu Ile Cys Pro Ala Cys Gln His Ala A1a Arg Cys
680 685 690
Asp Pro Glu Thr G1y Ala Cys Leu Cys Leu Pro Gly Phe Val Gly
695 700 705
Ser Arg Cys Gln Asp Val Cys Pro Ala Gly Trp Tyr Gly Pro Ser
710 715 720
Cys Gln Thr Arg Cys Ser Cys Ala Asn Asp Gly His Cys His Pro '
725 730 735
Ala Thr Gly His Cys Ser Cys Ala Pro Gly Trp Thr Gly Phe Ser
740 745 750
Cys Gln Arg Ala Cys Asp Thr Gly His Trp Gly Pro Asp Cys Ser
755 760 765
His Pro Cys Asn Cys Ser Ala G1y His Gly Ser Cys Asp Ala Ile
770 775 780
Ser Gly Leu Cys Leu Cys Glu Ala Gly Tyr Val Gly Pro Arg Cys
785 790 795
Glu Gln Gln Cys Pro Gln Gly His Phe Gly Pro Gly Cys Glu Gln
800 805 810
Leu Cys Gln Cys Gln His G1y Ala Ala Cys Asp His Val Ser Gly
815 820 825
Ala Cys Thr Cys Pro Ala Gly Trp Arg Gly Thr Phe Cys Glu His
830 835 840
Ala Cys Pro Ala Gly Phe Phe Gly Leu Asp Cys Arg Ser Ala Cys
845 850 855
Asn Cys Thr Ala Gly Ala Ala Cys Asp Ala Val Asn Gly Ser Cys
860 865 870
Leu Cys Pro Ala Gly Arg Arg Gly Pro Arg Cys Ala Glu Thr Cys
875 880 885
Pro Ala His Thr Tyr Gly His Asn Cys Ser Gln Ala Cys Ala Cys
890 895 900
Phe Asn Gly Ala Ser Cys Asp Pro Val His Gly Gln Cys His Cys
905 9l0 915
Ala Pro Gly Trp Met Gly Pro Ser Cys Leu Gln Glu Cys Leu Pro
920 925 930
Arg Asp Val Arg Ala Gly Cys Arg His Ser Gly Gly Cys Leu Asn
935 940 945
Gly Gly Leu Cys Asp Pro His Thr Gly Arg Cys Leu Cys Pro Ala
950 955 960
Gly Trp Thr Gly Asp Lys Cys Gln Ser Pro Cys Leu Arg Gly Trp
965 970 975
Phe Gly Glu Ala Cys Ala Gln Arg Cys Ser Cys Pro Pro Gly Ala
39/123
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980 985 990
Ala Cys His His Val Thr Gly Ala Cys Arg Cys Pro Pro Gly Phe
995 1000 1005
Thr Gly Ser Gly Cys Glu Gln Ala Cys Pro Pro Gly Ser Phe Gly
1010 1015 1020
Glu Asp Cys Ala Gln Met Cys Gln Cys Pro Gly Glu Asn Pro Ala
1025 1030 1035
Cys His Pro Ala Thr Gly Thr Cys Ser Cys Ala Ala Gly Tyr His
1040 1045 1050
Gly Pro Ser Cys Gln Gln Arg Cys Pro Pro Gly Arg Tyr Gly Pro
1055 1060 1065
Gly Cys Glu Gln Leu Cys Gly Cys Leu Asn Gly Gly Ser Cys Asp
1070 1075 1080
Ala Ala Thr Gly Ala Cys Arg Cys Pro Thr Gly Phe Leu Gly Thr
1085 1090 1095
Asp Cys Asn Leu Thr Cys Pro Gln Gly Arg Phe Gly Pro Asn Cys
1100 1105 1110
Thr His Val Cys Gly Cys Gly Gln Gly Ala Ala Cys Asp Pro Val
1115 1120 1125
Thr Gly Thr Cys Leu Cys Pro Pro Gly Arg Ala Gly Va1 Arg Cys
1130 1135 1140
Glu Arg Gly Cys Pro Gln Asn Arg Phe Gly Val Gly Cys Glu His
1145 1150 1155
Thr Cys Ser Cys Arg Asn,Gly Gly Leu Cys His Ala Ser Asn Gly
1160 1165 1170
Ser Cys Ser Cys Gly Leu Gly Trp Thr Gly Arg His Cys Glu Leu
1175 1180 1185
Ala Cys Pro Pro Gly Arg Tyr Gly Ala Ala Cys His Leu Glu Cys
1190 1195 1200
Ser Cys His Asn Asn Ser Thr Cys Glu Pro Ala Thr Gly Thr Cys
1205 1210 1215
Arg Cys Gly Pro Gly Phe Tyr Gly Gln Ala Cys Glu His Pro Cys
1220 1225 1230
Pro Pro Gly Phe His Gly Ala Gly Cys Gln Gly Leu Cys Trp Cys
1235 1240 1245
Gln His Gly Ala Pro Cys Asp Pro Ile Ser Gly Arg Cys Leu Cys
1250 1255 1260
Pro Ala Gly Phe His Gly His Phe Cys Glu Arg Gly Cys G1u Pro
1265 1270 1275
Gly Ser Phe Gly Glu Gly Cys His Gln Arg Cys Asp Cys Asp Gly
1280 1285 1290
Gly Ala Pro Cys Asp Pro Val Thr Gly Leu Cys Leu Cys Pro Pro
1295 1300 1305
Gly Arg Ser Gly Ala Thr Cys Asn Leu Asp Cys Arg Arg Gly.Gln
1310 1315 1320
Phe Gly Pro Ser Cys Thr Leu His Cys Asp Cys Gly Gly Gly Ala
1325 1330 1335
Asp Cys Asp Pro Val Ser Gly Gln Cys His Cys Val Asp Gly Tyr
1340 1345 1350
Met Gly Pro Thr Cys Arg Glu Gly Gly Pro Leu Arg Leu Pro Glu
1355 1360 1365
Asn Pro Ser Leu Ala Gln Gly Ser Ala Gly Thr Leu Pro Ala Ser
1370 1375 1380
Ser Arg Pro Thr Ser Arg Ser Gly Gly Pro Ala Arg His
1385 1390
40/123
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<210> 22
<211> 3695
<212> PRT
<213> Homo sapiens
<220>
<221> misc feature
<223> Incyte ID No: 6382722CD1
<400> 22
Met Ala Lys Arg Leu Cys Ala Gly Ser Ala Leu Cys Val Arg Gly
1 5 10 15
Pro Arg G1y Pro Ala Pro Leu Leu Leu Val Gly Leu Ala Leu Leu
20 25 30
Gly Ala Ala Arg Ala Arg Glu Glu Ala Gly Gly Gly Phe Ser Leu
35 40 45
His Pro Pro Tyr Phe Asn Leu Ala Glu Gly Ala Arg Ile Ala Ala
50 55 60
Ser Ala Thr Cys Gly Glu Glu Ala Pro Ala Arg Gly Ser Pro Arg
65 70 75
Pro Thr Glu Asp Leu Tyr Cys Lys Leu Val Gly G1y Pro Val Ala
80 85 90
Gly Gly Asp Pro Asn Gln Thr Ile Arg Gly G1n Tyr Cys Asp Ile
95 100 105
Cys Thr Ala Ala Asn Ser Asn Lys Ala His Pro Ala Ser Asn Ala
110 115 120
Ile Asp Gly Thr Glu Arg Trp Trp Gln Ser Pro Pro Leu Ser Arg
125 130 135
Gly Leu Glu Tyr Asn G1u Val Asn Val Thr Leu Asp Leu Gly Gln
140 145 150
Val Phe His Val Ala Tyr Val Leu Ile Lys Phe Ala Asn Ser Pro
155 160 165
Arg Pro Asp Leu Trp Val Leu Glu Arg Ser Met Asp Phe Gly Arg
170 175 180
Thr Tyr Gln Pro Trp Gln Phe Phe Ala Ser Ser Lys Arg Asp Cys
185 190 195
Leu Glu Arg Phe Gly Pro Gln Thr Leu Glu Arg Ile Thr Arg Asp
200 205 210
Asp Ala Ala Ile Cys Thr Thr Glu Tyr Ser Arg Ile Val Pro Leu
215 220 225
Glu Asn Gly Glu Ile Val Val Ser Leu Val Asn Gly Arg Pro Gly
230 235 240
Ala Met Asn Phe Ser Tyr Ser Pro Leu Leu Arg Glu Phe Thr Lys
245 250 255
Ala Thr Asn Val Arg Leu Arg Phe Leu Arg Thr Asn Thr Leu Leu
260 265 270
Gly His Leu Met Gly Lys Ala Leu Arg Asp Pro Thr Val Thr Arg
275 280 285
Arg Tyr Tyr Tyr Ser Ile Lys Asp Ile Ser Ile Gly Gly Arg Cys
290 295 300
Val Cys His Gly His Ala Asp Ala Cys Asp Ala Lys Asp Pro Thr
305 310 315
Asp Pro Phe Arg Leu GIn Cys Thr Cys Gln His Asn Thr Cys Gly
320 325 330
Gly Thr Cys Asp Arg Cys Cys Pro Gly Phe Asn Gln Gln Pro Trp
335 340 ~ 345
41/123
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Lys Pro Ala Thr Ala Asn Ser Ala Asn Glu Cys G1n Ser Cys Asn
350 355 360
Cys Tyr Gly His Ala Thr Asp Cys Tyr Tyr Asp Pro Glu Val Asp
365 370 375
Arg Arg Arg Ala Ser Gln Ser Leu Asp Gly Thr Tyr Gln Gly Gly
380 385 390
Gly Val Cys Ile Asp Cys Gln His His Thr Ala Gly Val Asn Cys
395 400 405
Glu Arg Cys Leu Pro Gly Phe Tyr Arg Ser Pro Asn His Pro Leu
410 415 420
Asp Ser Pro His Val Cys Arg Arg Cys Asn Cys Glu Ser Asp Phe
425 430 435
Thr Asp Gly Thr Cys Glu Asp Leu Thr Gly Arg Cys Tyr Cys Arg
440 445 450
Pro Asn Phe Ser Gly Glu Arg Cys Asp Val Cys Ala Glu Gly Phe
455 460 465
Thr Gly Phe Pro Ser Cys Tyr Pro Thr Pro Ser Ser Ser Asn Asp
470 475 480
Thr Arg G1u Gln Val Leu Pro Ala Gly Gln Ile Val Asn Cys Asp
485 490 495
Cys Ser Ala Ala Gly Thr Gln Gly Asn Ala Cys Arg Lys Asp Pro
500 505 510
Arg Val Gly Arg Cys Leu Cys Lys Pro Asn Phe Gln Gly Thr His
515 520 525
Cys Glu Leu Cys Ala Pro Gly Phe Tyr Gly Pro Gly Cys Gln Pro
530 535 540
Cys Gln Cys Ser Ser Pro Gly Val A1a Asp Asp Arg Cys Asp Pro
545 550 555
Asp Thr Gly Gln Cys Arg Cys Arg Val Gly Phe Glu Gly A1a Thr
560 565 570
Cys Asp Arg Cys Ala Pro Gly Tyr Phe His Phe Pro Leu Cys Gln
575 580 585
Leu Cys Gly Cys Ser Pro Ala Gly Thr Leu Pro Glu Gly Cys Asp
590 595 600
Glu Ala Gly Arg Cys Leu Cys Gln Pro Glu Phe Ala Gly Pro His
605 610 615
Cys Asp Arg Cys Arg Pro Gly Tyr His Gly Phe Pro Asn Cys Gln
620 625 630
Ala Cys Thr Cys Asp Pro Arg Gly Ala Leu Asp Gln Leu Cys Gly
635 640 645
Ala Gly Gly Leu Cys Arg Cys Arg Pro Gly Tyr Thr Gly Thr Ala
650 655 660
Cys Gln Glu Cys Ser Pro Gly Phe His Gly Phe Pro Ser Cys Val
665 670 675
Pro Cys His Cys Ser Ala Glu Gly Ser Leu His Ala Ala Cys Asp
680 685 690
Pro Arg Ser Gly Gln Cys Ser Cys Arg Pro Arg Val Thr Gly Leu
695 700 705
Arg Cys Asp Thr Cys Va1 Pro Gly Ala Tyr Asn Phe Pro Tyr Cys
710 ~ 715 720
Glu Ala Gly Ser Cys His Pro Ala Gly Leu Ala Pro Val Asp Pro
725 730 735
Ala Leu Pro Glu Ala Gln Val Pro Cys Met Cys Arg Ala His Val
740 745 750
Glu Gly Pro Ser Cys Asp Arg Cys Lys Pro Gly Phe Trp Gly Leu
755 760 765
42/123
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Ser Pro Ser Asn Pro Glu Gly Cys Thr Arg Cys Ser Cys Asp Leu
770 775 780
Arg Gly Thr Leu Gly Gly Val Ala Glu Cys Gln Pro Gly Thr Gly
785 790 795
Gln Cys Phe Cys Lys Pro His Val Cys Gly Gln Ala Cys Ala Ser
800 805 810
Cys Lys Asp Gly Phe Phe Gly Leu Asp Gln Ala Asp Tyr Phe Gly
815 820 825
Cys Arg Ser Cys Arg Cys Asp Ile Gly Gly Ala Leu Gly Gln Ser
830 835 840
Cys Glu Pro Arg Thr Gly Val Cys Arg Cys Arg Pro Asn Thr Gln
845 850 855
Gly Pro Thr Cys Ser Glu Pro Ala Arg Asp His Tyr Leu Pro Asp
860 865 870
Leu His His Leu Arg Leu Glu Leu Glu Glu Ala Ala Thr Pro Glu
875 880 885
Gly His Ala Val Arg Phe Gly Phe Asn Pro Leu Glu Phe Glu Asn
890 895 900
Phe Ser Trp Arg Gly Tyr Ala Gln Met Ala Pro Val Gln Pro Arg
905 910 915
Ile Val Ala Arg Leu Asn Leu Thr Ser Pro Asp Leu Phe Trp Leu
920 925 930
Val Phe Arg Tyr Val Asn Arg Gly Ala Met Ser Val Ser Gly Arg
935 940 945
Val Ser Val Arg Glu Glu Gly Arg Ser Ala Ala Cys Ala Asn Cys
950 955 960
Thr Ala Gln Ser Gln Pro Val Ala Phe Pro Pro Ser Thr Glu Pro
965 970 975
Ala Phe Ile Thr Val Pro Gln Arg Gly Phe G1y G1u Pro Phe Val
980 985 990
Leu Asn Pro Gly Thr Trp Ala Leu Arg Val Glu Ala Glu Gly Val
995 1000 1005
Leu Leu Asp Tyr Val Val Leu Leu Pro Ser Ala Tyr Tyr Glu Ala
1010 1015 1020
Ala Leu Leu Gln Leu Arg Val Thr G1u Ala Cys Thr Tyr Arg Pro
1025 1030 1035
Ser Ala Gln Gln Ser Gly Asp Asn Cys Leu Leu Tyr Thr His Leu
1040 1045 1050
Pro Leu Asp Gly Phe Pro Ser Ala Ala Gly Leu Glu Ala Leu Cys
1055 1060 1065
Arg Gln Asp Asn Ser Leu Pro Arg Pro Cys Pro Thr Glu Gln Leu
1070 1075 1080
Ser Pro Ser His Pro Pro Leu Ile Thr Cys Thr Gly Ser Asp Val
1085 1090 1095
Asp Val Gln Leu Gln Val Ala Val Pro Gln Pro Gly Arg Tyr Ala
1100 1105 1110
Leu Val Val Glu Tyr Ala Asn Glu Asp Ala Arg Gln Glu Val Gly
1115 1120 1125
Val Ala Val His Thr Pro Gln Arg Ala Pro Gln Gln Gly Leu Leu
1130 1135 1140
Ser Leu His Pro Cys Leu Tyr Ser Thr Leu Cys Arg Gly Thr Ala
1145 1150 1155
Arg Asp Thr Gln Asp His Leu Ala Val Phe His Leu Asp Ser Glu
1160 1165 1170
Ala Ser Val Arg Leu Thr Ala Glu Gln Ala Arg Phe Phe Leu His
1175 1180 1185
43/123
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Gly Val Thr Leu Val Pro Ile Glu G1u Phe Ser Pro Glu Phe Val
1190 1195 1200
Glu Pro Arg Val Ser Cys Ile Ser Ser His Gly Ala Phe Gly Pro
1205 1210 1215
Asn Ser Ala Ala Cys Leu Pro Ser Arg Phe Pro Lys Pro Pro Gln
1220 1225 1230
Pro Ile Ile Leu Arg Asp Cys Gln Val Ile Pro Leu Pro Pro Gly
1235 1240 1245
Leu Pro Leu Thr His Ala Gln Asp Leu Thr Pro Ala Thr Ser Pro
1250 1255 1260
Ala Gly Pro Arg Pro Arg Pro Pro Thr Ala Val Asp Pro Asp Ala
1265 1270 1275
Glu Pro Thr Leu Leu Arg Glu Pro Gln Ala Thr Val Val Phe Thr
1280 1285 1290
Thr His Val Pro Thr Leu Gly Arg Tyr Ala Phe Leu Leu His Gly
1295 1300 1305
Tyr Gln Pro Ala His Pro Thr Phe Pro Val Glu Val Leu Ile Asn
1310 1315 1320
Ala Gly Arg Val Trp Gln Gly His Ala Asn Ala Ser Phe Cys Pro
1325 1330 1335
His Gly Tyr Gly Cys Arg Thr Leu Val Val Cys Glu Gly G1n Ala
1340 1345 1350
Leu Leu Asp Val Thr His Ser Glu Leu Thr Val Thr Val Arg Val
1355 1360 1365
Pro Glu Gly Arg Trp Leu Trp Leu Asp Tyr Val Leu Val Val Pro
1370 1375 1380
Glu Asn Val Tyr Ser Phe Gly Tyr Leu Arg Glu Glu Pro Leu Asp
1385 1390 1395
Lys Ser Tyr Asp Phe Ile Ser His Cys Ala Ala Gln Gly Tyr His
1400 1405 1410
Ile Ser Pro Ser Ser Ser Ser Leu Phe Cys Arg Asn Ala Ala A1a
1415 1420 1425
Ser Leu Ser Leu Phe Tyr Asn Asn Gly Ala Arg Pro Cys Gly Cys
1430 1435 1440
His Glu Val G1y Ala Thr Gly Pro Thr Cys Glu Pro Phe Gly Gly
1445 1450 1455
Gln Cys Pro Cys His Ala His Val Ile Gly Arg Asp Cys Ser Arg
1460 1465 1470
Cys Ala Thr Gly Tyr Trp Gly Phe Pro Asn Cys Arg Pro Cys Asp
1475 1480 1485
Cys Gly Ala Arg Leu Cys Asp Glu Leu Thr Gly G1n Cys Ile Cys
1490 1495 1500
Pro Pro Arg Thr Ile Pro Pro Asp Cys Leu Leu Cys Gln Pro Gln
1505 1510 1515
Thr Phe Gly Cys His Pro Leu Val Gly Cys Glu Glu Cys Asn Cys
1520 1525 1530
Ser Gly Pro Gly Ile Gln Glu Leu Thr Asp Pro Thr Cys Asp Thr
1535 1540 1545
Asp Ser Gly Gln Cys Lys Cys Arg Pro Asn Val Thr Gly Arg Arg
1550 1555 1560
Cys Asp Thr Cys Ser Pro Gly Phe His Gly Tyr Pro Arg Cys Arg
1565 1570 1575
Pro Cys Asp Cys His Glu Ala Gly Thr Ala Pro Gly Val Cys Asp
1580 1585 1590
Pro Leu Thr Gly Gln Cys Tyr Cys Lys Glu Asn Val Gln Gly Pro
1595 1600 1605
44/123
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Lys Cys Asp Gln Cys Ser Leu Gly Thr Phe Ser Leu Asp Ala Ala
1610 ~ 1615 1620
Asn Pro Lys Gly Cys Thr Arg Cys Phe Cys Phe Gly Ala Thr Glu
1625 1630 1635
Arg Cys Arg Ser Ser Ser Tyr Thr Arg Gln Glu Phe Val Asp Met
1640 1645 1650
Glu Gly Trp Val Leu Leu Ser Thr Asp Arg Gln Val Val Pro His
1655 1660 1665
Glu Arg Gln Pro Gly Thr Glu Met Leu Arg Ala Asp Leu Arg His
1670 1675 1680
Val Pro G1u Ala Val Pro Glu Ala Phe Pro Glu Leu Tyr Trp Gln
1685 1690 1695
Ala Pro Pro Ser Tyr Leu Gly Asp Arg Val Ser Ser Tyr Gly Gly
1700 1705 1710
Thr Leu Arg Tyr Glu Leu His Ser Glu Thr Gln Arg Gly Asp Val
1715 1720 1725
Phe Val Pro Met Glu Ser Arg Pro Asp Val Val Leu Gln Gly Asn
1730 1735 1740
Gln Met Ser Ile Thr Phe Leu Glu Pro A1a Tyr Pro Thr Pro Gly
1745 1750 1755
His Val His Arg Gly Gln Leu Gln Leu Val Glu Gly Asn Phe Arg
1760 1765 1770
His Thr Glu Thr Arg Asn Thr Val Ser Arg Glu Glu Leu Met Met
1775 1780 1785
Val Leu Ala Ser Leu Glu Gln Leu G1n Ile Arg Ala, Leu Phe Ser
1790 1795 1800
Gln Ile Ser Ser Ala Val Ser Leu Arg Arg Val Ala Leu Glu Val
1805 1810 ' 1815
Ala Ser Pro Ala Gly Gln Gly Ala Leu Ala Ser Asn Val Glu Leu
1820 1825 1830
Cys Leu Cys Pro Ala Ser Tyr Arg Gly Asp Ser Cys Gln Glu Cys
1835 1840 1845
Ala Pro Gly Phe Tyr Arg Asp Val Lys Gly Leu Phe Leu Gly Arg
1850 1855 1860
Cys Val Pro Cys Gln Cys His Gly His Ser Asp Arg Cys Leu Pro
1865 1870 1875
Gly Ser Gly Val Cys Val Asp Cys Gln His Asn Thr Glu Gly Ala
1880 1885 1890
His Cys Glu Arg Cys Gln Ala Gly Phe Met Ser Ser Arg Asp Asp
1895 1900 1905
Pro Ser Ala Pro Cys Val Ser Cys Pro Cys Pro Leu Ser Val Pro
1910 1915 1920
Ser Asn Asn Phe Ala Glu Gly Cys Val Leu Arg Gly Gly Arg Thr
1925 1930 1935
Gln Cys Leu Cys Lys Pro Gly Tyr Ala Gly Ala Ser Cys Glu Arg
1940 1945 1950
Cys Ala Pro Gly Phe Phe Gly Asn Pro Leu Val Leu Gly Ser Ser
1955 1960 1965
Cys Gln Pro Cys Asp Cys Ser Gly Asn Gly Asp Pro Asn Leu Leu
1970 1975 1980
Phe Ser Asp Cys Asp Pro Leu Thr Gly Ala Cys Arg Gly Cys Leu
1985 1990 1995
Arg His Thr Thr Gly Pro Arg Cys Glu Ile Cys Ala Pro G1y Phe
2000 2005 2010
Tyr Gly Asn Ala Leu Leu Pro Gly Asn Cys Thr Arg Cys Asp Cys
2015 2020 2025
45/123
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Thr Pro Cys Gly Thr Glu Ala Cys Asp Pro His Ser Gly His Cys
2030 2035 2040
Leu Cys Lys Ala Gly Val Thr Gly Arg Arg Cys Asp Arg Cys Gln
2045 2050 2055
Glu Gly His Phe Gly Phe Asn Gly Cys Gly Gly Cys Arg Pro Cys
2060 2065 2070
Ala Cys Gly Pro Ala Ala Glu Gly Ser Glu Cys His Pro Gln Ser
2075 2080 2085
Gly Gln Cys His Cys Arg Pro Gly Thr Met Gly Pro Gln Cys Arg
2090 2095 2100
Glu Cys Ala Pro Gly Tyr Trp Gly Leu Pro Glu Gln Gly Cys Arg
2105 2110 2115
Arg Cys Gln Cys Pro Gly Gly Arg Cys Asp Pro His Thr Gly Arg
2120 2125 2130
Cys Asn Cys Pro Pro Gly Leu Ser Gly Glu Arg Cys Asp Thr Cys
2135 2140 2145
Ser Gln Gln His Gln Val Pro Val Pro Gly Gly Pro Val Gly His
2150 2155 2160
Ser Ile His Cys Glu Val Cys Asp His Cys Val Va1 Leu Leu Leu
2165 2170 2175
Asp Asp Leu Glu Arg Ala Gly Ala Leu Leu Pro Ala Ile His Glu
2180 2185 2190
Gln Leu Arg Gly Ile Asn Ala Ser Ser Met Ala Trp Ala Arg Leu
2195 2200 2205
His Arg Leu Asn Ala Ser Ile Ala Asp Leu Gln Ser Gln Leu Arg
2210 2215 2220
Ser Pro Leu Gly Pro Arg His Glu Thr Ala Gln Gln Leu Glu Val
2225 2230 2235
Leu Glu Gln Gln Ser Thr Ser Leu Gly Gln Asp Ala Arg Arg Leu
2240 2245 2250
Gly Gly Gln Ala Val Gly Thr Arg Asp Gln Ala Ser Gln Leu Leu
2255 2260 2265
Ala Gly Thr Glu A1a Thr Leu Gly His Ala Lys Thr Leu Leu Ala
2270 2275 2280
Ala Ile Arg Ala Val Asp Arg Thr Leu Ser Glu Leu Met Ser Gln
2285 2290 2295
Thr Gly His Leu Gly Leu Ala Asn Ala Ser Ala Pro Ser Gly Glu
2300 2305 2310
Gln Leu Leu Arg Thr Leu Ala Glu Val Glu Arg Leu Leu Trp Glu
2315 2320 2325
Met Arg Ala Arg Asp Leu G1y Ala Pro Gln Ala Ala Ala Glu Ala
2330 2335 2340
Glu Leu Ala Ala Ala Gln Arg Leu Leu A1a Arg Va1 Gln Glu Gln
2345 2350 2355
Leu Ser Ser Leu,Trp Glu Glu Asn Gln Ala Leu Ala Thr Gln Thr
2360 2365 2370
Arg Asp Arg Leu Ala Gln His Glu Ala Gly Leu Met Asp Leu Arg
2375 2380 2385
Glu Ala Leu Asn Arg Ala Val Asp Ala Thr Arg Glu Ala Gln Glu
2390 2395 2400
Leu Asn Ser Arg Asn Gln Glu Arg Leu Glu Glu A1a Leu Gln Arg
2405 2410 2415
Lys Gln Glu Leu Ser Arg Asp Asn A1a Thr Leu Gln Ala Thr Leu
2420 2425 2430
His Ala Ala Arg Asp Thr Leu Ala Ser Val Phe Arg Leu Leu His
2435 2440 2445
46/123
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Ser Leu Asp Gln Ala Lys Glu Glu Leu Glu Arg Leu Ala Ala Ser
2450 2455 2460
Leu Asp Gly Ala Arg Thr Pro Leu Leu Gln Arg Met Gln Thr Phe
2465 2470 2475
Ser Pro Ala Gly Ser Lys Leu Arg Leu Val Glu Ala Ala Glu Ala
2480 2485 2490
His Ala Gln Gln Leu Gly Gln Leu Ala Leu Asn Leu Ser Ser Ile
2495 2500 2505
Ile Leu Asp Val Asn Gln Asp Arg Leu Thr Gln Arg Ala Ile Glu
2510 2515 2520
Ala Ser Asn Ala Tyr Ser Arg Ile Leu Gln Ala Val Gln Ala Ala
2525 2530 2535
Glu Asp Ala Ala Gly Gln Ala Leu Gln Gln Ala Asp His Thr Trp
2540 2545 2550
Ala Thr Val Val Arg Gln Gly Leu Val Asp Arg Ala Gln Gln Leu
2555 2560 2565
Leu Ala Asn Ser Thr Ala Leu Glu Glu Ala Met Leu Gln G1u G1n
2570 2575 2580
Gln Arg Leu Gly Leu Val Trp Ala Ala Leu Gln Gly Ala Arg Thr
2585 2590 2595
Gln Leu Arg Asp Val Arg Ala Lys Lys Asp Gln Leu Glu Ala His
2600 2605 2610
Ile Gln Ala Ala Gln Ala Met Leu Ala Met Asp Thr Asp Glu Thr
2615 2620 2625
Ser Lys Lys Ile Ala His Ala Lys Ala Val Ala Ala Glu Ala Gln
2630 2635 2640
Asp Thr Ala Thr Arg Val Gln Ser Gln Leu Gln Ala Met G1n Glu
2645 2650 2655
Asn Va1 Glu Arg Trp Gln Gly Gln Tyr Glu G1y Leu Arg Gly Gln
2660 2665 2670
Asp Leu Gly Gln Ala Val Leu Asp Ala Gly His Ser Val Ser Thr
2675 2680 268'5
Leu Glu Lys Thr Leu Pro Gln Leu Leu A1a Lys Leu Ser I1e Leu
2690 2695 2700
Glu Asn Arg Gly Val His Asn Ala Ser Leu Ala Leu Ser Ala Ser
2705 2710 2715
Ile Gly Arg Val Arg Glu Leu Ile Ala Gln Ala Arg Gly Ala Ala
2720 2725 2730
Ser Lys Val Lys Val Pro Met Lys Phe Asn Gly Arg Ser Gly Val
2735 2740 2745
Gln Leu Arg Thr Pro Arg Asp Leu Ala Asp Leu Ala Ala Tyr Thr
2750 2755 2760
Ala Leu Lys Phe Tyr Leu Gln Gly Pro Glu Pro G1u Pro Gly Gln
2765 2770 2775
Gly Thr Glu Asp Arg Phe Val Met Tyr Met Gly Ser Arg Gln Ala
2780 2785 2790
Thr Gly Asp Tyr Met Gly Val Ser Leu Arg Asp Lys Lys Val His
2795 2800 2805
Trp Val Tyr Gln Leu Gly Glu Ala Gly Pro Ala Val Leu Ser Ile
2810 2815 2820
Asp Glu Asp Ile Gly Glu Gln.Phe Ala Ala Val Ser Leu Asp Arg
2825 2830 2835
Thr Leu Gln Phe Gly His Met Ser Val Thr Val Glu Arg Gln Met
2840 2845 2850
Ile Gln Glu Thr Lys Gly Asp Thr Val Ala Pro Gly Ala Glu Gly
2855 2860 2865
471123
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Leu Leu Asn Leu Arg Pro Asp Asp Phe Val Phe Tyr Val Gly Gly
2870 2875 2880
Tyr Pro Ser Thr Phe Thr Pro Pro Pro Leu Leu Arg Phe Pro Gly
2885 2890 2895
Tyr Arg Gly Cys Ile Glu Met Asp Thr Leu Asn Glu Glu Val Val
2900 2905 2910
Ser Leu Tyr Asn Phe Glu Arg Thr Phe Gln Leu Asp Thr Ala Val
2915 2920 2925
Asp Arg Pro Cys Ala Arg Ser Lys Ser Thr Gly Asp Pro Trp Leu
2930 2935 2940
Thr Asp Gly Ser Tyr Leu Asp Gly Thr Gly Phe Ala Arg Ile Ser
2945 2950 2955
Phe Asp Ser Gln Ile Ser Thr Thr Lys Arg Phe Glu Gln Glu Leu
2960 2965 2970
Arg Leu Val Ser Tyr Ser Gly Val Leu Phe Phe Leu Lys Gln Gln
2975 2980 ! 2985
Ser Gln Phe Leu Cys Leu Ala Val Gln Glu Gly Ser Leu Val Leu
2990 2995 3000
Leu Tyr Asp Phe Gly Ala Gly Leu Lys Lys Ala Val Pro Leu Gln
3005 3010 3015
Pro Pro Pro Pro Leu Thr Ser Ala Ser Lys Ala Ile Gln Val Phe
3020 3025 3030
Leu Leu Gly Gly Ser Arg Lys Arg Val Leu Val Arg Val Glu Arg
3035 3040 3045
Ala Thr Val Tyr Ser Val Glu Gln Asp Asn Asp Leu Glu Leu Ala
3050 3055 3060
Asp Ala Tyr Tyr Leu Gly Gly Val Pro Pro Asp Gln Leu Pro Pro
3065 3070 3075
Ser Leu Arg Arg Leu Phe Pro Thr Gly Gly Ser Val Arg Gly Cys
3080 3085 3090
Val Lys Gly Ile Lys Ala Leu Gly Lys Tyr Val Asp Leu Lys Arg
3095 3100 3105
Leu Asn Thr Thr Gly Val Ser Ala Gly Cys Thr Ala Asp Leu Leu
3110 3115 3120
Val Gly Arg Ala Met Thr Phe His Gly His Gly Phe Leu Arg Leu
3125 3130 3135
Ala Leu Ser Asn Val Ala Pro Leu Thr Gly Asn Val Tyr Ser Gly
3140 3145 3150
Phe Gly Phe His Ser Ala Gln Asp Ser Ala Leu Leu Tyr Tyr Arg
3155 3160 3165
A1a Ser Pro Asp Gly Leu Cys Gln Val Ser Leu Gln Gln Gly Arg
3170 3175 3180
Val Ser Leu Gln Leu Leu Arg Thr Glu Val Lys Thr Gln Ala Gly
3185 3190 3195
Phe Ala Asp Gly Ala Pro His Tyr Val Ala Phe Tyr Ser Asn Ala
3200 3205 3210
Thr Gly Val Trp Leu Tyr Val Asp Asp Gln Leu Gln Gln Met Lys
3215 3220 3225
Pro His Arg Gly Pro Pro Pro Glu Leu G1n Pro Gln Pro Glu Gly
3230 3235 3240
Pro Pro Arg Leu Leu Leu Gly Gly Leu Pro Glu Ser Gly Thr Ile
3245 3250 3255
Tyr Asn Phe Ser Gly Cys Ile Ser Asn Val Phe Val Gln Arg Leu
3260 3265 3270
Leu Gly Pro Gln Arg Val Phe Asp Leu Gln Gln Asn Leu Gly Ser
3275 3280 3285
48/123
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Val Asn Val Ser Thr Gly Cys Ala Pro Ala Leu Gln Ala Gln Thr
3290 3295 3300
Pro Gly Leu Gly Pro Arg Gly Leu Gln Ala Thr Ala Arg Lys Ala
3305 3310 3315
Ser Arg Arg Ser Arg Gln Pro Ala Arg His Pro Ala Cys Met Leu
3320 3325 3330
Pro Pro His Leu Arg Thr Thr Arg Asp Ser Tyr Gln Phe Gly Gly
3335 3340 3345
Ser Leu Ser Ser His Leu Glu Phe Val Gly Ile Leu Ala Arg His
3350 3355 33&0
Arg Asn Trp Pro Ser Leu Ser Met His Val Leu Pro Arg Ser Ser
3365 3370 3375
Arg Gly Leu Leu Leu Phe Thr Ala Arg Leu Arg Pro Gly Ser Pro
3380 3385 3390
Ser Leu Ala Leu Phe Leu Ser Asn Gly His Phe Val Ala Gln Met
3395 3400 3405
Glu Gly Leu Gly Thr Arg Leu Arg Ala Gln Ser Arg Gln Arg Ser
3410 3415 3420
Arg Pro Gly Arg Trp His Lys Val Ser Val Arg Trp Glu Lys Asn
3425 3430 3435
Arg Ile Leu Leu Val Thr Asp Gly Ala Arg Ala Trp Ser Gln Glu
3440 3445 3450
Gly Pro His Arg Gln His Gln Gly Ala Glu His Pro Gln Pro His
3455 3460 3465
Thr Leu Phe Val Gly G1y Leu Pro Ala Ser Ser His Sex Ser Lys
3470 3475 3480
Leu Pro Val Thr Val Gly Phe Ser Gly Cys Val Lys Arg Leu Arg
3485 3490 3495
Leu His Gly Arg Pro Leu Gly A1a Pro Thr Arg Met Ala Gly Val
3500 3505 3510
Thr Pro Cys Ile Leu Gly Pro Leu Glu Ala Gly Leu Phe Phe Pro
3515 3520 3525
G1y Ser Gly Gly Val Ile Thr Leu Asp Leu Pro Gly Ala Thr Leu
3530 3535 3540
Pro Asp Val G1y Leu Glu Leu Glu Val Arg Pro Leu Ala Val Thr
3545 3550 3555
Gly Leu Ile Phe His Leu Gly Gln Ala Arg Thr Pro Pro Tyr Leu
3560 3565 3570
Gln Leu Gln Val Thr Glu Lys Gln Val Leu Leu Arg Ala Asp Asp
3575 3580 3585
Gly Ala Gly Glu Phe Ser Thr Ser Val Thr Arg Pro Ser Val Leu
3590 3595 3600
Cys Asp Gly Gln Trp His Arg Leu Ala Val Met Lys Ser Gly Asn
3605 3610 3615
Val Leu Arg Leu Glu Val Asp Ala Gln Ser Asn His Thr Val Gly
3620 3625 3630
Pro Leu Leu Ala Ala Ala Ala Gly Ala Pro Ala Pro Leu Tyr Leu
3635 3640 3645
Gly Gly Leu Pro Glu Pro Met Ala Val Gln Pro Trp Pro Pro Ala
3650 3655 3660
Tyr Cys Gly Cys Met Arg Arg Leu Ala Val Asn Arg Ser Pro Val
3665 3670 3675
Ala Met Thr Arg Ser Val Glu Val His Gly Ala Val Gly Ala Ser
3680 3685 3690
Gly Cys Pro Ala Ala
3695
49/123
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WO 02/02634 PCT/USO1/21067
<210> 23
<211> 1255
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 55022490CD1
<400> 23
Met Val Arg Gly Gly Arg Trp Glu Gln Ala His Lys Lys Glu Pro
1 5 10 15
Leu Gly Val Trp Gly Pro Leu Pro Cys Val Arg Gly Ala Gln Gly
20 25 30
Thr Leu Gly Asp Arg Asn Gly Gly Thr Gly Gly Trp Arg His Trp
35 40 45
Gly Gly Cys Glu Gly Met Pro Met Pro Ser Ser Ser Gln Asn Val
50 55 60
Cys Thr Asn Ser Gly Ala Ser Val Gly Thr Thr Cys His Ser Lys
65 70 75
Leu Asp Ala Ala Va1 Asp Gly Thr Arg Cys Gly Glu Asn Lys Trp
80 85 90
Cys Leu Ser Gly Glu Cys Val Pro Val Gly Phe Arg Pro Glu Ala
95 100 105
Val Asp Gly Gly Trp Ser Gly Trp Ser Ala Trp Ser Ile Cys Ser
110 115 120
Arg Ser Cys Gly Met Gly Val Gln Ser Ala Glu Arg Gln Cys Thr
12.5 13 0 13 5
Gln Pro Thr Pro Lys Tyr Lys Gly Arg Tyr Cys Val Gly Glu Arg
140 145 150
Lys Arg Phe Arg Leu Cys Asn Leu Gln Ala Cys Pro Ala Gly His
155 160 165
Pro Ser Phe Arg His Val Gln Cys Ser His Phe Asp Ala Met Leu
170 175 180
Tyr Lys Gly G1n Leu His Thr Trp Val Pro Val Val Asn Asp Val
185 190 195
Asn Pro Cys Glu Leu His Cys Arg Pro Ala Asn Glu Tyr Phe Ala
200 205 210
Glu Lys Leu Arg Asp Ala Val Val Asp Gly Thr Pro Cys Tyr Gln
215 220 225
Val Arg Ala Ser Arg Asp Leu Cys Ile Asn Gly Ile Cys Lys Asn
230 235 240
Val Gly Cys Asp Phe Glu Ile Asp Ser Gly Ala Met Glu Asp Arg
245 250 255
Cys Gly Va1 Cys His Gly Asn Gly Ser Thr Cys His Thr Val Ser
260 265 270
Gly Thr Phe Glu Glu Ala Glu Gly Leu Gly Tyr Val Asp Val Gly
275 280 285
Leu Ile Pro Ala Gly Ala Arg Glu Ile Arg Ile Gln Glu Val Ala
290 295 300
Glu Ala Ala Asn Phe Leu Ala Leu Arg Ser Glu Asp Pro Glu Lys
305 310 315
Tyr Phe Leu Asn Gly Gly Trp Thr Ile Gln Trp Asn Gly Asp Tyr
320 325 330
Gln Val Ala Gly Thr Thr Phe Thr Tyr Ala Arg Arg G1y Asn Trp
335 340 345
50/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Glu Asn Leu Thr Ser Pro Gly Pro Thr Lys Glu Pro Val Trp Ile
350 355 360
Gln Leu Leu Phe Gln Glu Ser Asn Pro Gly Val His Tyr Glu Tyr
365 370 375
Thr Ile His Arg Glu Ala Gly Gly His Asp Glu Val Pro Pro Pro
380 385 390
Val Phe Ser Trp His Tyr Gly Pro Trp Thr Lys Cys Thr Val Thr
395 400 405
Cys Gly Arg Gly Val Gln Arg Gln Asn Val Tyr Cys Leu Glu Arg
410 415 420
Gln Ala Gly Pro Val Asp Glu Glu His Cys Asp Pro Leu Gly Arg
425 430 435
Pro Asp Asp Gln Gln Arg Lys Cys Ser Glu Gln Pro Cys Pro Ala
440 445 450
Arg Trp Trp Ala Gly Glu Trp Gln Leu Cys Ser Ser Ser Cys Gly
455 460 465
Pro Gly Gly Leu Ser Arg Arg Ala Val Leu Cys Ile Arg Ser Val
470 475 480
Gly Leu Asp Glu Gln Ser Ala Leu GIu,Pro Pro Ala Cys Glu His
485 490 495
Leu Pro Arg Pro Pro Thr Glu Thr Pro Cys Asn Arg His Val Pro
500 505 510
Cys Pro Ala Thr,Trp Ala Val Gly Asn Trp Ser Gln Cys Ser Val
515 520 525
Thr Cys Gly Glu Gly Thr Gln Arg Arg Asn Val Leu Cys Thr Asn
530 535 540
Asp Thr Gly Val Pro Cys Asp Glu Ala Gln Gln Pro Ala Ser Glu
545 550 555
Val Thr Cys Sex Leu Pro Leu Cys Arg Trp Pro Leu Gly Thr Leu
560 565 570
Gly Pro Glu Gly Ser Gly Ser Gly Ser Ser Ser His Glu Leu Phe
575 580 585
Asn Glu Ala Asp Phe I1e Pro His His Leu Ala Pro Arg Pro Ser
590 595 600
Pro Ala Ser Sex Pro Lys Pro Gly Thr Met Gly Asn Ala Ile Glu
605 610 615
Glu Glu Ala Pro Glu Leu Asp Leu Pro Gly Pro Val Phe Val Asp
620 625 630
Asp Phe Tyr Tyr Asp Tyr Asn Phe Ile Asn Phe His Glu Asp Leu
635 640 645
Ser Tyr Gly Pro Ser Glu Glu Pro Asp Leu Asp Leu Ala Gly Thr
650 655 660
Gly Asp Arg Thr Pro Pro Pro His Ser Arg Pro Ala Ala Pro Ser
665 670 675
Thr Gly Ser Pro Val Pro Ala Thr Glu Pro Pro Ala Ala Lys Glu
680 685 690
Glu Gly Val Leu Gly Pro Trp Ser Pro Ser Pro Trp Pro Ser Gln
695 700 705
Ala Gly Arg Ser Pro Pro Pro Pro Ser Glu Gln Thr Pro Gly Asn
710 715 720
Pro Leu Ile Asn Phe Leu Pro Glu Glu Asp Thr Pro Ile Gly Ala
725 730 735
Pro Asp Leu Gly Leu Pro Ser Leu Ser Trp Pro Arg Val Ser Thr
740 745 750
Asp Gly Leu G1n Thr Pro Ala Thr Pro Glu Ser Gln Asn Asp Phe
755 760 765
511123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Pro Val Gly Lys Asp Ser Gln Ser Gln Leu Pro Pro Pro Trp Arg
770 775 780
Asp Arg Thr Asn Glu Val Phe Lys Asp Asp Glu Glu Pro Lys Gly
785 790 795
Arg Gly Ala Pro His Leu Pro Pro Arg Pro Ser Ser Thr Leu Pro
800. 805 8l0
Pro Leu Ser Pro Val Gly Ser Thr His Ser Ser Pro Ser Pro Asp
815 820 825
Val Ala Glu Leu Trp Thr Gly G1y Thr Val Ala Trp Glu Pro Ala
830 835 840
Leu Glu Gly Gly Leu Gly Pro Val Asp Ser Glu Leu Trp Pro Thr
845 850 855
Val Gly Val Ala Ser Leu Leu Pro Pro Pro Ile Ala Pro Leu Pro
860 865 870
Glu Met Lys Val Arg Asp Ser Ser Leu Glu Pro Gly Thr Pro Ser
875 880 885
Phe Pro Thr Pro Gly Pro Gly Ser Trp Asp Leu Gln Thr Val Ala
890 895 900
Val Trp Gly Thr Phe Leu Pro Thr Thr Leu Thr Gly Leu Gly His
905 910 9~.5
Met Pro Glu Pro Ala Leu Asn Pro GIy Pro Lys Gly Gln Pro Glu
920 925 930
Ser Leu Ser Pro Glu Val Pro Leu Ser Ser Arg Leu Leu Ser Thr
935 940 945
Pro Ala Trp Asp Ser Pro Ala Asn Ser His Arg Val Pro Glu Thr
950 955 960
Gln Pro Leu Ala Pro Ser Leu Ala Glu Ala Gly Pro Pro Ala Asp
965 970 975
Pro Leu Val Val Arg Asn Ala Ser Trp Gln Ala Gly Asn Trp Ser
980 985 990
Glu Cys Ser Thr Thr Cys Gly Leu Gly A1a Val Trp Arg Pro Val
995 1000 1005
Arg Cys Ser Ser Gly Arg Asp Glu Asp Cys Ala Pro A1a Gly Arg
1010 1015 1020
Pro Gln Pro Ala Arg Arg Cys His Leu Arg Pro Cys Ala Thr Trp
1025 1030 1035
His Ser Gly Asn Trp Ser Lys Cys Ser Arg Ser Cys Gly Gly Gly
1040 1045 1050
Ser Ser Val Arg Asp Val Gln Cys Val Asp Thr Arg Asp Leu Arg
1055 1060 1065
Pro Leu Arg Pro Phe His Cys Gln Pro Gly Pro A1a Lys Pro Pro
1070 1075 1080
Ala His Arg Pro Cys Gly Ala Gln Pro Cys Leu Ser Trp Tyr Thr
1085 ~ 1090 . 1095
Ser Ser Trp Arg Glu Cys Ser Glu Ala Cys Gly Gly Gly Glu Gln
1100 1105 1110
Gln Arg Leu Val Thr Cys Pro Glu Pro Gly Leu Cys Glu Glu Ala
1115 1120 1125
Leu Arg Pro Asn Thr Thr Arg Pro Cys Asn Thr His Pro Cys Thr
1130 1135 1140
Gln Trp Val Va1 Gly Pro Trp Gly Gln Cys Ser Ala Pro Cys Gly
1145 1150 1155
Gly Gly Val Gln Arg Arg Leu Val Lys Cys Val Asn Thr Gln Thr
1160 1165 1170
Gly Leu Pro Glu Glu Asp Ser Asp Gln Cys Gly His Glu Ala Trp
1175 1180 1185
52/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Pro Glu Ser Ser Arg Pro Cys Gly Thr Glu Asp Cys Glu Pro Val
1190 1195 1200
Glu Pro Pro Arg Cys Glu Arg Asp Arg Leu Ser Phe Gly Phe Cys
1205 1210 1215
Glu Thr Leu Arg Leu Leu Gly Arg Cys Gln Leu Pro Thr Ile Arg
1220 1225 1230
Thr Gln Cys Cys Arg Ser Cys Ser Pro Pro Ser His Gly Ala Pro
1235 1240 1245
Ser Arg Gly His Gln Arg Val Ala Arg Arg
1250 1255
<210> 24
<211> 911
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 6755002CD1
<400> 24
Met Ala Gln Leu Phe Leu Pro Leu Leu Ala Ala Leu Val Leu Ala
1 5 10 15
Gln Ala Pro Ala Ala Leu Ala Asp Val Leu Glu Gly Asp Ser Ser
20 25 30
Glu Asp Arg Ala Phe Arg Val Arg Ile Ala Gly Asp Ala Pro Leu
35 40 45
Gln Gly Val Leu Gly G1y Ala Leu Thr Ile Pro Cys His Val His
50 55 60
Tyr Leu Arg Pro Pro Pro Ser Arg Arg A1a Val Leu Gly Ser Pro
65 70 75
Arg Val Lys Trp Thr Phe Leu Ser Arg Gly Arg Glu Ala Glu Val
80 85 90
Leu Val Ala Arg Gly Va1 Arg Val Lys Val Asn Glu Ala Tyr Arg
95 100 105
Phe Arg Val Ala Leu Pro Ala Tyr Pro Ala Ser Leu Thr Asp Val
110 115 120
Ser Leu Ala Leu Ser Glu Leu Arg Pro Asn Asp Ser Gly Ile Tyr
125 130 135
Arg Cys Glu Val Gln His Gly Ile Asp Asp Ser Ser Asp Ala Val
140 145 150
Glu Val Lys Val Lys Gly Val Val Phe Leu Tyr Arg Glu Gly Ser
155 160 165
Ala Arg Tyr Ala Phe Ser Phe Ser Gly Ala Gln G1u Ala Cys Ala
170 175 180
Arg Ile Gly Ala His Ile Ala Thr Pro G1u Gln Leu Tyr Ala Ala
185 190 195
Tyr Leu Gly Gly Tyr Glu Gln Cys Asp Ala Gly Trp Leu Ser Asp
200 205 210
Gln Thr Val Arg Tyr Pro Ile Gln Thr Pro Arg Glu Ala Cys Tyr
215 220 225
Gly Asp Met Asp Gly Phe Pro Gly Val Arg Asn Tyr Gly Val Val
230 235 240
Asp Pro Asp Asp Leu Tyr Asp Val Tyr Cys Tyr Ala Glu Asp Leu
245 250 255
Asn Gly Glu Leu Phe Leu Gly Asp Pro Pro Glu Lys Leu Thr Leu
53/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
260 265 270
Glu Glu Ala Arg Ala Tyr Cys Gln Glu Arg Gly Ala Glu Ile Ala
275 ~ 280 285
Thr Thr Gly Gln Leu Tyr Ala Ala Trp Asp Gly Gly Leu Asp His
290 295 300
Cys Ser Pro Gly Trp Leu Ala Asp Gly Ser Val Arg Tyr Pro Ile
305 310 315
Val Thr Pro Ser Gln Arg Cys Gly Gly Gly Leu Pro Gly Val Lys
320 325 330
Thr Leu Phe Leu Phe Pro Asn Gln Thr Gly Phe Pro Asn Lys His
335 340 345
Ser Arg Phe Asn Val Tyr Cys Phe Arg Asp Ser Ala Gln Pro Ser
350 355 360
Ala Ile Pro Glu Ala Ser Asn Pro Ala Ser Asn Pro Ala Ser Asp
365 370 375
Gly Leu Glu Ala Ile Val Thr Val Thr Glu Thr Leu Glu G1u Leu
380 385 390
Gln Leu Pro Gln Glu Ala Thr Glu Ser Glu Ser Arg Gly Ala Ile
395 400 405
Tyr Ser Ile Pro Ile Met Glu Asp Gly Gly Gly G1y Ser Ser Thr
410 415 420
Pro Glu Asp Pro Ala Glu Ala Pro Arg Thr Leu Leu Glu Phe Glu
425 430 ' 435
Thr Gln Ser Met Val Pro Pro Thr G1y Phe Ser Glu Glu Glu Gly
440 445 450
Lys Ala Leu Glu Glu Glu Glu Lys Tyr Glu Asp Glu Glu Glu Lys
455 460 465
Glu Glu Glu G1u Glu Glu Glu Glu Val Glu Asp Glu Ala Leu Trp
470 475 480
Ala Trp Pro Ser Glu Leu Ser Ser Pro Gly Pro Glu Ala Ser Leu
485 490 495
Pro Thr Glu Pro Ala Ala Gln Glu Lys Ser Leu Ser Gln Ala Pro
500 505 510
Ala Arg Ala Val Leu Gln Pro Gly Ala Ser Pro Leu Pro Asp Gly
5l5 520 525
Glu Ser Glu Ala Ser Arg Pro Pro Arg Val His Gly Pro Pro Thr
530 535 540
Glu Thr Leu Pro Thr Pro Arg Glu Arg Asn Leu Ala Ser Pro Ser
545 550 555
Pro Ser Thr Leu Val Glu Ala Arg Glu Val Gly Glu Ala Thr Gly
560 565 570
Gly Pro Glu Leu Ser Gly Val Pro Arg Gly Glu Ser Glu Glu Thr
575 580 585
Gly Ser Ser Glu Gly Ala Pro Ser Leu Leu Pro Ala Thr Arg Ala
590 595 600
Pro Glu Gly Thr Arg Glu Leu Glu Ala Pro Ser Glu Asp Asn Ser
605 610 615
Gly Arg Thr A1a Pro Ala Gly Thr Ser Val Gln Ala Gln Pro Val
620 625 630
Leu Pro Thr Asp Ser Ala Ser Arg Gly Gly Val Ala Val Val Pro
635 640 645
Ala Ser Gly Asp Cys Val Pro Ser Pro Cys His Asn Gly Gly Thr
650 655 660
Cys Leu Glu Glu Glu Glu Gly Val Arg Cys Leu Cys Leu Pro Gly
665 670 675
Tyr Gly G1y Asp Leu Cys Asp Val Gly Leu Arg Phe Cys Asn Pro
54/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
680 685 690
Gly Trp Asp Ala Phe Gln Gly Ala Cys Tyr Lys His Phe Ser Thr
695 ~ 700 705
Arg Arg Ser Trp Glu Glu Ala Glu Thr Gln Cys.Arg Met Tyr Gly
710 715 720
Ala His Leu Ala Ser Ile Ser Thr Pro Glu Glu Gln Asp Phe Ile
725 730 735
Asn Asn Arg Tyr Arg Glu Tyr Gln Trp Ile Gly Leu Asn Asp Arg
740 745 750
Thr Ile Glu Gly Asp Phe Leu Trp Ser Asp Gly Val Pro Leu Leu
755 760 765
Tyr Glu Asn Trp Asn Pro Gly Gln Pro Asp Ser Tyr Phe Leu Ser
770 775 780
Gly Glu Asn Cys Val Val Met Val Trp His Asp Gln Gly Gln Trp
785 790 795
Ser Asp Val Pro Cys Asn Tyr His Leu Ser Tyr Thr Cys Lys Met
800 805 810
Gly Leu Val Ser Cys Gly Pro Pro Pro Glu Leu Pro Leu Ala Gln
815 820 825
Val Phe Gly Arg Pro Arg Leu Arg Tyr Glu Val Asp Thr Val Leu
830 835 840
Arg Tyr Arg Cys Arg Glu Gly Leu Ala Gln Arg Asn Leu Pro Leu
845 850 855
Ile Arg Cys Gln Glu Asn Gly Arg Trp Glu Ala Pro Gln Ile Ser
860 865 870
Cys Val Pro Arg Arg Pro Ala Arg Ala Leu His Pro Glu Glu Asp
875 880 885
Pro'Glu Gly Arg Gln Gly~Arg Leu Leu Gly Arg Trp Lys Ala Leu
890 895 900
Leu Ile Pro Pro Ser Ser Pro Met Pro Gly Pro
905 910
<210> 25
<211> 467
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7350907CD1
<400> 25
Met Pro Gly Arg Trp Arg Trp Gln Arg Asp Met His Pro Ala Arg
1 5 10 15
Lys Leu Leu Ser Leu Leu Phe Leu Ile Leu Met Gly Thr Glu Leu
20 25 30
Thr G1n Val Leu Pro Thr Asn Pro Glu Glu Ser Trp Gln Val Tyr
35 40 45
Ser Ser Ala Gln Asp Ser Glu Gly Arg Cys Ile Cys Thr Val Val
50 55 60
Ala Pro Gln Gln Thr Met Cys Ser Arg Asp Ala Arg Thr Lys Gln
65 70 75
Leu Arg Gln Leu Leu Glu Lys Val Gln Asn Met Ser Gln Ser Ile
80 85 90
Glu Val Leu Asp Arg Arg Thr Gln Arg Asp Leu Gln Tyr Val Glu
95 100 105
55/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Lys Met Glu Asn Gln Met Lys Gly Leu Glu Ser Lys Phe Lys Gln
110 115 120
Val Glu Glu Ser His Lys Gln His Leu Ala Arg Gln Phe Lys Ala
125 230 135
Ile Lys Ala Lys Met Asp Glu Leu Arg Pro Leu Tle Pro Val Leu
140 145 150
Glu Glu Tyr Lys Ala Asp A1a Lys Leu Val Leu Gln Phe Lys Glu
155 160 165
Glu Val Gln Asn Leu Thr Ser Val Leu Asn Glu Leu Gln Glu Glu
170 175 180
Ile Gly Ala Tyr Asp Tyr Asp Glu Leu Gln Ser Arg Val Ser Asn
185 190 195
Leu Glu Glu Arg Leu Arg Ala Cys Met Gln Lys Leu Ala Cys Gly
200 205 ' 210
Lys Leu Thr Gly Ile Ser Asp Pro Val Thr Val Lys Thr Ser Gly
215 220 225
Ser Arg Phe Gly Ser Trp Met Thr Asp Pro Leu Ala Pro Glu Gly
230 ' 235 240
Asp Asn Arg Val Trp Tyr Met Asp Gly Tyr His Asn Asn Arg Phe
245 250 255
Val Arg Glu Tyr Lys Ser Met Val Asp Phe Met Asn Thr Asp Asn
260 265 270
Phe Thr Ser His Arg Leu Pro His Pro Trp Ser Gly Thr Gly Gln
275 280 285
Val Val Tyr Asn Gly Ser Ile Tyr Phe Asn Lys Phe Gln Ser His
290 295 300
Ile Ile Ile Arg Phe Asp Leu Lys Thr Glu Thr Ile Leu Lys Thr
305 310 315
Arg Ser Leu Asp Tyr Ala Gly Tyr Asn Asn Met Tyr His Tyr Ala
320 325 330
Trp Gly Gly His Ser Asp Ile Asp Leu Met Val Asp Glu Ser Gly
335 340 345
Leu Trp Ala Val Tyr Ala Thr Asn Gln Asn Ala Gly Asn Ile Val
350 355 360
Val Ser Arg Leu Asp Pro Val Ser Leu Gln Thr Leu Gln Thr Trp
365 370 375
Asn Thr Ser Tyr Pro Lys Arg Ser Ala Gly Glu Ala Phe Ile Ile
380 385 390
Cys Gly Thr Leu Tyr Val Thr Asn Gly Tyr Ser'Gly Gly Thr Lys
395 400 405
Val His Tyr Ala Tyr Gln Thr Asn Ala Ser Thr Tyr Glu Tyr Ile
410 415 420
Asp Ile Pro Phe Gln Asn Lys Tyr Ser His Ile Ser Met Leu Asp
425 430 435
Tyr Asn Pro Lys Asp Arg Ala Leu Tyr Ala Trp Asn Asn Gly His
440 445 450
Gln Ile Leu Tyr Asn Val Thr Leu Phe His Val Ile Arg Ser Asp
455 460 465
Glu Leu
<210> 26
<211> 1018
<212> PRT
<213> Homo sapiens
56/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<220>
<221> misc_feature
<223> Incyte ID No: 7474411CD1
<400> 26
Met Val Ser His Phe Met Gly Ser Leu Ser Val Leu Cys Phe Leu
1 5 10 15
Leu Leu Leu Gly Phe Gln Phe Val Cys Pro Gln Pro Ser Thr Gln
20 25 30
His Arg Lys Val Pro Gln Arg Met Ala Ala Glu Gly Ala Pro Glu
35 40 45
Asp Asp Gly Gly Gly Gly Ala Pro Gly Val Trp Gly Ala Trp Gly
50 55 60
Pro Trp Ser Ala Cys Ser Arg Ser Cys Ser Gly Gly Val Met Glu
65 70 75
Gln Thr Arg Pro Cys Leu Pro Arg Ser Tyr Arg Leu Arg Gly Gly
80 85 90
Gln Arg Pro Gly Ala Pro Ala Arg Ala Phe Ala Asp His Val Val
95 100 105
Ser Ala Val Arg Thr Ser Val Pro Leu His Arg Ser Arg Asp Glu
110 115 120
Thr Pro Ala Leu Ala Gly Thr Asp Ala Ser Arg Gln Gly Pro Thr
125 130 ~ 135
Val Leu Arg Gly Ser Arg His Pro Gln Pro Gln Gly Leu Glu Val
140 145 150
Thr Gly Asp Arg Arg Ser Arg Thr Arg Gly Thr I1e Gly Pro Gly
155 160 165
Lys Tyr Gly Tyr Gly Lys Ala Pro Tyr Ile Leu Pro Leu G1n Thr
170 175 180
Asp Thr Ala His Thr Pro Gln Arg Leu Arg Arg Gln Lys Leu Ser
185 190 195
Ser Arg His Ser Arg Ser Gln Gly A1a Ser Ser Ala Arg His Gly
200 205 210
Tyr Ser Ser Pro Ala His Gln Val Pro Gln His Gly Pro Leu Tyr
215 220 225
G1n Ser Asp Ser Gly Pro Arg Ser Gly Leu Gln Ala Ala Glu Ala
230 235 240
Pro Ile Tyr Gln Leu Pro Leu Thr His Asp Gln Gly Tyr Pro Ala
245 250 255
Ala Ser Ser Leu Phe His Ser Pro Glu Thr Ser Asn Asn His Gly
260 265 270
Val Gly Thr His Gly Ala Thr Gln Ser Phe Ser Gln Pro Ala Arg
275 280 285
Ser Thr Ala Ile Ser Cys Ile Gly Ala Tyr Arg Gln Tyr Lys Leu
290 ~ 295 300
Cys Asn Thr Asn Val Cys Pro Glu Ser Ser Arg Ser Ile Arg Glu
305 310 315
Val Gln Cys Ala Ser Tyr Asn Asn Lys Pro Phe Met Gly Arg Phe
320 325 330
Tyr G1u Trp Glu Pro Phe Ala Glu Val Lys Gly Asn Arg Lys Cys
335 340 345
Glu Leu Asn Cys Gln Ala Met Gly Tyr Arg Phe Tyr Val Arg Gln
350 355 360
Ala Glu Lys Val Ile Asp Gly Thr Pro Cys Asp Gln Asn Gly Thr
365 370 375
Ala Ile Cys Val Ser Gly Gln Cys Lys Ser Ile Gly Cys Asp Asp
57/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
380 385 390
Tyr Leu Gly Ser Asp Lys Val Val Asp Lys Cys Gly Val Cys Gly
395 400 405
Gly Asp Asn Thr Gly Cys Gln Val Val Ser Gly Val Phe Lys His
410 415 420
Ala Leu Thr Ser Leu Gly Tyr His Arg Val Val Glu Ile Pro Glu
425 430 43,5
Gly Ala Thr Lys Ile Asn Ile Thr G1u Met Tyr Lys Ser Asn Asn
440 445 450
Tyr Leu Ala Leu Arg Ser Arg Ser Gly Arg Ser Ile Ile Asn Gly
455 . 460 465
Asn Trp Ala Ile Asp Arg Pro Gly Lys Tyr Glu Gly Gly Gly Thr
470 475 480
Met Phe Thr Tyr Lys Arg Pro Asn Glu Ile Ser Ser Thr Ala Gly
485 490 495
Glu Ser Phe Leu Ala Glu Gly Pro Thr Asn Glu Ile Leu Asp Val
500 505 510
Tyr Met Ile His Gln Gln Pro Asn Pro Gly Val His Tyr Glu Tyr
515 520 525
Val Ile Met Gly Thr Asn A1a Ile Ser Pro Gln Val Pro Pro His
530 535 540
Arg Arg Pro Gly Glu Pro Phe Asn Gly Gln Met Val Thr Glu Gly
545 550 555
Arg Ser Gln Glu Glu Gly Glu Gln Lys Gly Arg Asn Glu Glu Lys
560 565 570
Glu Asp Leu Arg Gly Glu Ala Pro Glu Met Phe Thr Ser Glu Ser
575 ~ 580 585
Ala Gln Thr Phe Pro Val Arg His Pro Asp Arg Phe Ser Pro His
590 595 600
Arg Pro Asp Asn Leu Val Pro Pro Ala Pro Gln Pro Pro Arg Arg
605 610 615
Ser Arg Asp His Asn Trp Lys G1n Leu Gly Thr Thr Glu Cys Ser
620 625 630
Thr Thr Cys Gly Lys Gly Ser Gln Tyr Pro Ile Phe Arg Cys Val
635 640 645
His Arg Ser Thr His Glu Glu Ala Pro Glu Ser Tyr Cys Asp Ser
650 655 660
Ser Met Lys Pro Thr Pro Glu Glu Glu Pro Cys Asn Ile Phe Pro
665 670 675
Cys Pro Ala Phe Trp Asp Ile Gly Glu Trp Ser G1u Cys Ser Lys
680 685 690
Thr Cys Gly Leu Gly Met Gln His Arg Gln Val Leu Cys Arg Gln
695 700 705
Val Tyr Ala Asn Arg Ser Leu Thr Val Gln Pro Tyr Arg Cys Gln
710 715 720
His Leu Glu Lys Pro Glu Thr Thr Ser Thr Cys Gln Leu Lys Ile
725 730 735
Cys Ser Glu Trp Gln Ile Arg Thr Asp Trp Thr Ser Cys Ser Val
740 745 750
Pro Cys G1y Val Gly Gln Arg Thr Arg Asp Val Lys Cys Val Ser
755 760 765
Asn Ile Gly Asp Va1 Val Asp Asp Glu Glu Cys Asn Met Lys Leu
770 775 780
Arg Pro Asn Asp Tle Glu Asn Cys Asp Met Gly Pro Cys Ala Lys
785 790 795
Ser Trp Phe Leu Thr Glu Trp Ser Glu Arg Cys Ser Ala Glu Cys
58/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
800 805 810
Gly Ala Gly Val Arg Thr Arg Ser Val Val Cys Met Thr Asn His
815 820 825
Val Ser Ser Leu Pro Leu Glu Gly Cys Gly Asn Asn Arg Pro Ala
830 835 840
Glu Ala Thr Pro Cys Asp Asn Gly Pro Cys Thr Gly Lys Val Glu
845 850 855
Trp Phe Ala Gly Ser Trp Ser Gln Cys Ser Ile Glu Cys Gly Ser
860 865 870
Gly Thr Gln Gln Arg Glu Val Ile Cys Val Arg Lys Asn Ala Asp
875 880 885
Thr Phe Glu Val Leu Asp Pro Ser Glu Cys Ser Phe Leu Glu Lys
890 895 900
Pro Pro Ser Gln Gln Ser Cys His Leu Lys Pro Cys Gly Ala Lys
905 910 915
Trp Phe Ser Thr Glu Trp Ser Met Cys Ser Lys Ser Cys Gln Gly
920 925 930
Gly Phe Arg Val Arg Glu Val Arg Cys Leu Ser Asp Asp Met Thr
. 935 940 945
Leu Ser Asn Leu Cys Asp Pro G1n Leu Lys Pro Glu Glu Arg Glu
950 955 960
Ser Cys Asn Pro G1n Asp Cys Val Pro Glu Val Asp Glu Asn Cys
965 970 975
Lys Asp Lys Tyr Tyr Asn Cys Asn Val Val Val Gln Ala Arg Leu
980 985 990
Cys Val Tyr Asn Tyr Tyr Lys Thr Ala Cys Cys Ala Ser Cys Thr
995 1000 1005
Arg Val Ala Asn Arg Gln Thr Gly Phe Leu Gly Ser Arg
1010 1015
<210> 27
<211> 1458
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 4755911CD1
<400> 27
Met Gly Lys Glu Gln Glu Leu Val Gln Ala Val Lys Ala Glu Asp
l 5 10 15
Val Gly Thr Ala Gln Arg Leu Leu Gln Arg Pro Arg Pro Gly Lys
20 25 30
Ala Thr Arg Ser Leu Pro Gly Gly Arg Arg Arg Trp Met Asp Gly
35 40 45
Arg Val Asp Gln Pro Arg Val Arg Leu Arg Thr Tyr Ser Arg Val
50 55 60
Ser Val Ser Gly His Leu Cys G1y His Gly Gln Gly Ser A1a Glu
65 70 75
Leu Leu Gly Ser Thr Lys Lys Ile Asn Val Asn Phe Gln Asp Pro
80 85 90
Asp Gly Val Gly Phe Gly Val Lys Gly Gln Leu Pro Ala Ser Pro
95 100 105
Arg Pro Pro Gly Met Arg Pro Leu His Tyr Ala Ala Trp Gln Gly
110 115 120
59/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Arg Lys Glu Pro Met Lys Leu Val Leu Lys Ala Gly Ser Ala Val
125 130 135
Asn Ile Pro Ser Asp Glu Gly His Ile Pro Leu His Leu Ala AIa
140 145 150
Gln His Gly His Tyr Asp Val Ser Glu Met Leu Leu Gln His Gln
155 160 165
Ser Asn Pro Cys Met Val Asp Asn Ser Gly Lys Thr Pro Leu Asp
170 175 180
Leu Ala Cys Glu Phe Gly Arg Val Gly Val Val Gln Leu Leu Leu
185 190 195
Ser Ser Asn Met Cys Ala Ala Leu Leu Glu Pro Arg Pro Gly Asp
200 205 210
Ala Thr Asp Pro Asn Gly Thr Ser Pro Leu His Leu Ala Ala Lys
215 220 225
Asn Gly His Ile Asp Ile Ile Arg Leu Leu Leu Gln Ala Gly Ile
230 235 240
Asp Ile Asn Arg Gln Thr Lys Ser Gly Thr Ala Leu His Glu A1a
245 250 255
Ala Leu Cys Gly Lys Thr Glu Val Val Arg Leu Leu Leu Asp Ser
260 265 270
Gly Ile Asn Ala His Val Arg Asn Thr Tyr Ser Gln Thr Ala Leu
275 280 285
Asp Ile Val His Gln Phe Thr Thr Ser Gln Ala Ser Arg Glu Ile
290 295 300
Lys Gln Leu Leu Arg Glu Ala Ser Ala Ala Leu Gln Val Arg Ala
305 310 315
Thr Lys Asp Tyr Cys Asn Asn Tyr Asp Leu Thr Ser Leu Asn Val
320 325 330
Lys Ala Gly Asp I1e Ile Thr Val Leu Glu Gln His Pro Asp Gly
335 340 345
Arg Trp Lys Gly Cys Ile His Asp Asn Arg Thr G1y Asn Asp Arg
350 355 360
Val Gly Tyr Phe Pro Ser Ser Leu Gly Glu Ala Ile Val Lys Arg
365 370 375
Ala Gly Ser Arg A1a Gly Thr Glu Pro Ser Leu Pro Gln Gly Ser
380 385 390
Ser Ser Ser Gly Pro Ser Ala Pro Pro Glu Glu Ile Trp Val Leu
395 400 405
Arg Lys Pro Phe Ala Gly Gly Asp Arg Ser Gly Ser Ile Ser Gly
410 415 420
Met Ala Gly Gly Arg Gly Ser Gly Gly His Ala Leu His Ala Gly
425 430 435
Ser Glu Gly Val Lys Leu Leu Ala Thr Val Leu Ser Gln Lys Ser
440 445 450
Val Ser Glu Ser Gly Pro G1y Asp Ser Pro Ala Lys Pro Pro Glu
455 460 465
Gly Ser Ala Gly Val Ala Arg Ser Gln Pro Pro Val A1a His Ala
470 475 480
Gly Gln Val Tyr Gly G1u Gln Pro Pro Lys Lys Leu Glu Pro.Ala
485 490 495
Ser Glu Gly Lys Ser Ser Glu Ala Va1 Ser Gln Trp Leu Thr Ala
500 505 510
Phe Gln Leu Gln Leu Tyr A1a Pro Asn Phe Ile Ser Ala Gly Tyr
515 520 525
Asp Leu Pro Thr Ile Ser Arg Met Thr Pro Glu Asp Leu Thr Ala
530 535 540
60/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Ile Gly Val Thr Lys Pro Gly His Arg Lys Lys Ile Ala Ala Glu
545 550 555
Ile Ser Gly Leu Ser Ile Pro Asp Trp Leu Pro Glu His Lys Pro
560 565 570
A1a Asn Leu Ala Val Trp Leu Ser Met Ile Gly Leu Ala Gln Tyr
575 580 585
Tyr Lys Val Leu Val Asp Asn Gly Tyr Glu Asn Ile Asp Phe Ile
590 595 600
Thr Asp Ile Thr Trp Glu Asp Leu Gln Glu Ile Gly Ile Thr Lys
605 610 615
Leu Gly His Gln Lys Lys Leu Met Leu Ala Val Arg Lys Leu Ala
620 625 630
Glu Leu Gln Lys Ala Glu Tyr Ala Lys Tyr Glu Gly Gly Pro Leu
635 640 645
Arg Arg Lys Ala Pro Gln~Ser Leu Glu Val Met Ala Ile Glu Ser
650 655 660
Pro Pro Pro Pro Glu Pro Thr Pro Ala Asp Cys Gln Ser Pro Lys
665 670 675
Met Thr Thr Phe Gln Asp Ser Glu Leu Ser Asp Glu Leu Gln Ala
680 685 690
Ala Met Thr Gly Pro Ala Glu Val Gly Pro Thr Thr Glu Lys Pro
695 700 705
Ser Ser His Leu Pro Pro Thr Pro Arg Ala Thr Thr Arg Gln Asp
710 715 720
Ser Ser Leu Gly Gly Arg Ala Arg His Met Ser Ser Sex Gln Glu
725 730 735
Leu Leu Gly Asp Gly Pro Pro Gly Pro Ser Ser Pro Met Ser Arg
740 745 750
Ser Gln Glu Tyr Leu Leu Asp Glu Gly Pro Ala Pro Gly Thr Pro
755 760 765
Pro Arg Glu Ala Arg Pro Gly~Arg His Gly His Ser Ile Lys Arg
770 ~ 775 780
Ala Ser Val Pro Pro Val Pro G1y Lys Pro Arg Gln Val Leu Pro
785 790 795
Pro Gly Thr Ser His Phe Thr Pro Pro Gln Thr Pro Thr Lys Thr
800 805 810
Arg Pro Gly Ser Pro Gln Ala Leu Gly Gly Pro His Gly Pro Ala
815 820 825
Pro Ala Thr Ala Lys Val Lys Pro Thr Pro Gln Leu Leu Pro Pro
830 835 840
Thr Glu Arg Pro Met Ser Pro Arg Ser Leu Pro Gln Ser Pro Thr
845 850 855
His Arg Gly Phe Ala Tyr Val Leu Pro Gln Pro Val Glu Gly G1u
860 865 870
Val Gly Pro Ala Ala Pro Gly Pro Ala Pro Pro Pro Val Pro Thr
875 880 885
Ala Val Pro Thr Leu Cys Leu Pro Pro Glu Ala Asp Ala Glu Pro
890 895 900
Gly Arg Pro Lys Lys Arg Ala His Ser Leu Asn Arg Tyr Ala Ala
905 910 915
Ser Asp Ser Glu Pro Glu Arg Asp Glu Leu Leu Val Pro Ala Ala
920 925 930
Ala Gly Pro Tyr Ala Thr Val Gln Arg Arg Val Gly Arg Ser His
935 940 945
Ser Val Arg Ala Pro Ala Gly Ala Asp Lys Asn Val Asn Arg Ser
950 955 960
61/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Gln,Ser Phe Ala Val Arg Pro Arg Lys Lys Gly Pro Pro Pro Pro
965 970 975
Pro Pro Lys Arg Ser Ser Ser Ala Leu Ala Ser Ala Asn Leu Ala
980 985 990
Asp Glu Pro Val Pro Asp Ala Glu Pro Glu Asp Gly Leu Leu Gly
995 1000 1005
Val Arg Ala Gln Cys Arg Arg Ala Ser Asp Leu Ala Gly Ser Val
1010 1015 1020
Asp Thr Gly Ser Ala Gly Ser Val Lys Ser Ile Ala Ala Met Leu
1025 1030 1035
Glu Leu Ser Ser Ile Gly Gly Gly Gly Arg Ala Ala Arg Arg Pro
1040 ' 1045 1050
Pro Glu Gly His Pro Thr Pro Arg Pro Ala Ser Pro Glu Pro Gly
1055 1060 1065
Arg Val Ala Thr Val Leu Ala Ser Val Lys His Lys Glu Ala Ile
1070 1075 1080
Gly Pro Gly Gly Glu Val Val Asn Arg Arg Arg Thr Leu Ser Gly
1085 1090 1095
Pro Val Thr G1y Leu Leu Ala Thr Ala Arg Arg Gly Pro Gly Glu
1100 1105 1110
Ser~Ala Asp Pro Gly Pro Phe Val Glu Asp G1y Thr Gly Arg Gln
1115 1120 1125
Arg Pro Arg Gly Pro Ser Lys Gly Glu Ala Gly Val Glu Gly Pro
1130 1135 1140
Pro Leu Ala Lys Val Glu Ala Ser Ala Thr Leu Lys Arg Arg Ile
1145 1150 1155
Arg Ala Lys Gln Asn Gln Gln Glu Asn Val Lys Phe Ile Leu Thr
1160 1165 1170
Glu Ser Asp Thr Val Lys Arg Arg Pro Lys Ala Lys Glu Arg Glu
1175 1180 1185
Ala Gly Pro Glu Pro Pro Pro Pro Leu Ser Val Tyr His Asn Gly
1190 1195 1200
Thr Gly Thr Val Arg Arg Arg Pro A1a Ser Glu Gln Ala Gly Pro
1205 1210 1215
Pro Glu Leu Pro Pro Pro Pro Pro Pro Ala Glu Pro Pro Pro Thr
1220 1225 1230
Asp Leu Ala His Leu Pro Pro Leu Pro Pro Pro Glu Gly Glu Ala
1235 1240 1245
Arg Lys Pro Ala Lys Pro Pro Val Ser Pro Lys Pro Val Leu Thr
1250 1255 1260
Gln Pro Val Pro Lys Leu Gln Gly Ser Pro Thr Pro Thr Ser Lys
1265 1270 1275
Lys Val Pro Leu Pro Gly Pro Gly Ser Pro Glu Val Lys Arg Ala
1280 1285 1290
His Gly Thr Pro Pro Pro Val Ser Pro Lys Pro Pro Pro Pro Pro
1295 1300 1305
Thr Ala Pro Lys Pro Val Lys Ala Val Ala Gly Leu Pro Ser Gly
1310 1315 1320
Ser Ala Gly Pro Ser Pro Ala Pro Ser Pro Ala Arg Gln Pro Pro
1325 1330 1335
Ala Ala Leu Ala Lys Pro Pro Gly Thr Pro Pro Ser Leu Gly Ala
1340 1345 1350
Ser Pro Ala Lys Pro Pro Ser Pro Gly Ala Pro Ala Leu His Val
1355 1360 1365
Pro Ala Lys Pro Pro Arg Ala Ala Ala Ala Ala Ala Ala Ala Ala
1370 1375 1380
62/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Ala Ala Pro Pro A1a Pro Pro Glu Gly Ala Ser Pro Gly Asp Ser
1385 1390 1395
Ala Arg Gln Lys Leu Glu Glu Thr Ser Ala Cys Leu Ala Ala Ala
1400 1405 1410
Leu Gln Ala Va1 Glu Glu Lys Ile Arg Gln Glu Asp Ala Gln Gly
1415 1420 1425
Pro Arg Asp Ser Ala Ala Glu Lys Ser Thr Gly Ser Ile Leu Asp
1430 1435 1440
Asp Ile Gly Ser Met Phe Asp Asp Leu Ala Asp Gln Leu Asp Ala
1445 1450 1455
Met Leu Glu
<210> 28
<211> 323
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 379766CD1
<400> 28
Met Ala Ser Trp Thr Ser Pro Trp Trp Val Leu Ile Gly Met Val
1 5 10 15
Phe Met His Ser Pro Leu Pro Gln Thr Thr Ala Glu Lys Ser Pro
20 25 30
Gly Ala Tyr Phe Leu Pro Glu Phe Ala Leu Ser Pro Gln G1y Ser
35 40 45
Phe Leu Glu Asp Thr Thr Gly Glu Gln Phe Leu Thr Tyr Arg Tyr
50 55 60
Asp Asp Gln Thr Ser Arg Asn Thr Arg Ser Asp Glu Asp Lys Asp
65 70 75
Gly Asn Trp Asp Ala Trp Gly Asp Trp Ser Asp Cys Ser Arg Thr
80 85 90
Cys Gly Gly Gly Ala Ser Tyr Ser Leu Arg Arg Cys Leu Thr Gly
95 100 105
Arg Asn Cys Glu Gly Gln Asn Ile Arg Tyr Lys Thr Cys Ser Asn
110 115 120
His Asp Cys Pro Pro Asp Ala Glu Asp Phe Arg Ala Gln G1n Cys
125 130 135
Ser Ala Tyr Asn Asp Val Gln Tyr Gln Gly Arg Tyr Tyr G1u Trp
140 145 150
Leu Pro Arg Tyr Asn Asp Pro Ala Ala Pro Cys Ala Leu Lys Cys
155 160 165
His Ala Gln Gly Gln Asn Leu Val Val Glu Leu Ala Pro Lys Val
170 175 180
Leu Asp Gly Thr Arg Cys Asn Thr Asp Ser Leu Asp Met Cys Ile
185 190 195
Ser Gly Ile Cys Gln Ala Val Gly Cys Asp Arg Gln Leu Gly Ser
200 205 210
Asn Ala Lys Glu Asp Asn Cys Gly Val Cys Ala Gly Asp Gly Ser
215 220 225
Thr Cys Arg Leu Val Arg Gly Gln Ser Lys Ser His Val Ser Pro
230 235 240
Glu Lys Arg Glu Glu Asn Val Ile Ala Val Pro Leu Gly Ser Arg
63/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
245 250 255
Ser Val Arg Ile Thr Val Lys Gly Pro Ala Tyr Pro Val Ala Trp
260 265 270
Ala Leu Ala Ile Ser Ser Asn Thr Asn Cys Leu Va1 Leu Leu Cys
275 280 285
Lys Ala Asn Leu Ala Ser Ser Gly Pro Tyr Phe Ala Leu Ile Pro
290 295 300
Val Asn Pro Thr Thr Met Ala Leu Asn Thr Ala Ile Val Ser Gln
305 310 315
Ser Ala Val Leu Ile Asp Cys Leu
320
<210> 29
<211> 234
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 553744CD1
<400> 29
Met Met Ile His Ser Cys Leu Phe Ser Pro Phe His Ile Ala Phe
1 5 10 15
Ser Thr Pro Ala Ser Gln Leu Phe Ser Pro His Gly Ser Asn Pro
20 25 30
Ser Thr Pro Ala Ala Thr Pro Val Pro Thr Ala Ser Pro Val Lys
35 40 45
Ala I1e Asn His Pro Ser Ala Ser Ala Ala Ala Thr Val Ser Gly
50 55 60
Met Asn Leu Leu Asn Thr Val Leu Pro Val Phe Pro Gly Gln Val
65 70 75
Ser Ser Ala Val His Thr Pro Gln Pro Ser Ile Pro Asn Pro Thr
80 85 90
Val Ile Arg Thr Pro Ser Leu Pro Thr Ala Pro Val Thr Ser Ile
95 100 105
His Ser Thr Thr Thr Thr Pro Val Pro Ser Ile Phe Ser Gly Leu
1l0 115 120
Val Ser Leu Pro Gly Pro Ser Ala Thr Pro Thr Ala Ala Thr Pro
125 130 135
Thr Pro Gly Pro Thr Pro Arg Ser Thr Leu Gly Ser Ser Glu Ala
140 145 150
Phe Ala Ser Thr Ser Ala Pro Phe Thr Ser Leu Pro Phe Ser Thr
155 260 165
Ser Ser Ser Ala Ala Ser Thr Ser Asn Pro Asn Ser Ala Ser Leu
170 175 180
Ser Ser Val Phe Ala Gly Leu Pro Leu Pro Leu Pro Pro Thr Ser
185 ~ 190 195
Gln Gly Leu Ser Asn Pro Thr Pro Val Ile Ala Gly Gly Ser Thr
200 205 210
Pro Ser Val Ala Gly Pro Leu Gly Val Asn Ser Pro Ser Phe Val
215 220 225
Cys Val Lys Arg Phe Ser Asp Ile Gln
230
<210> 30
64/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<211> 377
<212> PRT
<213> Homo sapiens
<220>
<221> misc-feature
<223> Incyte ID No: 1825473CD1
<400> 30
Met Lys Thr Leu Pro Leu Phe Val Cys Ile Cys Ala Leu Ser Ala
1 5 10 15
Cys Phe Ser Phe Ser Glu Gly Arg Glu Arg Asp His Glu Leu Arg
20 25 30
His Arg Arg His His His Gln Ser Pro Lys Ser His Phe Glu Leu
35 40 45
Pro His Tyr Pro Gly Leu Leu Ala His Gln Lys Pro Phe Ile Arg
50 55 60
Lys Ser Tyr Lys Cys Leu His Lys Arg Cys Arg Pro Lys Leu Pro
65 ' 70 75
Pro Ser Pro Asn Asn Pro Pro Lys Phe Pro Asn Pro His Gln Pro
80 85 90
Pro Lys His Pro Asp Lys Asn Ser Ser Val Val Asn Pro Thr Leu
95 100 105
Val Ala Thr Thr Gln Ile Pro Ser Val Thr Phe Pro Ser Ala Ser
110 115 120
Thr Lys Ile Thr Thr Leu Pro Asn Va1 Thr Phe Leu Pro Gln Asn
125 130 135
Ala Thr Thr Ile Ser Ser Arg Glu Asn Val Asn Thr Ser Ser Ser
140 145 150
Val Ala Thr Leu Ala Pro Val Asn Ser Pro Ala Pro Gln Asp Thr
155 160 165
Thr Ala Ala Pro Pro Thr Pro Ser A1a Thr Thr Pro Ala Pro Pro
170 175 180
Ser Ser Ser Ala Pro Pro G1u Thr Thr Ala Ala Pro Pro Thr Pro
185 190 195
Ser Ala Thr Thr Gln Ala Pro Pro Ser Ser Ser Ala Pro Pro Glu
200 205 210
Thr Thr A1a Ala Pro Pro Thr Pro Pro Ala Thr Thr Pro Ala Pro
215 220 225
Pro Ser Ser Ser Ala Pro Pro Glu Thr Thr Ala Ala Pro Pro Thr
230 235 240
Pro Ser Ala Thr Thr Pro Ala Pro Leu Ser Ser Ser Ala Pro Pro
245 250 255
Glu Thr Thr Ala Val Pro Pro Thr Pro Ser Ala Thr Thr Leu Asp
260 265 270
Pro Ser Ser Ala Ser Ala Pro Pro Glu Thr Thr Ala Ala Pro Pro
275 280 285
Thr Pro Ser Ala Thr Thr Pro Ala Pro Pro Ser Ser Pro Ala Pro
290 295 300
Gln Glu Thr Thr Ala Ala Pro Ile Thr Thr Pro Asn Ser Ser Pro
305 310 315
Thr Thr Leu Ala Pro Asp Thr Ser Glu Thr Ser Ala Ala Pro Thr
320 325 330
His Gln Thr Thr Thr Ser Va1 Thr Thr Gln Thr Thr Thr Thr Lys
335 340 345
Gln Pro Thr Ser Ala Pro Gly Gln Asn Lys Ile Ser Arg Phe Leu
65/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
350 355 360
Leu Tyr Met Lys Asn Leu Leu Asn Arg Ile Ile Asp Asp Met Val
365 370 375
Glu Gln
<210> 31
<211> 833
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 7950094CD1
<400> 31
Met Ala Pro His Trp Ala Val Trp Leu Leu Ala Ala Arg Leu Trp
1 5 10 15
Gly Leu Gly Ile Gly Ala Glu Val Trp Trp Asn Leu Val Pro Arg
20 25 30
Lys Thr Val Ser Ser Gly Glu Leu Ala Thr Val Val Arg Arg Phe
35 40 45
Ser Gln Thr Gly Ile Gln Asp Phe Leu Thr Leu Thr Leu Thr Glu
50 55 60
Pro Thr Gly Leu Leu Tyr Val Gly Ala Arg Glu Ala Leu Phe Ala
65 70 75
Phe Ser Met Glu Ala Leu Glu Leu Gln Gly AIa Ile Ser Trp Glu
80 85 90
Ala Pro Val Glu Lys Lys Thr Glu Cys Ile Gln Lys Gly Lys Asn
95 100 105
Asn Gln Thr Glu Cys Phe Asn Phe Ile Arg Phe Leu Gln Pro Tyr
110 115 120
Asn Ala Ser His Leu Tyr Val Cys Gly Thr Tyr Ala Phe Gln Pro
125 130 135
Lys Cys Thr Tyr Val Asn Met Leu Thr Phe Thr Leu G1u His Gly
140° 145 150
Glu Phe Glu Asp Gly Lys Gly Lys Cys Pro Tyr Asp Pro Ala Lys
155 160 165
Gly His Ala Gly Leu Leu Val Asp Gly Glu Leu Tyr Ser Ala Thr
170 175 180
Leu Asn Asn Phe Leu Gly Thr Glu Pro Ile Ile Leu Arg Asn Met
185 190 195
Gly Pro His His Ser Met Lys Thr Glu Tyr Leu Ala Phe Trp°Leu
200 205 210
Asn Glu Pro His Phe Val Gly Ser Ala Tyr Val Pro Glu Ser Val
215 220 225
Gly Ser Phe Thr Gly Asp Asp Asp Lys Val Tyr Phe Phe Phe Arg
230 235 240
Glu Arg Ala Val Glu Ser Asp Cys Tyr Ala Glu Gln Val Val Ala
245 250 255
Arg Val Ala Arg Va1 Cys Lys Gly Asp Met Gly Gly Ala Arg Thr
260 265 270
Leu Gln Arg Lys Trp Thr Thr Phe Leu Lys Ala Arg Leu Ala Cys
275 280 285
Ser Ala Pro Asn Trp Gln Leu Tyr Phe Asn Gln Leu Gln Ala Met
290 295 300
66/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
His Thr Leu Gln Asp Thr Ser Trp His Asn Thr Thr Phe Phe Gly
305 310 315
Val Phe Gln Ala Gln Trp Gly Asp Met Tyr Leu Ser Ala Ile Cys
320 325 330
Glu Tyr Gln Leu Glu Glu Ile Gln Arg Val Phe Glu Gly Pro Tyr
335 340 345
Lys Glu Tyr His Glu Glu Ala Gln Lys Trp Asp Arg Tyr Thr Asp
350 355 360
Pro Val Pro Ser Pro Arg Pro Gly Ser Cys Ile Asn Asn Trp His
365 370 375
Arg Arg His Gly Tyr Thr Ser Ser Leu Glu Leu Pro Asp Asn Ile
380 385 390
Leu Asn Phe Val Lys'Lys His Pro Leu Met Glu Glu Gln Val Gly
395 400 405
Pro Arg Trp Ser Arg Pro Leu Leu Val Lys Lys Gly Thr Asn Phe
410 415 420
Thr His Leu Val Ala Asp Arg Val Thr Gly Leu Asp Gly Ala Thr
425 430 435
Tyr Thr Val Leu Phe Ile Gly Thr Gly Asp Gly Trp Leu Leu Lys
440 445 450
Ala Val Ser Leu Gly Pro Trp Val His Leu Ile Glu Glu Leu Gln
455 460 465
Leu Phe Asp Gln Glu Pro Met Arg Ser Leu Val Leu Ser Gln Ser
470 475 480
Lys Lys Leu Leu Phe Ala Gly Ser Arg Ser Gln Leu Val Gln Leu
485 490 495
Pro Val Ala Asp Cys Met Lys Tyr Arg Ser Cys A1a Asp Cys Val
500 505 510
Leu Ala Arg Asp Pro Tyr Cys Ala Trp Ser Val Asn Thr Ser Arg
515 520 525
Cys Va1 Ala Va1 Gly Gly His Ser Gly Ser Leu Leu Ile Gln His
530 535 540
Val Met Thr Ser Asp Thr Ser Gly Ile Cys Asn Leu Arg Gly Ser
545 550 555
Lys Lys Val Arg Pro Thr Pro Lys Asn Ile Thr Val Val Ala Gly
560 565 570
Thr Asp Leu Val Leu Pro Cys His Leu Ser Ser Asn Leu Ala His
575 580 585
Ala Arg Trp Thr Phe Gly Gly Arg Asp Leu Pro Ala G1u Gln Pro
590 595 600
Gly Ser Phe Leu Tyr Asp Ala Arg Leu Gln Ala Leu Val Val Met
605 610 615
Ala Ala Gln Pro Arg His Ala Gly Ala Tyr His Cys Phe Ser G1u
620 625 630
Glu Gln Gly Ala Arg Leu Ala Ala Glu Gly Tyr Leu Val Ala Val
635 640 645
Val Ala Gly Pro Ser Val Thr Leu Glu Ala Arg Ala Pro Leu Glu
650 655 660
Asn Leu Gly Leu Val Trp Leu Ala Val Val Ala Leu Gly Ala Val
665 670 675
Cys Leu Val Leu Leu Leu Leu Val Leu Ser Leu Arg Arg Arg Leu
680 685 690
Arg Glu Glu Leu Glu Lys Gly Ala Lys Ala Thr Glu Arg Thr Leu
695 700 705
Val Tyr Pro Leu Glu Leu Pro Lys Glu Pro Thr Ser Pro Pro Phe
710 715 720
67/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Arg Pro Cys Pro Glu Pro Asp G1u Lys Leu Trp Asp Pro Val Gly
725 730 ~ 735
Tyr Tyr Tyr Ser Asp Gly Ser Leu Lys Ile Val Pro Gly His Ala
740 745 750
Arg Cys Gln Pro Gly Gly Gly Pro Pro Ser Pro Pro Pro Gly Ile
755 760 765
Pro Gly Gln Pro Leu Pro Ser Pro Thr Arg Leu His Leu Gly Gly
770 775 780
Gly Arg Asn Ser Asn Ala Asn Gly Tyr Val Arg Leu Gln Leu Gly
785 790 795
Gly Glu Asp Arg Gly Gly Leu Gly His Pro Leu Pro Glu Leu Ala
800 805 810
Asp Glu Leu Arg Arg Lys Leu Gln Gln Arg Gln Pro Leu Pro Asp
815 820 825
Ser Asn Pro Glu Glu Ser Ser Val
830
<210> 32
<211> 1291
<212> PRT
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 7479484CD1
<400> 32
Met Phe Arg Pro Thr Thr Val Ala Val Asp Glu Asp Gly Gly Glu
1 5 10 15
Glu Asp Lys Asp Glu Ser Ser Thr Asn Ser Gly A1a Ser Ala Val
20 25 30
Ser Ser Cys Gly Phe Gly A1a Asp Phe Ser Thr Asp Lys Gly Gly
35 40 45
Ser Phe Thr Ser Val G1n Ile Thr Asn Thr Thr Gly Leu Ser Gln
50 55 60
A1a Pro Gly Leu Ala Ser Gln Gly Ile Ser Phe Gly Ile Lys Asn
65 70 75
Asn Leu Gly Pro Pro Leu GIn Lys Leu Gly Val Ser Phe Ser Phe
80 85 90
Ala Lys Lys Ala Pro Val Lys Leu Glu Ser Ile Ala Ser Val Phe
95 100 105
Lys Asp His Ala Glu Glu Gly Ser Ser G1u Asp Gly Thr Lys Ala
110 115 l20
Asp Glu Lys Ser Ser Asp Gln Gly Val Gln Lys Val Gly Asp Thr
125 l30 l35
Asp Gly Thr Gly Asn Leu Asp Gly Lys Lys Glu Asp Glu Asp Pro
140 145 150
Gln Asp Gly Gly Ser Leu Ala Ser Thr Leu Ser Lys Leu Lys Arg
155 160 165
Met Lys Arg Glu Glu Gly Thr Gly Ala Thr Glu Pro Glu Tyr Tyr
170 175 180
His Tyr Ile Pro Pro Ala His Cys Lys Val Lys Pro Asn Phe Pro
185 190 195
Phe Leu Leu Phe Met Arg Ala Ser Glu Gln Met Glu Gly Asp His
200 205 210
Ser Ala His Ser Lys Ser Ala Pro Glu Asn Arg Lys Ser Ser Ser
68/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
215 220 225
Pro Lys Pro Gln Gly Cys Ser Lys Thr Ala Ala Ser Pro Gly Ala
230 235 240
GIu Arg Thr Val Ser Glu Ala Ser Glu Leu Gln Lys Glu Ala Ala
245 250 255
Val Ala Gly Pro Ser Glu Pro Gly Gly Lys Thr Glu Thr Lys Lys
260 265 270
GIy Ser Gly Gly Gly Glu Asp Glu Gln Ser Val Glu Ser Arg Glu
275 280 285
Thr Ser Glu Ser Pro Met Cys Glu Ser Asn Pro Lys Asp Ile Ser
290 295 300
Gln Ala Thr Pro Ala Thr Lys Ala Gly Gln Gly Pro Lys His Pro
305 310 315
Thr Gly Pro Phe Phe Pro Val Leu Ser Lys Asp Glu Ser Thr Ala
320 325 330
Leu Gln Trp Pro Ser Glu Leu Leu Ile Phe Thr Lys Ala Glu Pro
335 340 345
Ser Ile Ser Tyr Ser Cys Asn Pro.Leu Tyr Phe Asp Phe Lys Leu
350 355 360
Ser Arg Asn Lys Asp Ala Lys AIa Lys Gly Thr GIu Lys Pro Lys
365 370 375
Asp Val Ala Gly Ser Ser Lys Asp His Leu Gln Ser Leu Asp Pro
380 385 390
Arg Glu Pro Asn Lys Ser Gln Glu Glu Glu Gln Asp Val Val Leu
395 400 405
Ser Ser Glu Gly Arg Val Asp Glu Pro Ala Ser G1y Ala Ala Cys
410 415 420
Ser Ser Leu Asn Lys G1n Glu Pro Gly Gly Ser His Met Ser Glu
425 430 435
Thr Glu Asp Thr Gly Arg Ser His Pro Ser Lys Lys Glu Pro Ser
440 445 450
Gly Lys Ser His Arg His Lys Lys Lys Lys Lys His Lys Lys Ser
455 460 465
Ser Lys His Lys Arg Lys His Lys Ala Asp Thr Glu Glu Lys Ser
470 475 480
Ser Lys Ala Glu Ser Gly Glu Lys Ser Lys Lys Arg Lys Lys Arg
485 490 495
Lys Arg Lys Lys Asn Lys Ser Ser Ala Ala Ala Asp Ser Glu Arg
500 505 510
Gly Pro Lys Ser G1u Pro Pro Gly Ser Gly Sex Pro Ala Pro Pro
515 520 525
Arg Arg Arg Arg Arg Ala Gln Asp Asp Ser Gln Arg Arg Ser Leu
530 535 540
Pro Ala Glu Glu Gly Asn Ser Gly Lys Lys Asp Asp Gly Gly Gly
545 550 555
Gly Ser Ser Cys Gln Asp His Ser Gly Arg Lys His Lys Gly Glu
560 565 570
Pro Pro Thr Ser Ser Cys Gln Arg Arg Ala Asn Thr Lys His Ser
575 580 585
Ser Arg Ser Ser His Arg Ser Gln Pro Ser Ser Gly Asp Glu Asp
590 595 600
Ser Asp Asp Ala Ser Ser His Arg Leu His Gln Lys Ser Pro Ser
605 610 615
Gln Tyr Ser Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu Glu
620 625 630
Glu Asp Glu Asp Ser Gly Ser Glu His Ser Arg Ser Arg Ser Arg
69/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
635 640 645
Ser Gly His Arg His Ser Ser His Arg Ser Ser Arg Arg Ser Tyr
650 655 660
Ser Ser Ser Ser Asp Ala Ser Ser Asp Gln Ser Cys Tyr Ser Arg
665 670 675
Gln His Ser Tyr Ser Asp Asp Ser Tyr Ser Asp Tyr Ser Asp Arg
680 685 ~ 690
Ser Arg Arg His Ser Lys Arg Ser His Asp Ser Asp Asp Ser Asp
695 700 705
Tyr Thr Ser Ser Lys His Arg Ser Lys Arg His Lys Tyr Ser Ser
710 715 720
Ser Asp Asp Asp Tyr Ser Leu Ser Cys Ser Gln Ser Arg Ser Arg
725 730 735
Ser Arg Ser His Thr Arg Glu Arg Ser Arg Ser Arg Gly Arg Ser
740 745 750
Arg Ser Ser Ser Cys Ser Arg Ser Arg Ser Lys Arg Arg Ser Arg
755 760 765
Ser Thr Thr Ala His Ser Trp Gln Arg Ser Arg Ser Tyr Ser Arg
770 775 780
Asp Arg Ser Arg Ser Thr'Arg Ser Pro Ser Gln Arg Ser Gly Ser
785 790 795
Arg Lys Gly Ser Trp Gly His Glu Ser Pro Glu Glu Arg Arg Ser
800 805 810
Gly Arg Arg Asp Phe Ile Arg Ser Lys Ile Tyr Arg Ser Gln Ser
815 820 825
Pro His Tyr Phe Gln Ser Gly Arg Gly Glu Gly Pro Gly Lys Lys
830 835 840
Glu Asp Gly Arg Gly Asp Asp Ser Lys Gly Ala Gly Leu Pro Ser
845 850 855
Gln Asn Ser Asn Thr Gly Thr Gly Arg Gly Ser Glu Ser Asp Cys
860 865 870
Ser Pro Glu Asp Lys Asn Ser Val Thr Ala Arg Leu Leu Leu Glu
875 880 885
Lys Ile Gln Ser Arg Lys Val Glu Arg Lys Pro Asn Val Cys Glu
890 895 900
Glu Val Leu Ala Thr Pro Asn Lys Ala Gly Leu Lys Tyr Lys Asn
905 910 915
Pro Pro Gln Gly Tyr Phe Gly Pro Lys Leu Pro Pro Ser Leu Gly
920 925 930
Asn Lys Pro Val Leu Pro Met.Ile Gly Lys Leu Pro Ala Thr Arg
935 940 945
Lys Ser Asn Lys Lys Cys Glu Glu Ser Gly Leu Glu Arg Gly G1u
950 955 960
Glu Gln Glu His Ser Glu Pro Glu Glu Gly Ser Pro Arg Ser Ser
965 970 975
Asp Ala Pro Phe Gly His Gln Phe Ser Glu Glu Ala Ala Gly Pro
980 985 990
Leu Ser Asp Pro Pro Pro Glu Glu Pro Lys Ser Glu Glu Ala Thr
995 1000 1005
Ala Asp His Ser Va1 Ala Pro Leu Gly Thr Pro Ala His Thr Asp
1010 1015 1020
Cys Tyr Pro Gly Asp Pro Ala Ile Ser His Asn Tyr Leu Pro Asp
1025 1030 1035
Pro Ser Asp Gly Asp Thr Leu Glu Ser Leu Asp Ser Gly Ser Gln
1040 1045 1050
Pro Gly Pro Val Glu Ser Ser Leu Leu Pro Ile Ala Pro Asp Leu
70/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
1055 1060 1065
Glu His Phe Pro Asn Tyr Ala Pro Pro Ser Gly Glu Pro Ser Ile
1070 1075 1080
Glu Ser Thr Asp Gly Thr Glu Asp Ala Ser Leu Ala Pro Leu Glu
1085 1090 1095
Ser Gln Pro Ile Thr Phe Thr Pro Glu Glu Met Glu Lys Tyr Ser
1100 1105 1110
Lys Leu Gln Gln Ala Ala Gln Gln His Ile Gln Gln Gln Leu Leu
1115 1120 1125
Ala Lys Gln Val Lys Ala Phe Pro Ala Ser Thr Ala Leu Ala Pro
. 2130 1135 1140
Ala Thr Pro Ala Leu Gln Pro Ile His Ile Gln Gln Pro Ala Thr
1145 1150 1155
Ala Ser Ala Thr Ser Ile Thr Thr Val Gln His Ala Ile Leu Gln
1160 1165 1170
His His Ala Ala Ala Ala Ala Ala Ala Ile Gly Ile His Pro His
1175 1180 1185
Pro His Pro Gln Pro Leu Ala Gln Val His His Ile Pro Gln Pro
1190 1195 1200
His Leu Thr Pro Ile Ser Leu Ser His Leu Thr His Ser Ile Ile
1205 . 1210 1215
Pro Gly His Pro Ala Thr Phe Leu Ala Ser His Pro Ile His TIe
1220 1225 1230
Ile Pro Ala Ser Ala Ile His Pro Gly Pro Phe Thr Phe His Pro
1235 1240 1245
Val Pro His Ala Ala Leu Tyr Pro Thr Leu Leu Ala Pro Arg Pro
1250 1255 1260
Ala Ala Ala Ala Ala Thr Ala Leu His Leu His Pro Leu Leu His
1265 1270 1275
Pro IIe Phe Ser Gly Gln Asp Leu Gln His Pro Pro Ser His Gly
1280 1285 1290
Thr
<210> 33
<211> 736
<212> PRT
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 6780147CD1
<400> 33
Met Ala Val Arg Ala Leu Lys Leu Leu Thr Thr Leu Leu Ala Val
1 5 10 15
Val Ala Ala Ala Ser~Gln Ala Glu Val Glu Ser Glu Ala G1y Trp
20 25 30
Gly Met Val Thr Pro Asp Leu Leu Phe Ala Glu Gly Thr Ala Ala
35 40 45
Tyr Ala Arg Gly Asp Trp Pro Gly Val Val Leu Ser Met Glu Arg
50 55 60
Ala Leu Arg Ser Arg Ala Ala Leu Arg A1a Leu Arg Leu Arg Cys
65 70 75
Arg Thr Gln Cys Ala Ala Asp Phe Pro Trp Glu Leu Asp Pro Asp
80 85 90
71/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Trp Ser Pro Ser Pro A1a Gln Ala Ser Gly Ala Ala Ala Leu Arg
95 100 105
Asp Leu Ser Phe Phe Gly Gly Leu Leu Arg Arg Ala Ala Cys Leu
l10 115 120
Arg Arg Cys Leu Gly Pro Pro Ala Ala His Ser Leu Ser Glu Glu
125 130 135
Met Glu~Leu Glu Phe Arg Lys Arg Ser Pro Tyr Asn Tyr Leu Gln
140 ~ 145 150
Val Ala Tyr Phe Lys Ile Asn Lys Leu Glu Lys Ala Val Ala Ala
155 160 165
Ala His Thr Phe Phe Val Gly Asn Pro Glu His Met Glu Met Gln
170 175 180
Gln Asn Leu Asp Tyr Tyr Gln Thr Met Ser Gly Val Lys Glu Ala
185 190 195
Asp Phe Lys Asp Leu Glu Thr Gln Pro His Met Gln Glu Phe Arg
200 205 210
Leu Gly Val Arg Leu Tyr Ser Glu Glu Gln Pro Gln Glu Ala Val
215 220 225
Pro His Leu Glu A1a Ala Leu Gln Glu Tyr Phe Val Ala Tyr Glu
230 235 240
Glu Cys Arg Ala Leu Cys Glu Gly Pro Tyr Asp Tyr Asp Gly Tyr
245 250 255
Asn Tyr Leu Glu Tyr Asn Ala Asp Leu Phe Gln Ala Ile Thr Asp
260 265 270
His Tyr Ile Gln Val Leu Asn Cys Lys Gln Asn Cys Val Thr Glu
275 280 285
Leu Ala Ser His Pro Ser Arg Glu Lys Pro Phe Glu Asp Phe Leu
290 295 300
Pro Ser His Tyr Asn Tyr Leu Gln Phe A1a Tyr Tyr Asn Ile Gly
305 320 325
Asn Tyr Thr Gln Ala Val Glu Cys Ala Lys Thr Tyr Leu Leu Phe
320 325 330
Phe Pro Asn Asp Glu Val Met Asn Gln Asn Leu Ala Tyr Tyr A1a
335 340 345
Ala Met Leu Gly Glu Glu His Thr Arg Ser Ile Gly Pro Arg Glu
350 355 360
Ser Ala Lys Glu Tyr Arg Gln Arg Ser Leu Leu Glu Lys Glu Leu
365 370 375
Leu Phe Phe Ala Tyr Asp Val Phe Gly I1e Pro Phe Val Asp Pro
380 385 390
Asp Ser Trp Thr Pro G1u Glu Val Ile Pro Lys Arg Leu Gln Glu
395 400 405
Lys Gln Lys Ser G1u Arg Glu Thr Ala Val Arg Ile Ser Gln Glu
410 415 420
I1e Gly Asn Leu Met Lys Glu Ile Glu Thr Leu Val Glu Glu Lys
425 430 435
Thr Lys Glu Ser Leu Asp Val Ser Arg Leu Thr Arg Glu Gly Gly
440 445 ~ 450
Pro Leu Leu Tyr Glu Gly Ile Ser Leu Thr Met Asn Sex Lys Leu
455 460 465
Leu Asn Gly Ser Gln Arg Val Val Met Asp Gly Val Ile Ser Asp
470 475 480
His Glu Cys Gln Glu Leu Gln Arg Leu Thr Asn Val Ala Ala Thr
485 490 495
Ser Gly Asp Gly Tyr Arg Gly Gln Thr Ser Pro His Thr Pro Asn
500 505 510
72/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Glu Lys Phe Tyr Gly Val Thr Val Phe Lys Ala Leu Lys Leu Gly
515 520 525
Gln Glu Gly Lys Val Pro Leu Gln Ser Ala His Leu Tyr Tyr Asn
530 535 540
Val Thr Glu Lys Val Arg Arg Ile Met Glu Ser Tyr Phe Arg Leu
545 550 555
Asp Thr Pro Leu Tyr Phe Ser Tyr Ser His Leu Val Cys Arg Thr
560 565 570
Ala Ile Glu Glu Val Gln Ala Glu Arg Lys Asp Asp Ser His Pro
575 580 585
Val His Val Asp Asn Cys Ile Leu Asn Ala Glu Thr Leu Val Cys
590 595 600
Val Lys Glu Pro Pro Ala Tyr Thr Phe Arg Asp Tyr Ser Ala Ile
605 610 615
Leu Tyr Leu Asn Gly Asp Phe Asp Gly Gly Asn Phe Tyr Phe Thr
620 625 630
Glu Leu Asp Ala Lys Thr Val Thr Ala Glu Val Gln Pro Gln Cys
635 640 645
Gly Arg Ala Val Gly Phe Ser Ser Gly Thr Glu Asn Pro His Gly
650 655 660
Val Lys Ala Val Thr Arg Gly Gln Arg Cys Ala Ile Ala Leu Trp
665 670 675
Phe Thr Leu Asp Pro Arg His Ser Glu Arg Asp Arg Val Gln Ala
680 685 690
Asp Asp Leu Val Lys Met Leu Phe Ser Pro Glu Glu Met Asp Leu
695 700 705
Ser Gln Glu Gln Pro Leu Asp Ala Gln Gln Gly Pro Pro Glu Pro
710 715 720
A1a Gln Glu Ser Leu Ser Gly Ser Glu Ser Lys Pro Lys Asp Glu
725 730 735
Leu
<210> 34
<211> 1896
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7204554CD1
<400> 34
Met Pro Leu Pro Pro Arg Ser Leu Gln Val Leu Leu Leu Leu Leu
1 5 10 15
Leu Leu Leu Leu Leu Leu Pro Gly Met Trp Ala Glu Ala Gly Leu
20 25 30
Pro Arg Ala Gly Gly Gly Ser Gln Pro Pro Phe Arg Thr Phe Ser
35 40 45
Ala Ser Asp Trp Gly Leu Thr His Leu Val Val His Glu Gln Thr
50 55 60
Gly Glu Val Tyr Val Gly Ala Val Asn Arg Ile Tyr Lys Leu Ser
65 70 75
Gly Asn Leu Thr Leu Leu Arg Ala His Val Thr Gly Pro Val Glu
80 85 90
Asp Asn Glu Lys Cys Tyr Pro Pro Pro Ser Val Gln Ser Cys Pro
73/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
95 100 105
His Gly Leu Gly Ser Thr Asp Asn Val Asn Lys Leu Leu Leu Leu
110 115 120
Asp Tyr Ala Ala Asn Arg Leu Leu Ala Cys Gly Ser Ala Ser Gln
125 130 135
Gly Ile Cys Gln Phe Leu Arg Leu Asp Asp Leu Phe Lys Leu Gly
240 145 150
Glu Pro His His Arg Lys Glu His Tyr Leu Ser Ser Val Gln Glu
155 160 165
Ala Gly Ser Met Ala Gly Val Leu Ile Ala Gly Pro Pro Gly Gln
170 175 ~ 180
Gly Gln Ala Lys Leu Phe Val Gly Thr Pro Ile Asp Gly Lys Ser
185 190 195
Glu Tyr Phe Pro Thr Leu Ser Ser Arg Arg Leu Met Ala Asn Glu
200 205 210
Glu Asp Ala Asp Met Phe Gly Phe Val Tyr Gln Asp Glu Phe Val
215 220 225
Ser Ser Gln Leu Lys Ile Pro Ser Asp Thr Leu Ser Lys Phe Pro
230 235 240
Ala Phe Asp Ile Tyr Tyr Val Tyr Ser Phe Arg Ser Glu Gln Phe
245 250 255
Val Tyr Tyr Leu Thr Leu Gln Leu Asp Thr Gln Leu Thr Ser Pro
260 265 ~ 270
Asp Ala Ala Gly Glu His Phe Phe Thr Ser Lys Ile Val Arg Leu
275 280 285
Cys Va1 Asp Asp Pro Lys Phe Tyr Ser Tyr Val Glu Phe Pro Ile
290 295 300
Gly Cys Glu Gln Ala Gly Val Glu Tyr Arg Leu Val Gln Asp Ala
305 310 315
Tyr Leu Ser Arg Pro Gly Arg Ala Leu Ala His Gln Leu Gly Leu
320 325 330
Ala Glu Asp Glu Asp Val Leu Phe Thr Val Phe Ala Gln Gly Gln
335 340 345
Lys Asn Arg Val Lys Pro Pro Lys Glu Ser Ala Leu Cys Leu Phe
350 355 360
Thr Leu Arg Ala Ile Lys Glu Lys Ile Lys Glu Arg Ile Gln Ser
365 370' 375
Cys Tyr Arg Gly Glu Gly Lys Leu Ser Leu Pro Trp Leu Leu Asn
380 385 390
Lys Glu Leu Gly Cys Ile Asn Ser Pro Leu Gln Ile Asp Asp Asp
395 400 405
Phe Cys Gly Gln Asp Phe Asn Gln Pro Leu Gly G1y Thr Val Thr
410 415 420
Ile Glu Gly Thr Pro Leu Phe Val Asp Lys Asp Asp Gly Leu Thr
425 430 435
Ala Val Ala Ala Tyr Asp Tyr Arg Gly Arg Thr Val Val Phe Ala
440 445 450
Gly Thr Arg Ser Gly Arg Ile Arg Lys Ile Leu Val Asp Leu Ser
455 460 465
Asn Pro Gly Gly Arg Pro Ala Leu Ala Tyr Glu Ser Val Val Ala
470 475 480
Gln Glu Gly Ser Pro Ile Leu Arg Asp Leu Val Leu Ser Pro Asn
485 490 495
His Gln Tyr Leu Tyr Ala Met Thr G1u Lys Gln Val Thr Arg Val
500 ~ 505 510
Pro Val Glu Ser Cys Val Gln Tyr Thr Ser Cys Glu Leu Cys Leu
74/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
515 520 525
Gly Ser Arg Asp Pro His Cys Gly Trp Cys Val Leu His Ser Ile
530 535 540
Cys Ser Arg Arg Asp Ala Cys Glu Arg Ala Asp Glu Pro Gln Arg
545 550 555
Phe Ala A1a Asp Leu Leu Gln Cys Val Gln Leu Thr Val Gln Pro
560 565 570
Arg Asn Val Ser Val Thr Met Ser Gln Val Pro Leu Val Leu Gln
575 580 585
Ala Trp Asn Val Pro Asp Leu Ser Ala Gly Val Asn Cys Ser Phe
590 595 600
Glu Asp Phe Thr Glu Ser Glu Ser Val Leu Glu Asp Gly Arg Ile
605 610 615
His Cys Arg Ser Pro Ser Ala Arg Glu Val Ala Pro Ile Thr Arg
620 625 630
Gly Gln Gly Asp Gln Arg Val Val Lys Leu Tyr Leu Lys Ser Lys
635 640 645
Glu Thr Gly Lys Lys Phe Ala Ser Val Asp Phe Val Phe Tyr Asn
650 655 660
Cys Ser Val His Gln Ser Cys Leu Ser Cys Val Asn Gly Ser Phe
665 670 , 675
Pro Cys His Trp Cys Lys Tyr Arg His Val Cys Thr His Asn Val
680 685 690
Ala Asp Cys Ala Phe Leu Glu Gly Arg Val Asn Val Ser Glu Asp
695 700 705
Cys Pro Gln Ile Leu Pro Ser Thr Gln Ile Tyr Val Pro Val Gly
710 715 720
Val Val Lys Pro Ile Thr Leu Ala Ala Arg Asn Leu Pro Gln Pro
725 730 735
Gln Ser GIy Gln Arg Gly Tyr Glu Cys Leu Phe His Ile Pro Gly
740 745 750
Ser Pro Ala Arg Val Thr Ala Leu Arg Phe Asn Ser Ser Ser Leu
755 760 765
Gln Cys Gln Asn Ser Ser Tyr Ser Tyr Glu Gly Asn Asp Val Ser
770 775 780
Asp Leu Pro Val Asn Leu Ser Val Val Trp Asn Gly Asn Phe Val
785 790 795
Ile Asp Asn Pro Gln Asn Ile Gln Ala His Leu Tyr Lys Cys Pro
800 805 810
Ala Leu Arg Glu Ser Cys Gly Leu Cys Leu Lys Ala Asp Pro Arg
815 820 825
Phe Glu Cys Gly Trp Cys Val Ala Glu Arg Arg Cys Ser Leu Arg
830 835 840
His His Cys Ala Ala Asp Thr Pro A1a Ser Trp Met His Ala Arg
845 850 855
His Gly Ser Ser Arg Cys Thr Asp Pro Lys Ile Leu Lys Leu Ser
860 865 870
Pro Glu Thr Gly Pro Arg Gln G1y Gly Thr Arg Leu Thr Ile Thr
875 880 885
Gly Glu Asn Leu Gly Leu Arg Phe Glu Asp Val Arg Leu Gly Val
890 895 900
Arg Val Gly Lys Val Leu Cys Ser Pro Val Glu Ser Glu Tyr Ile
905 910 915
Ser Ala Glu Gln Ile Val Cys Glu Tle Gly Asp Ala Ser Ser Val
920 925 930
Arg Ala His Asp Ala Leu Val Glu Val Cys Val Arg Asp Cys Ser
75/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
935 940 945
Pro His Tyr Arg Ala Leu Ser Pro Lys Arg Phe Thr Phe Val Thr
950 955 960
Pro Thr Phe Tyr Arg Val Sex Pro Ser Arg Gly Pro Leu Ser Gly
965 970 975
Gly Thr Trp Ile Gly Ile Glu Gly Ser His Leu Asn Ala Gly Ser
980 985 990
Asp Val Ala Val Ser Val Gly Gly Arg Pro Cys Ser Phe Ser Trp
995 1000 1005
Arg Asn Ser Arg Glu Ile Arg Cys Leu Thr Pro Pro Gly Gln Ser
1010 1015 1020
Pro Gly Ser Ala Pro Ile Ile Ile Asn Ile Asn Arg Ala Gln Leu
1025 1030 1035
Thr Asn Pro Glu Val Lys Tyr Asn Tyr Thr Glu Asp Pro Thr Tle
1040 1045 1050
Leu Arg Ile Asp Pro Glu Trp Ser Ile Asn Ser Gly Gly Thr Leu
1055 1060 1065
Leu Thr Val Thr Gly Thr Asn Leu Ala Thr Val Arg Glu Pro Arg
2070 1075 1080
Ile Arg Ala Lys Tyr Gly G1y Ile Glu Arg Glu Asn Gly Cys Leu
1085 1090 1095
Val Tyr Asn Asp Thr Thr Met Val Cys Arg Ala Pro Ser Val Ala
1100 1105 1110
Asn Pro Val Arg Ser Pro Pro Glu Leu Gly Glu Arg Pro Asp Glu
1115 1120 1125
Leu Gly Phe Val Met Asp Asn Val Arg Ser Leu Leu Val Leu Asn
1130 1135 1140
Ser Thr Ser Phe Leu Tyr Tyr Pro Asp Pro Val Leu Glu Pro Leu
1145 1150 1155
Ser Pro Thr Gly Leu Leu Glu Leu Lys Pro Ser Ser Pro Leu Ile
1160 1165 1170
Leu Lys Gly Arg Asn Leu Leu Pro Pro Ala Pro Gly Asn Ser Arg
1175 1180 1185
Leu Asn Tyr Thr Val Leu Ile G1y Ser Thr Pro Cys Thr Leu Thr
1190 1195 1200
Val Ser Glu Thr Gln Leu Leu Cys Glu Ala Pro Asn Leu Thr Gly
1205 1210 1215
Gln His Lys Val Thr Val Arg Ala Gly Gly Phe Glu Phe Ser Pro
1220 1225 1230
Gly Thr Leu Gln Val Tyr Ser Asp Ser Leu Leu Thr Leu Pro Ala
1235 1240 1245
Ile Val Gly Ile Gly Gly Gly Gly Gly Leu Leu Leu Leu Val Ile
1250 1255 1260
Val Ala Val Leu Ile Ala Tyr Lys Arg Lys Ser Arg Asp Ala Asp
1265 1270 1275
Arg Thr Leu Lys Arg Leu Gln Leu Gln Met Asp Asn Leu Glu Ser
1280 ' 1285 1290
Arg Val Ala Leu Glu Cys Lys Glu Ala Phe Ala Glu Leu G1n Thr
129 1300 1305
Asp Ile His Glu Leu Thr Asn Asp Leu Asp Gly Ala Gly Ile Pro
1310 1315 1320
Phe Leu Asp Tyr Arg Thr Tyr Ala Met Arg Val Leu Phe Pro Gly
1325 1330 1335
Ile Glu Asp His Pro Val Leu Lys Glu Met Glu Val Gln Ala Asn
1340 1345 1350
Val Glu Lys Ser Leu Thr Leu Phe Gly Gln Leu Leu Thr Lys Lys
76'/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
1355 1360 1365
His Phe Leu Leu Thr Phe Ile Arg Thr Leu Glu Ala Gln Arg Ser
1370 1375 1380
Phe Ser Met Arg Asp Arg G1y Asn Val A1a Ser Leu Ile Met Thr
1385 1390 1395
Ala Leu Gln Gly Glu Met Glu Tyr Ala Thr Gly Val Leu Lys Gln
1400 1405 1410
Leu Leu Ser Asp Leu Ile Glu Lys Asn Leu Glu Ser Lys Asn His
1415 1420 1425
Pro Lys Leu Leu Leu Arg Arg Thr Glu Ser Val Ala Glu Lys Met
1430 1435 1440
Leu Thr Asn Trp Phe Thr Phe Leu Leu Tyr Lys Phe Leu Lys Glu
1445 1450 1455
Cys Ala Gly Glu Pro Leu Phe Met Leu Tyr Cys Ala Ile Lys Gln
'1460 1465 1470
G1n Met Glu Lys Gly Pro Tle Asp Ala Ile Thr Gly Glu Ala Arg
1475 1480 1485
Tyr Ser Leu Ser Glu Asp Lys Leu Ile Arg G1n Gln Ile Asp Tyr
1490 1495 1500
Lys Thr Leu Thr Leu Asn Cys Val Asn Pro Glu Asn Glu Asn Ala
1505 1510 ~ 1515
Pro Glu Val Pro Val Lys Gly Leu Asp Cys Asp Thr Val Thr Gln
1520 1525 ~ 1530
Ala Lys Glu Lys Leu Leu Asp Ala Ala Tyr Lys Gly Val Pro Tyr
1535 1540 1545
Ser Gln Arg Pro Lys Ala Ala Asp Met Asp Leu Glu Trp Arg Gln
1550 1555 1560
Gly Arg Met Ala Arg Ile Ile Leu Gln Asp Glu Asp Val Thr Thr
1565 1570 1575
Lys Ile Asp Asn Asp Trp Lys Arg Leu Asn Thr Leu Ala His Tyr
1580 1585 1590
G1n Val Thr Asp Gly Ser Ser Val Ala Leu Val Pro Lys Gln Thr
1595 1600 - 1605
Ser Ala Tyr Asn Ile Ser Asn Ser Ser Thr Phe Thr Lys Ser Leu
1610 1615 1620
Ser Arg Tyr Glu Ser Met Leu Arg Thr Ala Ser Ser Pro Asp Ser
1625 1630 1635
Leu Arg Ser Arg Thr Pro Met Ile Thr Pro Asp Leu Glu Ser Gly
1640 1645 1650
Thr Lys Leu Trp His Leu Val Lys Asn His Asp His Leu Asp Gln
1655 1660 1665
Arg Glu Gly Asp Arg Gly Ser Lys Met Val Ser Glu Ile Tyr Leu
1670 1675 1680
Thr Arg Leu Leu Ala Thr Lys Gly Thr Leu Gln Lys Phe Val Asp
1685 1690 . 1695
Asp Leu Phe Glu Thr Ile Phe Ser Thr Ala His Arg Gly Ser Ala
1700 1705 1710
Leu Pro Leu Ala Ile Lys Tyr Met Phe Asp Phe Leu Asp Glu Gln
1715 1720 1725
Ala Asp Lys His Gln Ile His Asp Ala Asp Val Arg His Thr Trp
1730 1735 1740
Lys Ser Asn Cys Leu Pro Leu Arg Phe Trp Val Asn Val Ile Lys
1745 1750 1755
Asn Pro Gln Phe Val Phe Asp Ile His Lys Asn Ser Ile Thr Asp
1760 1765 ~ 1770
Ala Cys Leu Ser Val Val Ala Gln Thr Phe Met Asp Ser Cys Ser
77/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
1775 1780 1785
Thr Ser Glu His Lys Leu Gly Lys Asp Ser Pro Ser Asn Lys Leu
1790 1795 1800
Leu Tyr Ala Lys Asp Ile Pro Asn Tyr Lys Ser Trp Val Glu Arg
1805 1810 1815
Tyr Tyr Ala Asp Ile Ala Lys Met Pro Ala Ile Ser Asp Gln Asp
1820 1825 1830
Met Ser Ala Tyr Leu Ala Glu Gln Ser Arg Leu His Leu Ser Gln
1835 1840 1845
Phe Asn Ser Met Ser Ala Leu His Glu Ile Tyr Ser Tyr Ile Thr
1850 1855 1860
Lys Tyr Lys Asp Glu Ile Leu Ala Ala Leu Glu Lys Asp Glu Gln
1865 1870 1875
Ala Arg Arg Gln Arg Leu Arg Ser Lys Leu Glu Gln Val Val Asp
1880 1885 1890
Thr Met Ala Leu Ser Ser
1895
<210> 35
<211> 215
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 6833247CD1
<400> 35
Met Gly Leu Glu Lys Pro Gln Ser Lys Leu Glu Gly Gly Met His
1 5 10 15
Pro Gln Leu Ile Pro Ser Val Ile Ala Val Val Phe Ile Leu Leu
20 25 30
Leu Ser Val Cys Phe Ile Ala Ser Cys Leu Val Thr His His Asn
35 40 45
Phe Ser Arg Cys Lys Arg Gly Thr Gly Val His Lys Leu Glu His
50 55 60
His Ala Lys Leu Lys Cys Ile Lys Glu Lys Ser Glu Leu Lys Ser
65 70 75
Ala Glu Gly Ser Thr Trp Asn Cys Cys Pro Ile Asp Trp Arg Ala
80 85 90
Phe Gln Ser Asn Cys Tyr Phe Pro Leu Thr Asp Asn Lys Thr Trp
95 100 105
Ala Glu Ser Glu Arg Asn Cys Ser Gly Met Gly Ala His Leu Met
110 115 120
Thr Ile Ser Thr Glu Ala Glu Gln Asn Phe Ile Ile Gln Phe Leu
125 130 135
Asp Arg Arg Leu Ser Tyr Phe Leu G1y Leu Arg Asp Glu Asn Ala
140 145 150
Lys Gly Gln Trp Arg Trp Val Asp Gln Thr Pro Phe Asn Pro Arg
155 160 165
Arg Val Phe Trp His Lys Asn Glu Pro Asp Asn Ser Gln Gly Glu
170 175 180
Asn Cys Val Val Leu Val Tyr Asn Gln Asp Lys Trp Ala Trp Asn
185 190 195
Asp Val Pro Cys Asn Phe Glu Ala Ser Arg Ile Cys Lys Ile Pro
200 205 ~ 210
78/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
Gly Thr Thr Leu Asn
215
<210> 36
<211> 579
<212> PRT
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 4148119CD1
<400> 36
Met Gly Arg Pro Thr Gln Trp Pro Ser Leu Leu Leu Leu Leu Leu
1 5 10 15
Leu Pro Gly Pro Pro Pro Val Ala Gly Leu Glu Asp Ala Ala Phe
20 25 30
Pro His Leu G1y Glu Ser Leu Gln Pro Leu Pro Arg Ala Cys Pro
35 40 45
Leu Arg Cys Ser Cys Pro Arg Val Asp Thr Val Asp Cys Asp Gly
50 55 60
Leu Asp Leu Arg Val Phe Pro Asp Asn Ile Thr Arg Ala Ala Gln
65 70 75
His Leu Ser Leu Gln Asn Asn Gln Leu Gln Glu Leu Pro Tyr Asn
80 85 90
Glu Leu Ser Arg Leu Ser Gly Leu Arg Thr Leu Asn Leu His Asn
95 100 105
Asn Leu Ile Ser Ser Glu Gly Leu Pro Asp Glu Ala Phe Glu Ser
110 115 120
Leu Thr Gln Leu Gln His Leu Cys Val Ala His Asn Lys Leu Ser
125 130 135
Val Ala Pro Gln Phe Leu Pro Arg Ser Leu Arg Val Ala Asp Leu
140 145 150
Ala Ala Asn Gln Val Met Glu Ile Phe Pro Leu Thr Phe Gly Glu
155 160 165
Lys Pro Val Leu Arg Ser Val Tyr Leu His Asn Asn Gln Leu Ser
170 175 180
Asn Ala Gly Leu Pro Pro Asp Ala Phe Arg Gly Ser Glu Ala Ile
185 190 195
Ala Thr Leu Ser Leu Ser Asn Asn Gln Leu Ser Tyr Leu Pro Pro
200 205 210
Ser Leu Pro Pro Ser Leu G1u Arg Leu His Leu Gln Asn Asn Leu
215 220 225
Ile Ser Lys Val Pro Arg Gly Ala Leu Ser Arg Gln Thr Gln Leu
230 235 240
Arg Glu Leu Tyr Leu Gln His Asn Gln Leu Thr Asp Ser Gly Leu
245 250 255
Asp Ala Thr Thr Phe Ser Lys Leu His Ser Leu Glu Tyr Leu Asp
260 265 270
Leu Ser His Asn Gln Leu Thr Thr Val Pro Ala Gly Leu Pro Arg
275 280 285
Thr Leu Ala Ile Leu His Leu Gly Arg Asn Arg Ile Arg Gln Val
290 295 300
Glu Ala Ala Arg Leu His Gly Ala Arg Gly Leu Arg Tyr Leu Leu
305 310 315
Leu Gln His Asn Gln Leu Gly Ser Ser Gly Leu Pro Ala Gly Ala
79/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
320 325 330
Leu Arg Pro Leu Arg Gly Leu His Thr Leu His Leu Tyr Gly Asn
335 340 345
Gly Leu Asp Arg Val Pro Pro Ala Leu Pro Arg Arg Leu Arg Ala
350 355 360
Leu Val Leu Pro His Asn His Val Ala Ala Leu Gly Ala Arg Asp
365 370 375
Leu Val Ala Thr Pro Gly Leu Thr Glu Leu Asn Leu Ala Tyr Asn
380 385 390
Arg Leu Ala Ser Ala Arg Val His His Arg Ala Phe Arg Arg Leu
395 400 405
Arg Ala Leu Arg Ser Leu Asp Leu Ala Gly Asn Gln Leu Thr Arg
410 415 420
Leu Pro Met Gly Leu Pro Thr Gly Leu Arg Thr Leu Gln Leu Gln
425 430 435
Arg Asn Gln Leu Arg Met Leu Glu Pro Glu Pro Leu Ala Gly Leu
440 445 450
Asp Gln Leu Arg Glu Leu Ser Leu Ala His Asn Arg Leu Arg Val
455 460 465
Gly Asp Ile Gly Pro Gly Thr Trp His Glu Leu Gln Ala Leu Gln
470 475 480
Met Leu Asp Leu Ser His Asn Glu Leu Ser Phe Val Pro Pro Asp
485 490 495
Leu Pro Glu Ala Leu Glu Glu Leu His Leu Glu Gly Asn Arg Ile
500 505 510
Gly His Val Gly Pro Glu Ala Phe Leu Ser Thr Pro Arg Leu Arg
515 520 525
Ala Leu Phe Leu Arg Ala Asn Arg Leu His Met Thr Ser Ile Ala
530 535 540
Ala Glu Ala Phe Leu Gly Leu Pro Asn Leu Arg Val Val Asp Thr
545 550 555
Ala Gly Asn Pro Glu Gln Val Leu Ile Arg Leu Pro Pro Thr Thr
560 565 570
Pro Arg Gly Pro Arg Ala Gly Gly Pro
575
<210> 37
<211> 1211
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1888682CB1
<400> 37
ccgggacggt cacatcccgc tgcaggggcg ggcggaggcc gccgcactgc ctcccgcacc 60
ggggacccag gccagcgtcc gggcaacgcc ccctgctccc ggacagactc cgtggcccgc 120
tcgagccctg ggggctccgc agacccgcgc ccgctccgcc cgcagctcgg ccccgcgctg 180
cccgcgtcgc cgggcccgcg ccgggatggg gtaggggcag cgccaccgag tcgggcgatg 240
ggccgccctc tgggcaccga gcagcccccc gaggcctgac caaccgcgag gaccggcgga 300
ggagccccgc ctggatgtca agcggatgcc aagcggatgc cacagttccc cccccagcgg 360
actccgtggg gacatggctt cgctggtgcc cctttcccca tatctaagcc ccacggtcct 420
cctgctggtc agctgtgacc tgggcttcgt gcgagcagac cggcctccct ctcctgtgaa 480
tgtgacggtc actcacctca gagccaactc ggccactgtg tcctgggacg tcccagaagg 540
caacatcgtc attggctact ccatttccca gcaacggcag aatggccccg ggcagcgtgt 600
80/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gattcgggag gtgaacacca ccacccgggc ctgtgccctc tggggcctgg ctgaagacag 660
tgactacaca gtgcaggtca ggagcatcgg ccttcgggga gagagtcccc cagggccccg 720
ggtgcacttc cgaactctca agggttctga ccggctacct tcaaacagtt caagcccagg 780
tgacatcaca gtggaaggtc tggatggaga gcggccactg cagactgggg aagtggtcat 840
cattgtggtg gtgttgctca tgtgggctgc tgtaattggg ctgttctgcc gtcagtatga 900
catcatcaag gacaatgact ccaacaacaa tcccaaggag aagggaaagg ggccggaaca 960
gagtcctcag ggaaggccag tggggacaag acagaaaaag tcaccatcta tcaacaccat 1020
cgacgtttga gtgaagaaac acacccagaa gagagatgca ctaacaactg gggataggga 1080
tggggtcagg gggagcccaa gatggtgatc tgcccgagac tcccagaggg tattgccact 1140
cccacaatct caggcctggt acccatcctc tttccactgt gagcagagcc agaaggtagg 1200
tctgttcaga g 1211
<210> 38
<211> 1523
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1794980CB1
<400> 38
ggcggctggc ggcgcgggca ggcaggcggg gaggacaggc tgggggcggc gaccgcgagg 60
ggccgcgcgc ggagggcgcc tggtgcagca tgggcggccc gcgggcttgg gcgctgctct 120
gcctcgggct cctgctcccg ggaggcggcg ctgcgtggag catcggggca gctccgttct 180
ccggacgcag gaactggtgc tcctatgtgg tgacccgcac catctcatgc catgtgcaga 240
atggcaccta ccttcagcga gtgctgcaga actgcccctg gcccatgagc tgtccgggga 300
gcagctacag aactgtggtg agacccacat acaaggtgat gtacaagata gtgaccgccc 360
gtgagtggag gtgctgccct gggcactcag gagtgagctg cgaggaagtt gcagcttcct 420
ctgcctcctt ggagcccatg tggtcgggca gtaccatgcg gcggatggcg cttcggccca 480
cagccttctc aggttgtctc aactgcagca aagtgtcaga gctgacagag cggctgaagg 540
tgctggaggc caagatgacc atgctgactg tcatagagca gccagtacct ccaacaccag 600
ctacccctga ggaccctgcc ccgctctggg gtccccctcc tgcccagggc agccccggag 660
atggaggcct ccaggaccaa gtcggtgctt gggggcttcc cgggcccacc ggccccaagg 720
gagatgccgg cagtcggggc ccaatgggga tgagaggccc accaggtcca cagggccccc 780
cagggagccc tggccgggct ggagctgtgg gcacccctgg agagagggga cctcctgggc 840
caccagggcc tcctggcccc cctgggcccc cagcccctgt tgggccaccc catgcccgga 900
tctcccagca tggagaccca ttgctgtcca acaccttcac tgagaccaac aaccactggc 960
cccagggacc cactgggcct ccaggccctc cagggcccat gggtccccct gggcctcctg 1020
gccccacagg tgtccctggg agtcctggtc acataggacc cccaggcccc actggaccca 1080
aaggaatctc tggccaccca ggagagaagg gcgagagagg actgcgtggg gagcctggcc 1140
cccaaggctc tgctgggcag cggggggaac ctggccctaa gggagaccct ggtgagaaga 1200
gccactgggg ggaggggttg caccagctac gcgaggcttt gaagatttta gctgagaggg 1260
ttttaatctt ggaaacaatg attgggctct atgaaccaga gctggggtct ggggcgggcc 1320
ctgccggcac aggcaccccc agcctccttc ggggcaagag gggcggacat gcaaccaact 1380
accggatcgt ggcccccagg agccgggacg agagaggctg agttggtggc ggcccctgag 1440
gcagaccagg ccaggcttcc cctcctacct ggactcggcc agctgcctcc agggaccgcc 1500
cgtccataat tcaggagcgt ccc 1523
<210> 39
<211> 1368
<212> DNA
<213> Homo Sapiens
<220>
<221> misc feature
81/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<223> Incyte ID No:°5533958CB1
<400> 39
ctgccgggtg tgccgggtgt ccagcgaacc cctttcccaa accttcgggg agaagggagg 60
tgggaggagg caaagaaact acaggcaggg agctggaagg gggggtgggg ggggcaggag 120
acaagaaatc aagacaccag gcagcaggac acacacacac tcacatacac tcacacacat 180
agagaccaac agatagacag ctacctaaag cctgaaagac tgacagcaac acagaaaaaa 240
agaaacaggc agaaagagag acaaagacag aaatagaaac agactaacac acagagtcaa 300
aaatacagag acagaaagac agggagaaag agaaacagaa aattagacac caaagacata 360
cgaacaggga ggaaggccga ctgaaagaaa gacggagaag aggagagaga agccagggcc 420
gagcgtgcca gcaggcggat ggagggcggc ctggtggagg aggagacgta gtggcctggg 480
ctgagctggg tgggccggga gaagcgggtg cctcagagtg ggggtggggg catgggaggg 540
gcaggcattc tgctgctgct gctggctggg gcgggggtgg tggtggcctg gagaccccca 600
aagggaaagt gtcccctgcg ctgctcctgc tctaaagaca gcgccctgtg tgagggctcc 660
ccggacctgc ccgtcagctt ctctccgacc ctgctgtcac tctcactcgt caggacggga 720
gtcacccagc tgaaggccgg cagcttcctg agaattccgt ctctgcacct gctcctcttc 780
acctccaact ccttctccgt gattgaggac gatgcatttg cgggcctgtc ccacctgcag 840
tacctcttca tcgaggacaa tgagattggc tccatctcta agaatgccct cagaggactt 900
cgctcgctta cacacctaag cctggccaat aaccatctgg agaccctccc cagattcctg 960
ttccgaggcc tggacaccct tactcacgtg gacctccgcg ggaacccgtt ccagtgtgac 1020
tgccgcgtcc tctggctcct gcagtggatg cccaccgtga atgccagcgt ggggaccggc 1080
gcctgtgcgg gccccgcctc cctgagccac atgcagctcc accacctcga ccccaagact 1140
ttcaagtgca gagccatagg tggggggctt tcccgatggg gtgggaggcg ggagatctgg 1200
gggaaaggct gccagggcca agaggctcgt ctcactccct gccctgccat ttcccggagt 1260
gggaagaccc tgagcaagca gcactgcctt cctgagcccc agttttctca tctgtaaagt 1320
gggggtaata aacagtgata taggagtgcc atggaaaaaa aaaaaaaa 1368
<210> 40
<211> 3157
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_~eature
<223> Incyte ID No: 60210196CB1
<400> 40
tggtcgttcc tcggtttgcc atccattggg cccctgccct ccatccccgt ggaggcccct 60
tgtctgggtg ttcgcactca acgtcgatgt gttgataatg gtgccttttt cgtgaagaaa 120
ctgcctgagt ctcacttcca gaagtttata ggtccacccg ttctctccag cgtccgccag 180
cccagatctc gcatgcgcat ctgtgtctgc ccctctttgc cttctgcctg tccctgggtg 240
cccctcaggg tcagaatcac cctttccgcc cgcactggcc cccacatcac ctgtcttgtc 300
cccactggcc ttccctgagg actctgttcc ggcccctttc ccttctcctt gggattgttg 360
ttggagtcat tgtccttgat gatgtcatac tgacggcaga acagcccaat tacagctgaa 420
acacaataca gtctgagccc agagagccgc ggggaccatg gagccggtgc cgctgcagga 480
cttcgtgcgc gccttggacc ccgcctccct cccgcgcgtg~ctgcgggtct gctcgggggt 540
ctacttcgag ggctccatct atgagatctc tgggaatgag tgctgcctct ccacggggga 600
cctgatcaag gtcacccagg tccgcctcca gaaggtggtc tgtgagaacc cgaagaccag 660
ccagaccatg gagctcgccc ccaacttcca gggctacttc acccccctca acaccccaca 720
gagctatgaa accctggagg agctggtctc tgccacaact cagagctcca agcagctgcc 780
cacttgcttc atgtcgaccc acaggattgt cacagagggc agggtggtga ctgaggacca 840
gctcctcatg cttgaggctg tggtgatgca cctcgggatc cgctctgccc gctgtgtcct 900
gggcatggag ggtcagcagg tcatcctgca cctgccccta tcccagaagg ggcccttctg 960
gacatgggag cctagtgccc ctcgaactct gctccaggtc ctacaggatc cagccctgaa 1020
agacctcgtc ctcacctgcc ccaccctgcc ctggcattcc ctgatcctgc ggccccagta 1080
tgagatccaa gccatcatgc acatgcgcag gaccattgtc aagatccctt ctaccctgga 1140
82/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ggtcgacgtg gaggacgtca ccgcctcctc ccggcacgtc cactttatca aaccgctgct 1200
gctgagcgag gtcctggcct gggaaggccc tttccccctg tccatggaga tcctggaggt 1260
tcctgagggc cgccccatct tcctcagccc gtgggtgggc tccttgcaaa aaggccagag 1320
gctttgcgtc tatggcctag cctcaccacc ctggcgggtc ctggcctcaa gcaagggccg 1380
caaggtgccc aggcacttcc tggtgtcagg gggctaccaa ggcaagctgc ggcggcggcc 1440
aagggagttc cccacggcct atgacctcct aggtgctttc cagccaggcc ggccactccg 1500
ggtggtggcc acaaaggact gtgagggcga gagggaggag aatcccgagt tcacgtccct 1560
ggctgtgggt gaccggctgg aggtgctggg gcctggccag gcccatgggg cccagggcag 1620
tgacgtggat gtcttggttt gtcagcggct gagtgaccag gctggggagg atgaggagga 1680
agagtgcaaa gaggaggcag agagcccaga gcgggtcctg ctgcccttcc acttccctgg 1740
cagtttcgtg gaggagatga gtgacagccg gcgctacagc ctggcagatc tgactgccca 1800
gttttcactg ccttgtgagg tcaaggtggt ggccaaggac accagccacc ccactgaccc 1860
tctgacctcc ttcctgggcc tgcggctgga ggagaagatc acagagccat tcttggtggt 1920
gagcctagac tctgagcctg ggatgtgctt tgagatccct ccccggtggc tggacctgac 1980
tgttgtgaag gccaaggggc agccagactt gccagagggg tctctcccca tagccacagt 2040
ggaggagctg acagacacct tctattatcg tcttcggaag ttaccagcct gtgagatcca 2100
agccccccca cccaggcccc ctaaaaatca gggcctcagc aagcagagga gacacagcag 2160
tgagggaggc gtcaagtctt ctcaagtctt aggattgcag caacacgctc ggctgcccaa 2220
acccaaggcg aagaccttgc cagagttcat caaggatggc tccagtacgt acagcaagat 2280
tcctgcccac aggaagggcc acaggcccgc taagccccaa aggcaggatc tagatgatga 2340
tgaacatgat tatgaagaaa tacttgagca atttcagaaa accatctaag tgctggagga 2400
accacgcttc ctaactgctg cttctcaggg aatccgacac cagccaacca ttttaagcct 2460
ctaaaagacc tcgggcaagt ctcacagaaa ctgagctgca gacggggagt agctttgtgg 2520
aaactgattt gatggacact gcaccagctt ccttcaggtt ctagattctt gctacttagg 2580
gcgggctggt ttggacctaa catctcgcac gtgactccct cagcctcaga gccttgggat 2640
gcagagcagc tggcagggtt cctctcaatc ctgcaacccc agctgtccca ccggtggatg 2700
cagaggggaa tccgaggcca tcaaccttgg tgacagcagc gcagtgccaa tgctgatcac 2760
actgcatggg agattttgtt aacgtctgcc acccccactc tcacccccaa gctctaagcc 2820
cccgggaggc ctggactgtc ttcctcatct ctgtagcacc aagcctgata gatctgtata 2880
tggtaaacag gggtttaacc acatgtggtt aacatggatt aatgtgggaa tttggcttca 2940
agaacacaac cttaggacct tgggccccaa aagctggtgg tgaaatgaga ggagccaatt 3000
taagaagacc cttatggaga cctgaggctg cagaaactgg taggtttcat caggtggtta 3060
aagtcgtcaa agttgtaagt gactaaccaa gattatttca ttttaaaacc acagaataaa 3120
aatgacacct gagcttctct aaaaaaaaaa aaaaaaa 3157
<210> 41
<211> 3264
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 815125CB1
<400> 41
ggagccgggg cagccagaag aggtgggaaa agcggaggag gacgcccagg aggaggcggc 60
ggcggcggcc gggaagtgaa aggtctcgca aagttcagcg gcggctgcgg gcgccgagcc 120
ccgggctagc ggcagacgag cccgcagggc cgctccgcgg ggcagcgcag ccaggccggc 180
tatggtcccg gggctcccgc cgccccccag gtgcccggga cccgccaggc cgggtgcgcg 240
agggtcaccc cacctccccg cgcggtcccg gcccctggct cccagctgcc ggcgaccgct 300
gaccgagccc ggcgccccag gaggaggaag aaaccagggc cccgttccct cccgaggacg 360
gcggcgcttc atcccgcagc ccagaggtct cggctccctc cggcacccgc ccggcccggc 420
tgctcccggc tcctcccggc catggggagc tgcgcgcggc tgctgctgct ctggggctgc 480
acggtggtgg ccgcaggact gagtggagta gctggagtga gttcccgctg tgaaaaagcc 540
tgcaaccctc ggatgggaaa tttggctttg gggcgaaaac tctgggcaga caccacctgc 600
ggtcagaatg ctaccgaact gtactgcttc tacagtgaga acacggatct gacttgtcgg 660
83/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
cagcccaaat gtgacaagtg caatgctgcc tatcctcacc tggctcacct gccatctgcc 720
atggcagact catccttccg gtttcctcgc acatggtggc agtctgcgga ggatgtgcac 780
agagaaaagg tccagttaga cctggaagct gaattctact tcactcacct aattgtgatg 840
ttcaagtccc ccaggccagc tgccatggtg ctggaccgct cccaggactt tgggaaaaca 900
tggaagcctt ataagtactt tgcgactaac tgctccgcta catttggcct ggaagatgat 960
gttgtcaaga agggcgctat ttgtacttct aaatactcca gtccttttcc atgcactgga 1020
ggagaggtta ttttcaaagc tttgtcacca ccatacgata cagagaaccc ttacagtgcc 1080
aaagttcagg agcagctgaa gatcaccaac cttcgcgtgc agctgctgaa acgacagtct 1140
tgtccctgtc agagaaatga cctgaacgaa gagcctcaac attttacaca ctatgcaatc 1200
tatgatttca ttgtcaaggg cagctgcttc tgcaatggcc acgctgatca atgcatacct 1260
gttcatggct tcagacctgt caaggcccca ggaacattcc acatggtcca tgggaagtgt 1320
atgtgtaagc acaacacagc aggcagccac tgccagcact gtgccccgtt atacaatgac 1380
cggccatggg aggcagctga tggcaaaacg ggggctccca acgagtgcag aacctgcaag 1440
tgtaatgggc atgctgatac ctgtcacttc gacgttaatg tgtgggaggc atcagggaat 1500
cgtagtggtg gtgtctgtga tgactgtcag cacaacacag aaggacagta ttgccagagg 1560
tgcaagccag gcttctatcg~tgacctgcgg agacccttct cagctccaga tgcttgcaaa 1620
ccgtgttcct gccatccagt aggatcagct gtccttcctg ccaactcagt gaccttctgc 1680
gaccccagca atggtgactg cccttgcaag cctggggtgg cagggcgacg ttgtgacagg 1740
tgcatggtgg gatactgggg cttcggagac tatggctgtc gaccatgtga ctgtgcaggg 1800
agctgtgacc ctatcaccgg agactgcatc agcagccaca cagacataga ctggtatcat 1860
gaagttcctg acttccgtcc cgtgcacaat aagagcgaac cagcctggga gtgggaggat 1920
gcgcaggggt tttctgcact tctacactca ggtaaatgcg aatgtaagga acagacatta 1980
ggaaatgcca aggcattctg tggaatgaaa tattcatatg tgctaaaaat aaagatttta 2040
tcagctcatg ataaaggtac tcatgttgag gtcaatgtga agattaaaaa ggtcttaaaa 2100
tctaccaaac tgaagatttt ccgaggaaag cgaacattat atccagaatc atggacggac 2160
agaggatgca cttgtccaat cctcaatcct ggtttggaat accttgtagc aggacatgag 2220
gatataagaa caggcaaact aattgtgaat atgaaaagct ttgtccagca ctggaaacct 2280
tctcttggaa gaaaagtcat ggatatttta aaaagagagt gcaagtagca ttaagatgga 2340
tagcacataa tggcacttgt ctatgtacaa aacacaaact ttagagcaag aagacctcag 2400
acaggaaact ggaatttttt aaagtgccaa aacatataga aatgtttgaa tgcatgggtc 2460
ttatctaatt tatctcttct ggacccatgt ttaaatacag ttttatttca tgaagagaaa 2520
tgaaaacccc tacactgata tctgttttct atgggactga ttctgaaatt cttaactatt 2580
aagaatattt taatagcagc atgacattta gcagtaatcc attaagggca gtacctctaa 2640
caaggacgcc ttccagcttc agctatgtta cttacgtttg atgctactta aagtaatgaa 2700
tgacgtttta aggaatccct aaccctacta tcagaaaagg tgtttgttaa agagccttct 2760
cttgtgtgtt acgcatgaac tttggtctgt aggtgttaaa tggaacctct ccatgtgtat 2820
atagtatttc cttgtataaa gcactttact acctaccact tgtgttgtga acgtttggtg 2880
actgctgttg aaagaaggaa aagggtgtgt gagaaagcct actgaagcag cagcactgcc 2940
actacatgtg gacaaaagtg aacatataaa agaagttgtg ctatttaact btgaatactt 3000
ggagaaacta ggtgaagatg caaccagaaa ggagaatatg tatgcgtgaa gtctcagctt 3060
tgagctggag gctagattcc aagatgacag ccatgatgaa actttttaaa aaactaaacc 3120
agaagagact ttaaaataag agaaagaaat cataaatgta gacatatgct tggctaaagg 3180
ggaaatggac tttaaatttt aaagagctca tttgcaatgc acttgtatac acttcaaaaa 3240
ttattgtaga cacagcattt gtta 3264
<210> 42
<211> 3383
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1386915CB1
<400> 42
tgcgatctag aacgtccgac ctctcctctc ccagccagtc gtggctggcc tttcaaagtg 60
84/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
tgcagttgtc tcctccctgt ccagccccat cgtcgcccag gaccagctgg gccgcggtct 120
gacctgaggc tgctgctcag cgccggggcg ctggcgctct ccattcgagc accttccagc 180
ataccgctcg gctccgggag ccgctctgca aagttgagca gctcagagcg caagctttgc 240
ctctcgactt ctccctcctt gggtccccgg cgcccccgcc tcccacgatc cctttcacta 300
ggagcagcca gtcccagcgg gctggcaact tgcacccctt cctagtcatc ctccctgaaa 360
cgcgaccatg ctgttaaggg gcgtcctcct ggcgttgcaa gccctgcagc tcgccggtgc 420
cctcgacctg cccgctgggt cctgtgcctt tgaagagagc acttgcggct ttgactccgt 480
gttggcctct ctgccgtgga ttttaaatga ggaaggccat tacatttatg tggatacctc 540
ctttggcaag cagggggaga aagctgtgct gctaagtcct gacttacagg ctgaggaatg 600
gagctgcctc cgtttggtct accagataac cacatcttcg gagtctctgt cagatcccag 660
ccagctgaac ctctacatga gatttgaaga tgaaagcttt gatcgcttgc tttggtcagc 720
taaggaacct tcagacagct ggctcatagc cagcttggat ttgcaaaaca gttccaagaa 780
attcaagatt ttaatagaag gtgtactagg acagggaaac acagccagca tcgcactatt 840
tgaaatcaag atgacaaccg gctactgtat tgaatgtgac tttgaagaaa atcatctctg 900
tggctttgtg aaccgctgga atcccaatgt gaactggttt gttggaggag gaagtattcg 960
gaatgtccac tccattctcc cacaggatca caccttcaag agtgaactgg gccactacat 1020
gtacgtggac tcagtttatg tgaagcactt ccaggaggtg gcacagctca tctccccgtt 1080
gaccacggcc cccatggctg gctgcctgtc attttattac cagatccagc aggggaatga 1140
caatgtcttt tccctttaca ctcgggatgt ggctggcctt tacgaggaaa tctggaaagc 1200
agacaggcca gggaatgctg cctggaacct tgcggaggtc gagttcaatg ctccttaccc 1260
catggaggtt atttttgaag ttgctttcaa tggtcccaag ggaggttatg ttgccctgga 1320
tgatatttca ttctctcctg ttcactgcca gaatcagaca gaacttctgt tcagtgccgt 1380
ggaagccagc tgcaattttg agcaagatct ctgcaacttt taccaagata aagaaggtcc 1440
aggttggacc cgagtgaaag taaaaccaaa catgtatcgg gctggagacc acactacagg 1500
cttagggtat tacctgctag ccaacacaaa gttcacatct cagcctggct acattggaag 1560
gctctatggg ccctccctac caggaaactt gcagtattgt ctgcgttttc attatgccat 1620
ctatggattt ttaaaaatga gtgacaccct agcagtttac atctttgaag agaaccatgt 1680
ggttcaagag aagatctggt ctgtgttgga gtccccaagg ggtgtttgga tgcaagctga 1740
aatcaccttt aagaagccca tgcctaccaa ggtggttttc atgagcctat gcaaaagttt 1800
ctgggactgt gggcttgtag ccctggatga cattacaata caattgggaa gctgctcatc 1860
ttcagagaaa cttccacctc cacctggaga gtgtactttc gagcaagatg aatgtacatt 1920
tactcaggag aaaagaaacc ggagcagctg gcacaggagg aggggagaaa ctcccacttc 1980
ctacacagga ccaaagggag atcacactac tggggtaggc tactacatgt acattgaggc 2040
ctcccatatg gtgtatggac aaaaagcacg cctcttgtcc aggcctctgc gaggagtctc 2100
tggaaaacac tgcttgacct ttttctacca catgtatgga gggggcactg gcctgctgag 2160
tgtttatctg aaaaaggaag aagacagtga agagtccctc ttatggagga gaagaggtga 2220
acagagcatt tcctggctac gagcactgat tgaatacagc tgtgagaggc aacaccagat 2280
aatttttgaa gccattcgag gagtatcaat aagaagtgat attgccattg atgatgttaa 2340
atttcaggca ggaccctgtg gagaaatgga agatacaact caacaatcat caggatattc 2400
tgaggactta aatgaaattg agtattaaga aatgatctgc attggattta ctagacgaaa 2460
accatacctc tcttcaatca aaatgaaaac aaagcaaatg aatactggac agtcttaaca 2520
attttataag ttataaaatg actttagagc accctccttc attacttttg caaaaacata 2580
ctgactcagg gctctttttt tctttttgca tatgacaact gttactagaa atacaggcta 2640
ctggttttgc atagatcatt catcttaatt ttggtaccag ttaaaaatac aaatgtacta 2700
tattgtagtc attttaaagt acacaaaggg cacaatcaaa atgagatgca ctcatttaaa 2760
tctgcattca gtgaatgtat tgggagaaaa ataggtcttg caggtttcct tttgaatttt 2820
aagtatcata aatatttttt aagtaaataa tacggggtgt cagtaatatc tgcagaatga 2880
atgcagtctt tcatgctaat gagttagtct ggaaaaataa agtcttattt tctatgtttt 2940
attcatagaa atggagtatt aatttttaat attttcacca tatgtgataa caaaggatct 3000
ttcatgaatg tccaagggta agtcagtatt aattaatgct gtattacaag gcaatgctac 3060
cttctttatt ccccctttga actacctttg aagtcactat gagcacatgg atagaaattt 3120
aacttttttt tgtaaagcaa gcttaaaatg tttatgtata catacccagc aacttttata 3180
aatgtgttaa acaattttac tgatttttat aataaatatt ttggtaagat tttgaataat 3240
atgaattcag gcagatatac taaactgctt ttatttactt gtttagaaaa ttgtatatat 3300
atgtttgtgt atcctaacag ctgctatgaa attataaaat tacctaataa aaataatttg 3360
aaaatcttaa aaaaaaaaaa aaa 3383
85/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 43
<211> 2741
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte TD No: 1344495CB1
<400> 43
ggcagctgcg ggtcgcgggt cgcgggtcgc gagtcgccgg tcgccggtcg cggcggagcc 60
tgggcgctga gtgaagaaaa tgaggcacga ggaattgtta accaagacct tccaaggccc 120
agctgttgtg tgtgggactc cgaccagcca cgtatacatg tttaagaatg gcagtgggga 180
ctcgggggac tcttctgaag aagagtctca ccgtgtggtt ttgcggcccc ggggcaagga 240
gcgccacaag agcggtgtcc accagcctcc ccaggcggga gcaggtgacg tggtgctgct 300
gcagcgggag ctggcccagg aggacagcct caacaagctg gcgctgcagt atggctgcaa 360
agttgcagat atcaagaaag tcaacaactt catcagagaa caagacttat atgctttgaa 420
atctgttaag attccagtga gaaaccatgg gatcctgatg gagacccaca aagaactgaa 480
accccttctg agcccgtctt ccgagaccac agtgaccgtg gaactgccag aggcagacag 540
agcaggcgcg ggcaccggtg cccaggccgg ccaactgatg ggcttcttta aggggattga 600
ccaggatatt gagcgtgcag tgcagtcaga aatctttcta catgaaagtt actgcatgga 6&0
cacctcccat cagccactgc tcccggcacc tccgaagacg'cctatggatg gtgcagattg 720
tggcattcag tggtggaatg ctgttttcat catgctgctg attggtattg tcttgcctgt 780
cttttatttg gtctacttta aaatacaagc tagtggtgag acccctaata gcttgaacac 840
aactgtcatc cccaatggct cgatggcaat gggtacagtt ccagggcaag cccccagact 900
agcagttgca gtgccagccg tcacttctgc agacagccag ttcagtcaga ccacccaagc 960
ggggagctaa gctttgtttt taaagactcg gcccagcttt agcaattggc tgttgatgtg 1020
cctcagctgt cactggcgat gtcctagggg tgctgcattt tgcttccggg gaaggatgga 1080
cacttttcag aagtcactgc agtattccca attgcactgg ccctgggcat ggccttaccc 1140
agtctaagct ggcaggatct aaaacagcag cgacctcggc ccctatccag agaggtgcag 1200
caagagagcc atttccctgt gacatttagt ggactggcca gttcatagca gcactgtgag 1260
gacccccaag ttggacgtgc tcggagggaa agatttatgg cctctgtcga gggacctgca 1320
gcgtgagagc cagtggcatc tgcgcggctt gcctggctct tgctgtatcc tcacttcctg 1380
tggagcgggg attggctctg agaaggagtg ttctctgtct gcctggcaaa ggtgctgtgg 1440
aataggcttg gcatgccacc ctgttttaga gagtgacagt tacagttgta acaagcctac 1500
ttcatattgg ccccctcagt tagccttttt gaggcaatgc catttctaga gttgaaaaag 1560
ccctggaccc aaactgcggc actgttgaat aaagggcagt cctactcctg tccttttaga 1620
gtggcttagt gtgacacaca ggcatctccc aggccaagca cacacaggct gcgcccagtt 1680
ccgcaggagc cgtcccacag cgtggctctc tggattctcc cacttgtcct ccttggaagg 1740
agctcttgct ggccagtgtt tggaggggag gatgagtgcc tgtcactgag gcctcactat 1800
ggttggcgtc tgaagctggg cggtcgtcag gcctgtgctg agagccgcag cccctgtgca 1860
cacctaacac agggcgctcc ccctgctgct tccctggctc agttcttcgg agetccagag 1920
tgagaaggcc gcttcgtcct ttttctctgg gtgatgccct tagaataaca ctatatgcaa 1980
tgtaactcac aatgttccag gaccaaagac ttgatggagg ggctagaggc gacccttgtt 2040
gtaaaaggcg atcagaacac ctgagggagg aaggggcttg cagttttccc agcccttctc 2100
gctgccaagg cagcagtggt gctgtggatg ggctggggac tgcgggacag agcctgctac 2160
tacttgggag ttggtgctgc cctgtggcat ggaggggtgg gaggggctga gatggctgct 2220
ggcccggcct ccaagagttc tggacaggag gcagacactg cccagatgct cggtggaggg 2280
acagtgatgg cctttgactc atgaggcctg gagaaaagta tcaaaggtct caccatgtaa 2340
gagtgatttc cgatttctct cctttcagtt gtgtgaaaaa acagctggcc tgggttccat 2400
tagcaaatta aatcatcttc aatcttaaat tagagaccag aatgatcttc aggataaaaa 2460
gaacttctga atctctgcaa taggaaatgt ttcgatcatg caagtgcttt cccagccaaa 2520
tgtctgtgct ctctgtgtca ctgagggcca caggttcctc taacatctgt cactgtcact 2580
tcaccaggca ggccttggag ttccatgaca aaatcacttt tgtcagacaa agaatgtatc 2640
ctttactttt ctcaaatgga ataaaattat ttcttctgtg gaggaaaatt gattccccct 2700
ttttatttaa tttttttttg gagacagtct cactccttcc c 2741
86/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 44
<211> 2076
<212> DNA
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 1485774CB1
<400> 44
cggggctcca gccaggagcc ctgctgccca gggcatggcc aaacctttct tccgactcca 60
gaagtttctc cgccgaacac agttcctgct gttcttcctc acggctgcct acctgatgac 120
cggcagcctg ctgctgctgc agcgggtccg cgtggctctc ccacagggcc cccgggcacc 180
cggccccctg cagaccttgc cagtggccgc cgtggcgctg ggcgtgggct tgctggacag 240
cagagccctg cacgaccctc gagtcagccc agagctgctg ctgggtgtgg acatgctgca 300
gagccccctg acccggcccc ggcccggccc ccgctggctc cggagccgca actcggagct 3&0
gcgtcagttg cgtcgccgct ggttccacca cttcatgagt gactcccagg gaccgcccgc 420
cctgggcccc gaggctgcca ggcccgccat ccacagccga ggcacctaca ttggatgctt 480
cagtgacgat ggccatgaga ggactctgaa aggagctgtg ttttatgact tgagaaagat 540
gactgtctcc cactgccagg atgcgtgtgc tgagcggtcc tatgtctacg ccggcttgga 600
ggccggggcg gagtgttact gcgggaaccg gctgccagcg gtgagcgtgg ggctggaaga 660
gtgtaaccat gagtgcaaag gcgagaaggg ctctgtgtgc ggggctgtgg accggctctc 720
cgtgtaccgt gtggacgagc tgcagccggg ctccaggaag cggcggaccg ccacctaccg 780
cggatgcttc cgactgccag agaacatcac acatgccttc cccagctccc tgatacaggc 840
caatgtgacc gtggggactt gctcgggctt ttgttcccag aaagagttcc ccttggccat 900
tctcaggggc tgggaatgct actgtgctta ccctaccccc cggttcaacc tgcgggatgc 960
catggacagc tcagtatgtg gccaggaccc tgaggcacag aggctggcag aatactgtga 1020
ggtctaccag acacctgtgc aagacactcg ttgtacagac aggaggttcc tgcctaacaa 1080
atccaaagtg tttgtggctt tgtcaagctt cccaggagcc gggaacacgt gggcacggca 1140
cctcattgag catgccactg gcttctatac agggagctac tactttgatg gaaccctcta 1200
caacaaaggg ttcaagggcg aaaaggacca ctggcggagc cgacgcacca tctgtgtcaa 1260
aacccacgag agtggcagga gggagattga gatgtctgat tcagccatcc tgctaatccg 1320
gaacccatac aggtccctgg tggcagaatt caacagaaaa tgtgccgggc acctgggata 1380
tgcagctgac cgcaactgga agagcaaaga gtggccggac tttgtcaaca gctacgcctc 1440
gtggtggtcc tcgcacgtcc tggactggct caagtacggg aagcggctgc tggtggtgca 1500
ctacgaggag ctgcggcgca gcctggtgcc cacgttacgg gagatggtgg ccttcctcaa 1560
cgtgtctgtg agcgaggagc ggctgctctg cgtggagaac aacaaggagg gcagcttccg 1620
gcggcgcggc cggcgctccc acgaccctga gcccttcacc ccggagatga aagacttgat 1680
caatggctac atccggacgg tggaccaagc cctgcgtgac cacaactgga cggggctgcc 1740
cagggagtat gtgcccagat gataggcctg gcccacgccg ccgcccccgc tgagtgacgc 1800
aatcgcacca cggggctgcg ctccccactc tgatgctcag gcccgtggcc tcactgggac 1860
gaacggtggg tggggggctc accctggtgc tgcctcccgc acaaggagac ctggacacaa 1920
cagacacaca tcacaaggcg aacacaaatg gacacacata cctggccatg aacccacacc 1980
tcctcagaca ctcagacacc actccaggct catagcccgt cttgatgcag agaagccccc 2040
acgtgggtgt gccaggcacc ccagatacaa atgttt 2076
<210> 45
<211> 2957
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7289372CB1
<220>
87/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<221> unsure
<222> 311
<223> a, t, c, g, or other
<400> 45
cataagattg ctttacacca gggttcctga aatcaaggaa aatactggcc aaaatcaccg 60
accccattct accttcaatt acctagattc tgcgtccccg gcgctaggta cccaatcctg 120
gctgtccgac cacaggatcc ccggcaggga cgggtcacag tgctctcacc cctcgaccat 180
tttcgaaaaa accttcctct gcaaacgcat tgcgccctcc ccatgggtcc gcgggcgggg 240
actccaggcc cgagcagtcg gtgtgaagtt ctgtgttctg aactggggct gagcaagatg 300
cgatggtctc ntaccgctgg gccgcccgta gcgacggcag gagtaggggt attgatctcc 360
acggaagccc caaaccctcg ccatcgagag acccccatgg cccggggtga tggctgtggg 420
gcttggtgct cccagagagc tcagtggcta cagaatgggt ggggattctg cgtgtctccc 480
ggagcctgaa cccctttcct ggttatggcc ggtagctgtc tccagggact aacgtgggca 540
gcgcaggggg gcggaaaccg ggttttagcc aaatgcctcg acatcgccgc gcctccgcct 600
cctcgtcgct gaaagaaatg tcggggtttc atcagagcta gggagcgaca gtcgggaaca 660
gcgagtctgc cgaagccggc tgttgtgtga gggtgtgaga cggcggggcg gtgaggggcc 720
accgcggctt gggggatagt gcgtgtgggg ttgaccgtgt gtctgcttga gaggctgtga 780
agatatgggg ggcagatatg ggagaaatgc tcgggcctga agtccccagc ccaccgtgct 840
caagagtagc ggacgttttg ccaccatcct tgtctgtgct actgtctgct gcagcttccg 900
tgccccgttc tcctggagca gggcgtaaaa gcggcttgca ttcaattagc agcgaagctc 960
gcgggcgctg gcgggacagg cgcgtgaggc cacaacacat gcgtgtatct tgcttgggct 1020
atcttccctg ctctgccacg ccgggtctgg agaaggggtt tcagccccag gacatttact 1080
gagagtcggc gaatattggg agccgcgatg ttcccccttc gggccctgtg gttggtctgg 1140
gcgcttctag gagtggccgg atcatgcccg gagccgtgcg cctgcgtgga caagtacgct 1200
caccagttcg cggactgcgc ttacaaagag ttgcgtgagg tgccggaagg actgcctgcc 1260
aacgtgacga cgcttagtct gtccgcgaac aagatcactg tgctgcggcg cggggccttc 1320
gccgacgtca cacaggtcac gtcgctgtgg ctggcgcaca atgaggtgcg caccgtggag 1380
ccaggcgcac tggccgtgct gagtcagctc aagaacctcg atctgagcca caacttcata 1440
tccagctttc cgtggagcga cctgcgcaac ctgagcgcgc tgcagctgct caaaatgaac 1500
cacaaccgcc tgggctctct gccccgggac gcactcggtg cgctacccga cctgcgttcc 1560
ctgcgcatca acaacaaccg gctgcgtacg ctggcgcctg gcaccttcga cgcgcttagc 1620
gcgctgtcac acttgcaact ctatcacaat cccttccact gcggctgcgg ccttgtgtgg 1680
ctgcaggcct gggccgcgag cacccgggtg tccttacccg agcccgactc cattgcttgt 1740
gcctcgcctc ccgcgctgca gggggtgccg gtgtaccgcc tgcccgccct gccctgtgca 1800
ccgcccagcg tgcatctgag tgccgagcca ccgcttgaag cacccggcac cccactgcgc 1860
gcaggactgg cgttcgtgtt acactgcatc gccgacggcc accctacgcc tcgcctgcaa 1920
tggcaacttc agatccccgg tggcaccgta gtcttagagc caccggttct gagcggggag 1980
gacgacgggg ttggggcgga ggaaggagag ggagaaggag atggggattt gctgacgcag 2040
acccaagccc aaacgccgac tccagcaccc gcttggccgg cgcccccagc cacaccgcgc 2200
ttcctggccc tcgcaaatgg ctccctgttg gtgcccctcc tgagtgccaa ggaggcgggc 2160
gtctacactt gccgtgcaca caatgagctg ggcgccaact ctacgtcaat acgcgtggcg 2220
gtggcagcaa ccgggccccc aaaacacgcg cctggcgccg ggggagaacc cgacggacag 2280
gccccgacct ctgagcgcaa gtccacagcc aagggccggg gcaacagcgt cctgccttcc 2340
aaacccgagg gcaaaatcaa aggccaaggc ctggccaagg tcagcattct cggggagacc 2400
gagacggagc cggaggagga cacaagtgag ggagaggagg ccgaagacca gatcctcgcg 2460
gacccggcgg aggagcagcg ctgtggcaac ggggacccct ctcggtacgt ttctaaccac 2520
gcgttcaacc agagcgcaga gctcaagccg cacgtcttcg agctgggcgt catcgcgctg 2580
gatgtggcgg agcgcgaggc gcgggtgcag ctgactccgc tggctgcgcg ctggggccct 2640
gggcccggcg gggctggcgg agccccgcga cccgggcggc gacccctgcg cctactctat 2700
ctgtgtccag cggggggcgg cgcggcagtg cagtggtccc gcgtagagga aggcgtcaac 2760
gcctactggt tccgcggcct gcggccgggt accaactact ccgtgtgcct ggcgctggcg 2820
ggcgaagcct gccacgtgca agtggtgttt ccaccaagaa ggagctccca tcgctgctgg 2880
tcatagtggc agtgagcgta tccctcctgg tgctggccac agtgcccctt ctgggcgccg 2940
cctgttgcca tctgctg 2957
88/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 46
<211> 1223
<212> DNA
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID IVo: 1672338CB1
<400> 46
ggcacctgga gggccgcact cccgttccag ccaggctgag ccttctgtcc cctgcctctg 60
gggcctggga accccccttc ttctttctcc tgaatggcac ccccgcccta gaatccagac 120
accgagtttc ccactgtggc tggttcaagg gtatgtgaga gctccctggt~gacagtctgt 180
ggctgagcat ggccctccca gccctgggcc tggacccctg gagcctcctg ggccttttcc 240
tcttccaact gcttcagctg ctgctgccga cgacgaccgc ggggggaggc gggcaggggc 300
ccatgcccag ggtcagatac tatgcagggg atgaacgtag ggcacttagc ttcttccacc 360
agaagggcct ccaggatttt gacactctgc tcctgagtgg tgatggaaat actctctacg 420
tgggggctcg agaagccatt ctggccttgg atatccagga tccaggggtc cccaggctaa 480
agaacatgat accgtggcca gccagtgaca gaaaaaagag tgaatgtgcc tttaagaaga 540
agagcaatga gacacagtgt ttcaacttca tccgtgtcct ggtttcttac aatgtcaccc 600
atctctacac ctgcggcacc ttcgccttca gccctgcttg taccttcatt gtgagttctc 660
tggtgcccag cgctcaggcc cccaagcatc ccttctcaca tctacccacg actttcctct 720
gtagctctgg aaaactctgg ccttccagat gcaggaccct catgaacttc ctggccccag 780
accaatttcc ctctatgtcc ctttcccttc cttcctcaag cccctcattt cccagatgtg 840
agaccttggc gttctggccc cccagcctct ctccccattt aggaacttca agattcctac 900
ctgttgccca tctcggagga caaggtcatg gagggaaaag gccaaagccc ctttgacccc 960
gctcacaagc atacggctgt cttggtgggt gagtatcagg tttcccactt catcccaaca 1020
tctactttct ccagtcacgc tgtgaaatat ggaatattac agagttttcc aaaaggcagg 1080
ggaaactggg tgtggtgatg cgtgcatatg gtcccagtta tttggaagct gaagttgaag 1140
gatgcttgag tttaggggtt tgagtctagc ctgggcaaca cagcgagatc gtctcaaaaa 2200
aaaaaaaaaa aaaaaaaaaa aaa 1223
<210> 47
<211> 2888
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 184661CB1
<400> 47
cgcacgacgt aaatcctgcg gctacatgag cggctcggaa ttcggctcga gcccggcccg 60
ggcagctgcg gctcgggatc cgtcgagggg aggccgagct tgccaagctg gcgcccagcg 120
gggtcatggt gcccggcgcc cgcggcggcg gcgcactggc gcgggctgcc gggcggggcc 180
tcctggcttt gctgctcgcg gtctccgccc cgctccggct gcaggcggag gagctgggtg 240
atggctgtgg acacctagtg acttatcagg atagtggcac aatgacatct aagaattatc 300
ccgggaccta ccccaatcac actgtttgcg aaaagacaat tacagtacca aaggggaaaa 360
gactgattct gaggttggga gatttggata tcgaatccca gacctgtgct tctgactatc 420
ttctcttcac cagctcttca gatcaatatg gtccatactg tggaagtatg actgttccca 480
aagaactctt gttgaacaca agtgaagtaa ccgtccgctt tgagagtgga tcccacattt 540
ctggccgggg ttttttgctg acctatgcga gcagcgacca tccagattta ataacatgtt 600
tggaacgagc tagccattat ttgaagacag aatacagcaa attctgccca gctggttgta 660
gagacgtagc aggagacatt tctgggaata tggtagatgg atatagagat acctctttat 720
tgtgcaaagc tgccatccat gcaggaataa ttgctgatga actaggtggc cagatcagtg 780
tgcttcagcg caaagggatc agtcgatatg aagggattct ggccaatggt gttctttcga 840
89/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gggatggttc cctgtcagac aagcgatttc tgtttacctc caatggttgc agcagatcct 900
tgagttttga acctgacggg caaatcagag cttcttcctc atggcagtcg gtcaatgaga 960
gtggagacca agttcactgg tctcctggcc aagcccgact tcaggaccaa ggcccatcat 1020
gggcttcggg cgacagtagc aacaaccaca aaccacgaga gtggctggag atcgatttgg 1080
gggagaaaaa gaaaataaca ggaattagga ccacaggatc tacacagtcg aacttcaact 1140
tttatgttaa gagttttgtg atgaacttca aaaacaataa ttctaagtgg aagacctata 1200
aaggaattgt gaataatgaa gaaaaggtgt ttcagggtaa ctctaacttt cgggacccag 1260
tgcaaaacaa tttcatccct cccatcgtgg ccagatatgt gcgggttgtc ccccagacat 1320
ggcaccagag gatagccttg aaggtggagc tcattggttg ccagattaca caaggtaatg 1380
attcattggt gtggcgcaag acaagtcaaa gcaccagtgt ttcaactaag aaagaagatg 1440
agacaatcac aaggcccatc ccctcggaag aaacatccac aggaataaac attacaacgg 1500
tggctattcc attggtgctc cttgttgtcc tggtgtttgc tggaatgggg atctttgcag 1560
cctttagaaa gaagaagaag aaaggaagtc cgtatggatc agcagaggct cagaaaacag 1620
actgttggaa gcagattaaa tatccctttg ccagacatca gtcagctgag tttaccatca 1680
gctatgataa tgagaaggag atgacacaaa agttagatct catcacaagt gatatggcag 1740
attaccagca gcccctcatg attggcaccg ggacagtcac gaggaagggc tccaccttcc 1800
ggcccatgga cacggatgcc gaggaggcag gggtgagcac cgatgccggc ggccactatg 1860
actgcccgca gcgggccggc cgccacgagt acgcgctgcc ctggcgcccc cggagcccga 1920
gtacgccacg cccatcgtgg agcggcacgt gctgcgcgcc cacacgttct ctgcgcagag 1980
cggctaccgc gtcccagggc cccagcccgg ccacaaacac tccctctcct cgggcggctt 2040
ctcccccgta gcgggtgtgg gcgcccagga cggagactat caaaggccac acagcgcaca 2100
gcctgcgggc aggggctacg accggcccaa agctgtcagc gccctcgcca ccgaaagcgg 2160
acaccctgac tctcagaagc ccccaacgca tcccgggacg agtgacagct attctgcccc 2220
cagagactgc ctcacacccc tcaaccagac ggccatgact gcccttttgt gaacacaatg 2280
tgaaagaagc ctgctgtggt actgagcgtc gggctgtcac aaggcactgg aagaagggag 2340
cctgctggtc cagagtgtgc gtgtgtatcg gtgtgtgtgt acacttgcat gtgtgtgtgt 2400
gatccagtag gatcctagag acaacctgtc atactgttta caaaattgtg cagctggttt 2460
cgtgctgacc cttagggtgc gtctgttggg ttttgttggg ctagaaaaat gaaaattttt 2520
agatggcgtt ttcattcctc tgactgatat tgagctgctt tggtgttaaa ggtgtaatgt 2580
gtacagagtt gtatttaaca ataataaaag taacttaagt ttgctctatc agattttagt 2640
tctgcacaga ggttaagtgg gaaaatgcag ctgttgcaaa atgtatataa atagtatgtt 2700
catttttttc agtatattat ctgatactgt gttagcagca ggtctgtctt aaacctagtc 2760
ttgttgttat ttgagtcatt tcctctcctt tgataactag aactgaaagc atttttaaca 2820
ttcttctcct ggaagaaatg aattacttga agcatgaaaa gcacaccagg gtggttgttt 2880
atttagca 2888
<210> 48
<211> 3142
<212> DNA
<213> Homo sapiens
<220>
<221> misc feature
<223> Incyte ID No: 3719737CB1
<400> 48.
tgcgcgcagg ctcacaggcc ctgggagtga gctggtgccc ggcgacctgg cacccgcgcc 60
tggatatggg gcgtctacat cgtcccagga gcagcaccag ctacaggaac ctgccgcatc 120
tgtttctgtt tttcctcttc gtgggaccct tcagetgcct cgggagttac agccgggcca 180
ccgagcttct gtacagccta aacgagggac tacccgcggg ggtgctcatc ggcagcctgg 240
ccgaggacct gcggctgctg cccaggtctg cagggaggcc ggacccgcag tcgcagctgc 300
cagagcgcac cggtgctgag tggaaccccc ctctctcctt cagcctggcc tcccggggac 360
tgagtggcca gtacgtgacc ctagacaacc gctctgggga gctgcacact tcagctcagg 420
agatcgacag ggaggccctg tgtgttgaag ggggtggagg gactgcgtgg agcggcagcg 480
tttccatctc ctcctctcct tctgactctt gtcttttgct gctggatgtg cttgtcctgc 540
ctcaggaata cttcaggttt gtgaaggtga agatcgccat cagagacatc aatgacaacg 600
90/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ccccgcagtt ccctgtttcc cagatctcgg tgtgggtccc ggaaaatgca cctgtaaaca 660
cccgactggc catagagcat cctgctgtgg acccagatgt aggcattaat ggggtacaga 720
cctatcgctt actggactac catggtatgt tcaccctgga cgtggaggag aatgagaatg 780
gggagcgcac cccctaccta attgtcatgg gtgctttgga cagggaaacc caggaccagt 840
atgtgagcat catcatagct gaggatggtg ggtctccacc acttttgggc agtgccactc 900
tcaccattgg catcagtgac attaatgaca attgccctct cttcacagac tcacaaatca 960
atgtcactgt gtatgggaat gctacagtgg gcaccccaat tgcagctgtc caggctgtgg 1020
ataaagactt ggggaccaat gctcaaatta cttattctta cagtcagaaa gttccacaag 1080
catctaagga tttatttcac ctggatgaaa acactggagt cattaaactt ttcagtaaga 1140
ttggaggaag tgttctggag tcccacaagc tcaccatcct tgctaatgga ccaggctgca 1200
tccctgctgt aatcactgct cttgtgtcca ttattaaagt tattttcaga ccccctgaaa 1260
ttgtccctcg ttacatagca aacgagatag atggtgttgt ttatctgaaa gaactggaac 1320
ccgttaacac tcccattgcg tttttcacca taagagatcc agaaggtaaa tacaaggtta 1380
actgctacct ggatggtgaa gggccgttta ggttatcacc ttacaaacca tacaataatg 1440
aatatttact agagaccaca aaacctatgg actatgagct acagcagttc tatgaagtag 1500
ctgtggtggc ttggaactct gagggatttc atgtcaaaag ggtcattaaa gtgcaacttt 1560
tagatgacaa tgataatgct ccaattttcc ttcaaccctt aatagaacta accatcgaag 1620
agaacaactc acccaatgcc tttttgacta agctgtatgc tacagatgcc gacagcgagg 1680
agagaggcca agtttcatat tttctgggac ctgatgctcc atcatatttt tccttagaca 1740
gtgtcacagg aattctgaca gtttctactc agctggaccg agaagagaaa gaaaagtaca 1800
gatacactgt cagagctgtt gactgtggga agccacccag agaatcagta gccactgtgg 1860
ccctcacagt gttggataaa aatgacaaca gtcctcggtt tatcaacaag gacttcagct 1920
tttttgtgcc tgaaaacttt ccaggctatg gtgagattgg agtaattagt gtaacagatg 1980
ctgacgctgg acgaaatgga tgggtcgccc tctctgtggt gaaccagagt gatatttttg 2040
tcatagatac aggaaagggt atgctgaggg ctaaagtctc tttggacaga gagcagcaaa 2100
gctcctatac tttgtgggtt gaagctgttg atgggggtga gcctgccctc tcctctacag 2260
caaaaatcac aattctcctt ctagatatca atgacaaccc tcctcttgtt ttgtttcctc 2220
agtctaatat gtcttatctg ttagtactgc cttctactct gccaggctcc ccggttacag 2280
aagtctatgc tgtcgacaaa gacacaggca tgaatgctgt catagcttac agcatcatag 2340
ggagaagagg tcctaggcct gagtccttca ggattgaccc taaaactggc aacattactt 2400
tggaagaggc attgctgcag acagattatg ggctccatcg cttactggtg aaagtgagtg 2460
atcatggtta tcccgagcct ctccactcca cagtcatggt gaacctattt gtcaatgaca 2520
ctgtcagtaa tgagagttac attgagagtc ttttaagaaa agaaccagag attaatatag 2580
aggagaaaga accacaaatc tcaatagaac cgactcatag gaaggtagaa tctgtgtctt 2640
gtatgcccac cttagtagct ctgtctgtaa taagcttggg ttccatcaca ctggtcacag 2700
ggatgggcat atacatctgt ttaaggaaag gggaaaagca tcccagggaa gatgaaaatt 2760
tggaagtaca gattccactg aaaggaaaaa ttgacttgca tatgcgagag agaaagccaa 2820
tggatatttc taatatttga tatttcatgg tggaataaca cagagaaatg ttttaactga 2880
ctttggatct tcatcaccta aaaaagagtg tgttgatggc agttccaatg aaggacaact 2940
aatttataac ttgttctata ttgtaaatag ctgtttacag gtttttaaat ttaaattcag 3000
aggttataaa atgtgtacag catttttaag tgaaaattag tactaacagc tataggactt 3060
gtatttaaaa aaaaaaaaaa aaagcttgga catggtttgc agctttcata caccaagcag 3120
atgtttgata aaacctgggg gt 3142
<210> 49
<211> 4749
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 5773251CB1
<400> 49
gtgcttgcag tggtggaatt cctagagcgt taaatattca gtgataagtg ggcagggttg 60
aggctgaaaa gatagatagg ggccaggtca aagtgggtta atttatgtgc tgtttgtacc 120
91/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
aacaagcttg gactttggta ttgtgacagg cagttaggag gcattcaaga cttaagcaga 180
gtgacatggt aaaattactc cagaaaacgt tcaaattata tttgatgatc cactaccaat 240
ttcatacagt cagccagaga aggtgaatgg agagtccaag agcagcagta ccagcgagag 300
tggggacagt gataacatga ggatttccag ctgcagcgat gaaagtagta acagcaacag 360
cagtcgtaag agtgacaatc attcaccagc tgtggtcact accactgtga gcagcaaaaa 420
gcagccatca gttcttgtta catttccaaa ggaagagaga aaatctgttt ctggcaaggc 480
ttcaataaaa ttgtcagaaa ctatcagtga agggaccagt aattctctat ctacttgtac 540
aaaatctggt ccatctcccc tttcttctcc aaatgggaag ttaacagtag caagtcctaa 600
gcgtgggcaa aagagggaag aaggatggaa agaagttgta agaaggtcaa agaaagtcgg 660
aggctggctt tggctgcgaa aagagaaaaa agaaaagaga agagaaggaa gaaaaaggaa 720
gaacaaagaa ggaaactaga agaaattgaa gccaaaaata aaagagaact ttgaactcca 780
agctgctcaa gaaaaagaaa agcttaaagt tgaagatgag cctgaagtct tgacagaacc 840
tccaagtgcc acaaccacta ctaccatagg tatatctgca acctggacaa ctttggcagg 900
ttctcatggt aaaagaaata ataccataac tacaaccagt tcaaagagga aaaacaggaa 960
aaataaaatt actccagaaa acgttcaaat tatatttgat gatccactac caatttcata 1020
cagtcagcca gagaaggtga atggagagtc caagagcagc agtaccagcg agagtgggga 1080
cagtgataac atgaggattt ccagctgcag cgatgaaagt agtaacagca acagcagtcg 1140
taagagtgac aatcattcac cagctgtggt cactaccact gtgagcagca aaaagcagcc 1200
atcagttctt gttacatttc caaaggaaga gagaaaatct gtttctggca aggcttcaat 1260
aaaattgtca gaaactatca gtgaagggac cagtaattct ctatctactt gtacaaaatc 1320
tggtccatct cccctttctt ctccaaatgg gaagttaaca gtagcaagtc ctaagcgtgg 1380
gcaaaagagg gaagaaggat ggaaagaagt tgtaagaagg tcaaagaaag tatctgttcc 1440
atcaactgtg atatccagag tgattggaag aggaggctgt aatatcaatg ctattcggga 1500
gtttactggt gcacacatag atattgataa acagaaagac aagactggag accggataat 1560
cactataagg ggtggcactg aatcaacaag acaagcaact caattgatta atgctttgat 1620
caaggatcca gacaaagaaa ttgatgaact tattccaaag aatcgtttga aaagctcctc 1680
agcaaattcc aaaatagggt catcagcacc taccaccact gctgctaaca cttccttaat 1740
gggaattaaa atgacaactg tagctctgtc atcaacatct caaactgcca cagcactcac 1800
tgtgcctgca atttcttctg catccactca caaaaccatt aagaacccag tgaataatgt 1860
gaggcctggt tttccagttt ctcttccatt agcatatcct cctccacagt ttgcacatgc 1920
tttgcttgct gctcagactt tccagcagat ccgtccacca aggttgccca tgacccactt 1980
tggaggtact tttccaccag ctcaatccac ttggggtccg tttcctgtca ggcctttgag 2040
ccctgccaga gctactaact cgcctaagcc tcacatggtg cctcgccata gcaatcagaa 2100
tagcagtggt tctcaggtga attcagcagg ttctttaact tcaagcccaa caactacaac 2160
cagttcatca gcttcaacgg tgcctggtac atctacaaat ggcagtccaa gttcaccttc 2220
tgtccgaagg cagctttttg tcacagttgt gaagacatcc aatgccacca caacaacagt 2280
cacaaccacg gcaagcaaca acaacactgc acccacaaat gccacatatc ctatgcctac 2340
tgccaaagaa cactatccag tatcatcccc atcttcccca tcaccaccag cccagccagg 2400
aggggtttct agaaacagcc ctttggattg tggatcagca tctccaaata aagtggcatc 2460
ttcctccgaa caggaagcag gtagtccacc agtagtagaa acaacaaaca ctagacctcc 2520
aaacagcagc agttcttctg ggagttcatc agctcattct aatcagcaac aacctccggg 2580
atctgtttct caggaaccaa gaccacctct tcagcagtct caggttcctc ccccggaagt 2640
tagaatgact gttcctcctt tagcaacaag ttctgctcca gtggcggtgc cttctactgc 2700
cccagtgact taccctatgc ctcagacacc aatgggatgc ccccagccta ctcctaaaat 2760
ggaaacccct gctattagac caccccctca tggcacaact gcccctcaca agaattcagc 2820
ttcagtgcaa aattcatctg ttgcagtcct tagtgtcaat cacattaaaa gacctcacag 2880
tgttccctct tctgtccagc taccttcgac cttaagtaca caaagtgctt gtcagaattc 2940
agtacatcca gcaaataagc ctattgctcc caatttcagt gcccccttac catttgggcc 3000
ctttagcaca ttgtttgaaa acagccctac ttctgctcat gccttctggg gaggatctgt 3060
tgtttcatct cagtcaacac cagaatctat gctatcagga aaatcctcat atttgccaaa 3120
ttcagatcct ttacatcagt ctgatacttc caaagctcca ggttttagac caccattaca 3180
gagacctgct ccaagtccct caggtattgt caatatggac tcgccatatg gttctgtaac 3240
accttcttca acacatttgg gaaactttgc ttcaaacatt tcaggaggtc agatgtacgg 3300
acctggggca ccccttggag gagcacccgc agctgctaac tttaacagac aacatttttc 3360
cccgcttagt ttgttgactc cgtgttcatc agcatcaaat gattcttctg cacagtcagt 3420
atcctcggga gttcgtgcac catctcctgc cccatcatca gtaccgttag ggtcagaaaa 3480
92/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gcccagcaat gtgtctcagg acaggaaagt tccagtccct attgggactg aacgttctgc 3540
acgtatcagg caaactggaa cgtcagctcc atctgttatt gggagcaatt tgtctacatc 3600
agtaggacat agtggcatct ggtcctttga agggattggt ggcaatcaag acaaagtaga 3660
ctggtgtaac cctgggatgg gaaatcctat gatccacaga ccgatgtctg acccaggagt 3720
attttcacaa catcaagcaa tggagcgaga tagtacagga attgtaactc cttctggtac 3780
attccatcag catgttcctg caggctacat ggactttcct aaagttgggg gtatgccttt 3840
ttctgtgtat gggaatgcaa tgattcctcc agtagcacct atccctgatg gtgctggagg 3900
acccatattt aatggccctc atgctgcaga cccttcttgg aactcactga taaagatggt 3960
ttccagctcc acggaaaata atggccctca aacggtgtgg actggaccct gggcacctca 4020
catgaacagt gtgcatatga accagcttgg ctgatgagga tcagcttgtt agcctgcaga 4080
ttccttttca tttggaggaa atcacaagtg gccgaaaaaa aaaattatgc tcccaaatca 4140
ttctactgat gtgcttgact gaagtgtgta ggctttttgc agaagatctt actaactgac 4200
ctattttctg tgaacatttg tgactgccca ttccccatca tcatccgttt taccttagtt 4260
agcatttttc ttatcatttt tctttttttc tttccctctt cccctttgga cataactttc 4320
tgttgaagct gttctttggc tggttggttt tagtactgta aactgcttct gagcaaacac 4380
ggaaatttag caaaattatg taaacttgat cctgaagttt tagaatggca aataaatgta 4440
caattgttta cataacagaa aaggctaagc agaaagtaaa tttcaatatg tcagtataga 4500
ggctctactt tatgtagact taaattaatg tgagatatgt accttcatat tcagaaatct 4560
ggatgtttcc ttcatacatt aaactattaa taagcataac ttttctactg gtgtaattta 4620
agtataaagt aaaataatgg gcattatcat tggatgtttc cccacattgg cttttaaaat 4680
acccatcttg ctttcttttt ggtttatttg tagcaaggca catatagaag aagaaatttc 4740
tggcttttc 4749
<210> 50
<211> 4155
<212> DNA
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 5426470CB1
<400> 50
gccgtcgggg cgggcgtctg gcgagctgca gagaccagat taaaggattt acctgaagag 60
aaagcattct attcatcaga gactggacaa gagttactct tgcatttggc aattaaagat 120
gatgtttcca tggaaacagt tgatcctgct ttcattcatt ggctgcttag gaggtgagct 180
tctcttacaa ggccctgtat ttatcaaaga acccagcaac agcattttcc ctgttggttc 240
agaagataaa aaaataactt tgcattgtga agcaagaggc aatccatcac ctcattacag 300
atggcagctg aatggaagtg atattgatat gagtatggaa catcgttata agttgaatgg 360
aggaaatctt gtggttatta atcccaacag aaattgggat acaggaactt accaatgttt 420
tgcaacaaat tcacttggaa caattgtcag cagagaagcc aaacttcagt ttgcctatct 480
tgaaaatttt aaaaccaaaa tgaggagtac agtgtctgtg cgtgaaggcc agggagttgt 540
gctgctctgc ggccccccac cacactctgg agaactgtca tatgcttgga tcttcaatga 600
atacccatcg tttgttgaag aagatagtcg gagatttgtc tcccaggaga cagggcacct 660
ctacatatct aaggtggagc cgtctgatgt gggaaattac acatgtgtgg tgacaagtat 720
ggtgacaaat gcccgagtgc tgggctctcc aactcctttg gtgctacgtt ctgatggtgt 780
gatgggtgaa tatgaaccta aaatagaagt tcagtttcca gaaactcttc cagcagctaa 840
aggttcgact gtgaaattgg aatgttttgc ccttggaaat cccatacctc agattaattg 900
gagaagaagt gatgggctgc cattttccag caaaattaaa ttaaggaagt tcagtggtgt 960
gcttgaaatc cccaacttcc aacaggaaga tgcaggttcc tatgaatgca ttgctgagaa 1020
ttcacgagga aaaaatgttg ccagagggcg tctcacttac tatgcaaagc cccattgggt 1080
tcaactcata aaggatgtgg aaatagccgt ggaggacagt ctttattggg aatgcagggc 1140
aagcggcaag cccaagcctt cctaccgatg gctgaaaaat ggagcagccc tggtgctaga 1200
ggagagaaca cagatagaaa atggtgccct tacaatatca aacctaagtg tgactgattc 1260
tggcatgttc caatgcatag cagaaaacaa acatggcctt gtttattcca gtgctgagct 1320
caaagttgtt gcttctgctc cagatttttc aaagaatcca atgaagaagt tggttcaggt 1380
93/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gcaggtgggc agcctggtca gcttggattg taaacccaga gcctccccaa gggcactctc 1440
ttcctggaag aagggggatg tgagcgtgca ggagcatgaa agaatttctt tgttaaacga 1500
tggaggactc aaaatagcca atgtgactaa agctgatgct ggaacttaca cctgcatggc 1560
agaaaaccag tttgggaaag caaatggcac aacacatttg gttgttacgg aaccaacaag 1620
aataactttg gcaccatcta acatggatgt ttctgttggt gaaagcgtca tattgccctg 1680
ccaggtacaa catgacccgc tgttagacat catctttacc tggtatttca atggggccct 1740
tgcagatttt aagaaagatg gatctcactt tgagaaagtt ggtgggagtt catctggtga 1800
tttaatgatc agaaacattc agctgaaaca cagtgggaaa tatgtttgta tggtgcaaac 1860
gggggtggac agtgtttcat ctgctgctga cctcatagta agaggttcac ctggaccacc 1920
agaaaatgtg aaggtagatg aaattacaga cacaacagcc caactctctt ggaaagaagg 1980
taaagacaac catagcccag ttatatccta ttctatccag gctcggacac ctttctccgt 2040
gggttggcaa accgtcacaa cagtgcctga ggtcatcgat gggaagacgc acacagccac 2100
tgtagttgag ttaaacccat gggtggaata tgaatttcgg gttgtagcca gtaacaaaat 2160
tggaggtgga gaaccaagtt taccctcaga aaaagtaaga actgaagagg cagttccaga 2220
agtgcctcct tctgaagtca atggaggagg cggaagccgg tctgaacttg tgataacctg 2280
ggatccagtc cctgaagaac tacagaatgg tgaaggtttt gggtatgttg ttgctttccg 2340
ccctcttggg gttaccacct ggatccagac agtggtgaca tcccctgaca ccccaagata 2400
tgtctttagg aatgaaagca tcgtgccata ttcaccatat gaagttaaag tgggtgttta 2460
taataacaaa ggtgaaggac catttagccc agtgacaaca gtgttctctg cagaagaaga 2520
gcctacagtg gccccatctc aagtctctgc aaatagccta tcttcctcag aaattgaggt 2580
ttcatggaac accattcctt ggaagttgag caatggacat ttactgggct atgaggtgcg 2640
gtactggaat gggggtggaa aggaggaatc atccagtaag atgaaagtgg caggaaatga 2700
gacatcagcc agactacggg gcctgaagag caacctggcc tattacacgg ctgtccgggc 2760
ttacaacagt gccggcgctg ggccttttag cgccacagtt aatgtaacca ccaagaaaac 2820
gcctcccagt cagccaccag gaaatgttgt ttggaatgcc acagacacta aagtgttact 2880
taattgggag caagttaaag ccatggagaa tgagtcagaa gtaacaggat ataaagtttt 2940
ctataggact agcagtcaaa ataacgtaca agtactgaac acaaataaaa cttcagctga 3000
acttgtgctg cccattaaag aggactacat tattgaagtc aaggccacaa cagatggagg 3060
ggatgggacc agtagtgaac agatcaggat tccacgaata accagtatgg atgcaagagg 3120
atccacttca gccatctcga atgtccaccc tatgtcaagt tatatgccta tagtactgtt 3180
cttaattgta tatgtcctgt ggtgatatta actccttttt attatttatt ggaaagttat 3240
ttggttacca aaaaaagtgc tttcatgaaa tgcagtgatt atgcatgttt ttttcaactc 3300
ttatttttaa ctttctactt cattataggt aaatatgaat ataattaaaa aaacagtaaa 3360
tccttttagg ggaatctgaa atgccttaat attaacttga taaaccaaag gaatttacat 3420
attacatact tcagactttt gatataaatg ttcttaaact atgagtttaa gcactgccta 3480
tggataaaga ctcacacact ctcacatgta cacacacacg catgagaatt tctttttaca 3540
ttgaaaaact ctttcattta attcaaatgc tattttccca ttataatagc attatttgga 3600
agacttaacc agtatcaatt tgaaatgctg atttaagtcc ccaaggatga aaaatacatt 3660
ttaaaaatta ttttgttgga gaggagtggc atgtgattca aaagagcatt gttggaaaat 3720
gctactgtgg ggcttagaag aatgatgttt ggtttggtat gctgctaact agttgtaaga 3780
ctttacaaat cactttgcca tctgtacctc tcaattattc ctctataaaa tatggagata 3840
ataataccta tctgatcaga ctttgcccca tgaattagtt tttaaaagat aaagactgaa 3900
gtatgaaagt gcttttgtca ccccaaatgc aattgaccca tgcaaaatat tagcatgaat 3960
ttatttaatc acataaaagt catgaagacc agccagattt tcaagcttca ttctgtttca 4020
ttcagttata ttccaaaatt caaatgatca cattttattc tttctcaaaa aaaaaaaagt 4080
ttttttaaat taaaaaagga attgtttcct tcacagctat gaataagctt tcaggtttta 4140
ttaaaaccta gagga 4155
<210> 51
<211> 1327
<212> DNA
<213> Homo sapiens
<220>
<221> misc_~eature
<223> Incyte ID No: 7087904CB1
94/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<400> 51
gcgagctgaa agctgctgga gagtgagcag ccctagcagg gatggacatg atgctgttgg 60
tgcagggtgc ttgttgctcg aaccagtggc tggcggcggt gctcctcagc ctgtgctgcc 120
tgctaccctc ctgcctcccg gctggacaga gtgtggactt cccctgggcg gccgtggaca 180
acatgatggt cagaaaaggg gacacggcgg tgcttaggtg ttatttggaa gatggagctt 240
caaagggtgc ctggctgaac cggtcaagta ttatttttgc gggaggtgat aagtggtcag 300
tggatcctcg agtttcaatt tcaacattga ataaaaggga ctacagcctc cagatacaga 360
atgtagatgt gacagatgat ggcccataca cgtgttctgt tcagactcaa catacaccca 420
gaacaatgca ggtgcatcta actgtgcaag ttcctcctaa gatatatgac atctcaaatg 480
atatgaccgt caatgaagga accaacgtca ctcttacttg tttggccact gggaaaccag 540
agccttccat ttcttggcga cacatctccc catcagcaaa accatttgaa aatggacaat 600
atttggacat ttatggaatt acaagggacc aggctgggga atatgaatgc agtgcggaaa 660
atgatgtgtc attcccagat gtgaggaaag taaaagttgt tgtcaacttt gctcctacta 720
ttcaggaaat taaatctggc accgtgaccc ccggacgcag tggcctgata agatgtgaag 780
gtgcaggtgt gccgcctcca gcctttgaat ggtacaaagg agagaagaag ctcttcaatg 840
gccaacaagg aattattatt caaaatttta gcacaagatc cattctcact gttaccaacg 900
tgacacagga gcacttcggc aattatactt gtgtggctgc caacaagcta ggcacaacca 960
atgcgagcct gcctcttaac cctccaagta cagcccagta tggaattacc gggagcgctg 1020
atgttctttt ctcctgctgg taccttgtgt tgacactgtc ctctttcacc agcatattct 1080
acctgaagaa tgccattcta caataaattc aaagacccat aaaaggcttt taaggattct 1140
ctgaaagtgc tgatggctgg atccaatctg gtacagttgt taaaagcgcg tgggatttat 1200
cagcagtgct acctgggatg accgctttgg aaaatgccct tatttatcct tatccaccct 1260
tttgaaagaa ctccttgagg cgacattgcc tttaaacgac gcgaatctaa gatacggccg 1320
ttgcacc 1327
<210> 52
<211> 5529
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7477312CB1
<400> 52
atgcagctga gccgcgccgc cgccgccgcc gccgccgccc ctgcggagcc cccggagccg 60
ctgtcccccg cgccggcccc ggccccggcc ccccccggcc ccctcccgcg cagcgcggcc 120
gacggggctc cggcgggggg gaaggggggg ccggggcgcc gcgcgcggag tccccgggcg 180
ctccgttccc cggcgcgagc ggccccggcc cgggccccgg cgcggggatg gacggccccg 240
gggccagggg ccagcgccgt ggtcgtgcgc gtcggcatcc cggacctgca gcagacgaag 300
tgcctgcgcc tggacccggc cgcgcccgtg tgggccgcca agcagcgcgt gctctgcgcc 360
ctcaaccaca gcctccagga cgcgctcaac tatgggcttt tccagccgcc ctcccggggc 420
cgcgccggca agttcctgga tgaggagcgg ctcctgcagg agtacccgcc caacctggac 480
acgcccctgc cctacctgga gtttcgatac aagcggcgag tttatgccca gaacctcatc 540
gatgataagc agtttgcaaa gcttcacaca aaggcgaacc tgaagaagtt catggactac 600
gtccagctgc atagcacgga caaggtggca cgcctgttgg acaaggggct ggaccccaac 660
ttccatgacc ctgactcagg agagtgcccc ctgagcctcg cagcccagct ggacaacgcc 720
acggacctgc taaaggtgct gaagaatggt ggtgcccacc tggacttccg cactcgcgat 780
gggctcactg ccgtgcactg tgccacacgc cagcggaatg cggcagcact gacgaccctg 840
ctggacctgg gggcttcacc tgactacaag gacagccgcg gcttgacacc cctctaccac 900
agcgccctgg ggggtgggga tgccctctgc tgtgagctgc ttctccacga ccacgctcag 960
ctggggacca ccgacgagaa tggctggcag gagatccacc aggcctgccg ctttgggcac 1020
gtgcagcatc tggagcacct gctgttctat ggggcagaca tgggggccca gaacgcctcg 1080
gggaacacag ccctgcacat ctgtgccctc tacaaccagg agagctgtgc tcgtgtcctg 1140
ctcttccgtg gagctaacag ggatgtccgc aactacaaca gccagacagc cttccaggtg 1200
gccatcatcg cagggaactt tgagcttgca gaggttatca agacccacaa agactcggat ~~1260
95/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gttggacagg acagtcatga cttgctacat cctatgccca ctggggtccc agagtggggc 1320
ctgtacacag aagaggaact ggaaggaggt gccgccttct ctgtaccatt cagggaaacc 1380
cccagctatg cgaagcggcg gcgactggct ggccccagtg gcttggcatc ccctcggcct 1440
ctgcagcgct cagccagcga tatcaacctg aagggggagg cacagccagc agcttctcct 1500
ggaccctcgc tgagaagcct cccccaccag ctgctgctcc agcggctgca agaggagaaa 1560
gatcgtgacc gggatgccga ccaggagage aacatcagtg gccctttagc aggcagggcc 1620
ggccaaagca agatcaggag ctgtattcga attcgagctc ggttccccgc gccccctgcg 1680
ccccccgcac cgccgccccg gggcccgaag cggaaacttt acagcgccgt ccccggccgc 1740
aagttcatcg ccgtgaaggc gcacagcccg cagggtgaag gcgagatccc gctgcaccgc 1800
ggcgaggccg tgaaggtgct cagcattggg gagggcggtt tctgggaggg aaccgtgaaa 1860
ggccgcacgg gctggttccc ggccgactgc gtggaggaag tgcagatgag gcagcatgac 1920
acacggcctg aaacgcggga ggaccggacg aagcggctct ttcggcacta cacagtgggc 1980
tcctacgaca gcctcacctc acacagcgat tatgtcattg atgacaaagt ggctgtcctg 2040
cagaaacggg accacgaggg ctttggtttt gtgctccggg gagccaaagc agagaccccc 2100
atcgaggagt tcacgcccac gccagccttc ccggcgctgc agtatctcga gtcggtggac 2160
gtggagggtg tggcctggag ggccgggctg cgcacgggag acttcctcat cgaggtgaac 2220
ggggtgaacg tggtgaaggt cggacacaag caggtggtgg ctctgattcg ccagggtggc 2280
aaccgcctcg tcatgaaggt tgtgtctgtg acaaggaagc cagaagagga cggggctcgg 2340
cgcagagccc caccgccccc caagagggcc cccagcacca cactgaccct gcgctccaag 2400
tccatgacag ctgagctcga ggaacttgag aagctggacg agatgctggc agccgccgca 2460
gagccaacgc tgcggccaga catcgcagac gcagactcca gagccgccac cgtcaaacag 2520
aggcccacca gtcggaggat cacacccgcc gagattagct cattgtttga acgccagggc 2580
ctcccaggcc cagagaagct gccgggctcc ttgcggaagg ggattccacg gaccaagtct 2640
gtaggggagg acgagaagct ggcgtccctg ctggaagggc gcttcccgcg gagcacctcg 2700
atgcaagacc cggtgcgcga gggtcgcggc atcccgcccc cgccgcagac cgcgccgcct 2760
cccccgcccg cgccctacta cttcgactcg gggccgcccc cggccttctc gccgccgccc 2820
ccgccgggcc gcgcctacga cacggtgcgc tccagcttca agcccggcct ggaggcgcgc 2880
ctgggcgcgg gcgctgccgg cctgtacgag ccgggcgcgg ccctcggccc gctgccgtat 2940
cccgagcggc agaagcgcgc gcgctccatg atcatcctgc aggactcggc gcccgagtcg 3000
ggcgacgccc ctcgaccccc gcccgcggcc accccgcccg agcgacccaa gcgccggccg 3060
cggccgcccg gccccgacag cccctacgcc aacctgggcg ccttcagcgc cagcctcttc 3120
gctccgtcca agccgcagcg ccgcaagagc cccctggtga agcagctgca ggtggaggac 3180
gcgcaggagc gcgcggccct ggccgtgggc agccccggtc ccggcggcgg cagcttcgcc 3240
cgcgagccct ccccgaccca ccgcggtccg cgcccgggtg gcctcgacta cggcgcgggc 3300
gatggcccgg ggctcgcgtt cggcggcccg ggcccggcca aggaccggcg gctggaggag 3360
cggcgccgct ccactgtgtt cctgtccgtg ggggccatcg agggcagcgc ccccggcgcg 3420
gatctgccat ccctacagcc ctcccgctcc atcgacgagc gcctcctggg gaccggcccc 3480
accgccggcc gcgacctgct gctgccctcc ccggtgtctg ccctgaagcc gttggtcagc 3540
ggcccgagcc tggggccctc gggttccacc ttcatccacc cactcaccgg caaacccctg 3600
gaccccagct cacccctggc ccttgccctg gctgcccgag agcgagctct ggcctcccag 3660
gcgccctccc ggtcccccac acccgtgcac agtcccgacg ccgaccgccc cggacccctg 3720
tttgtggatg tacaggcccg ggacccagag cgagggtccc tggcttcccc ggctttctcc 3780
ccacggagcc cagcctggat tcctgtgcct gctcgcaggg aggcagagaa ggtcccccgg 3840
gaggagcgga agtcacccga ggacaagaag tccatgatcc tcagcgtcct ggacacatcc 3900
ctgcagcggc cagctggcct catcgttgtg cacgccacca gcaacgggca ggagcccagc 3960
aggctggggg gggccgaaga ggagcgcccg ggcaccccgg agttggcccc ggcccccatg 4020
cagtcagcgg ctgtggcaga gcccctgccc agcccccggg cccagccccc tggtggcacc 4080
ccggcagacg ccgggccagg ccagggcagc tcagaggaag agccagagct ggtgtttgct 4140
gtgaacctgc cacctgccca gctgtcgtcc agcgatgagg agaccaggga ggagctggcc 4200
cgaattgggt tggtgccacc ccctgaagag tttgccaacg gggtcctgct ggccacccca 4260
ctcgctggcc cgggcccctc gcccaccacg gtgcccagcc cggcctcagg gaagcccagc 4320
agtgagccac cccctgcccc tgagtctgca gccgactctg gggtggagga ggctgacaca 4380
cgcagctcca gcgaccccca cctggagacc acaagcacca tctccacggt gtccagcatg 4440
tccaccttga gctcggagag cggggaactc actgacaccc acacctcctt cgctgacgga 4500
cacacttttc tactcgagaa gccaccagtg cctcccaagc ccaagctcaa gtccccgctg 4560
gggaaggggc cggtgacctt cagggacccg ctgctgaagc agtcctcgga cagcgagctc 4620
96/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
atggcccagc agcaccacgc cgcctctgcc gggctggcct ctgccgccgg gcctgcccgc 4680
cctcgctacc tcttccagag aaggtccaag ctatgggggg accccgtgga gagccggggg 4740
ctccctgggc ctgaagacga caaaccaact gtgatcagtg agctcagctc ccgcctgcag 4800
cagctgaaca aggacacgcg ttccctgggg gaggaaccag ttggtggcct gggcagcctg 4860
ctggaccctg ccaagaagtc gcccatcgca gcagctcggc tcttcagcag cctcggtgag 4920
ctgagctcca tttcagcgca gcgcagcccc gggggcccgg gcggcggggc ctcgtactcg 4980
gtgaggccca gtggccgcta ccccgtggcg agacgcgccc cgagcccggt gaagcccgcg 5040
tcgctggagc gggtggaggg gctgggggcg ggcgcggggg gcgcagggcg gcccttcggc 5100
ctcacgcccc ccaccatcct caagtcgtcc agcctctcca tcccgcacga gcccaaggag 5160
gtgcgcttcg tggtgcgcag cgtgagcgcg cgcagtcgct ccccctcgcc gtcgccgctg 5220
ccctcgcccg cgtccggccc cggccccggc gcccccggcc cacgccgacc cttccagcag 5280
aagccgctgc agctctggag caagttcgac gtgggcgact ggctggagag catccaccta 5340
ggcgagcacc gcgaccgctt cgaggaccat gagatagaag gcgcgcacct acccgcgctt 5400
accaaggacg acttcgtgga gctgggcgtc acgcgcgtgg gccaccgcat gaacatcgag 5460
cgcgcgctca ggcagctgga cggcagctga cgccccaccc ccactcccgc cccaggccga 5520
gcccgcggc
5529
<210> 53
<211> 1623
<212> DNA
<213> Homo sapiens
<220>
<221> mist feature
<223> Incyte ID No: 2739431CB1
<400> 53
tgatatttga agaagtgttt tcatctatcc aagaaaaata tgatgtctcc atcccaagcc 60
tcactcttat tcttaaatgt atgtattttt atttgtggag aagctgtaca aggtaactgt 120
gtacatcatt ctacggactc ttcagtagtt aacattgtag aagatggatc taatgcaaaa 180
gatgaaagta aaagtaatga tactgtttgt aaggaagact gtgaggaatc atgtgatgtt 240
aaaactaaaa ttacacgaga agaaaaacat ttcatgtgta gaaatttgca aaattctatt 300
gtttcctaca caagaagtac caaaaaacta ctaaggaata tgatggatga gcaacaagct 360
tccttggatt atttatctaa tcaggtaatg tgtgacatgg attacagagg aggtggatgg 420
actgtgatac agaaaagaat tgatgggata attgatttcc agag.gttgtg gtgtgattat 480
ctggatggat ttggagatct tctaggagaa ttttggctag gactgaaaaa gattttttat 540
atagtaaatc agaaaaatac cagttttatg ctgtatgtgg ctttggaatc tgaagatgac 600
actcttgctt atgcatcata tgataatttt tggctagagg atgaaacgag attttttaaa 660
atgcacttag gacggtattc aggaaatgct ggtgatgcat tccggggtct caaaaaagaa 720
gataatcaaa atgcaatgcc ttttagcaca tcagatgttg ataatgatgg gtgtcgccct 780
gcatgcctgg tcaatggtca gtctgtgaag agctgcagtc acctccataa caagaccggc 840
tggtggttta acgagtgtgg tctagcaaat ctaaatggca ttcatcactt ctctggaaaa 900
ttgcttgcaa ctggaattca atggggcacg tggaccaaaa acaactcacc tgtcaagatt 960
aaatctgttt caatgaaaat tagaagaatg tacaatccat attttaaata atctcattta 1020
acattgtaat gcaagttcta caatgataat atattaaaga tttttaaaag tttatctttt 1080
cacttagtgt ttcaaacata ttaggcaaaa tttaactgta gatggcattt agatgttatg 1140
agtttaatta gaaaacttca attttgtagt attctataaa agaaaacatg gcttattgta 1200
tgtttttact tctgactata ttaacaatat acaatgaaat ttgtttcaag tgaactacaa 1260
cttgtcttcc taaaatttat agtgatttta aaggattttg ccttttcttt gaagcatttt 1320
taaaccataa tatgttgtaa ggaaaattga agggaatatt ttacttattt ttatacttta 1380
tatgattata taatctacag ataatttcta ctgaagacag ttacaataaa taactttatg 1440
cagattaata tataagctac acatgatgta aaaaccttac tatttctagg tgatgccata 1500
ccattttaaa agtagtaaga gtttgctgcc caaatagttt ttcttgtttt catatctaat 1560
catggttaac tattttgtta ttgtttgtaa taaatatatg tacttttata tcctgaaaaa 1620
aaa 1623
97/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 54
<211> 2242
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7473606CB1
<400> 54
ccacaagggc ctgactgagc gagcgagcat ggacggccgc ggggctttct ggacagtggc 60
cattcccaga gccaggcagg aaggcctcgg gaggctgggg ctcccgttcc cggtgaagcg 120
gacgccgcca gcgccccaga acccaggagg aagcacacag gccccacaga gagtggttgg 180
caagagtcac tcggggatta ggatgccggc caaatcgcgg aatttgaggc tggaatccaa 240
gctcaacagg aaagtagtga aatacaaatg gggaaaacag ggctctggag cggggaggga 300
gctggtgccg gcatttccca ccas.cgccgg tttaggaaga cgggaccgat gccggccgcc 360
ccctgctgga ggggatgtgg catctcacgg gctgccaggg agcggggttg gctactcctg 420
caaccagcgt gaagagggtc tcaggggagg ctgtggtggg~ atcccccacg tgcccttgtt 480
cctctcaccg ttacctctgg atgcctcggg gcaaaggcct tcttccacct atagacagag 540
tctacgcagg ggtcttggaa cccgggcaca ccagtcccca gctaacgaaa tccccgagtt 600
gggggatttg agagggtcac gtttggccca agaacccgca gtcctctttg gtcttcggcc 660
ctctatttct aagcgtgggc ttctggcacg gcggctctgg gcacagccca tgctgctttc 720
gggctgggtg gtttcaacga cgacaacaat tatcacagtg acggtgacct tcaccccaac.780
aggactgctg tgtgtgaagc actcaagagg gcccctacaa ccaacctgcc aggagtcggc 840
tcctgaaaac agggtcggaa aagcgctaat tactttttcc aaaggctgga gggcttcact 900
ccggctggcg ccgccgccta gcgcgctcct gcttcgccgc cacggtccgg gggggctgcc 960
ggtcccgggt accatgtgtg acggcgccct gctgcctccg ctcgtcctgc ccgtgctgct 1020
gctgctggtt tggggactgg acccgggcac aggtagcgcc ccctcccaca gccctcttca 1080
ccccgcgtcc tgcggctacc ttccctctgc gttctcgcgg cgtcctggcg gcccgggggc 1140
ggcggcggga ccgctgacgg cgcccgagcg gaggaggcgc gggccgcggc cggagtacgg 1200
gaatcgggtg gctccgtggc aggcgcgccg ccgccgggtc tccgctcgcc gatgcgcggc 1260
gccgttccgg gaggtgctcg cgcggctgcg ccggagaccc tccccgggtg gcgcgggcca 1320
gcgtggagct gtcggcgacg cggcggccga cgtggaggtg gtgctcccgt ggcgggtgcg 1380
ccccgacgac gtgcacctgc cgccgctgcc cgcagccccc gggccccgac ggcggcgacg 1440
cccccgcacg cccccagccg ccccgcgcgc ccggcccgga gagcgcgccc tgctgctgca 1500
cctgccggcc ttcgggcgcg acctgtacct tcagctgcgc cgcgacctgc gcttcctgtc 1560
ccgaggcttc gaggtggagg aggcgggcgc ggcccggcgc cgcggccgcc ccgccgagct 1620
gtgcttctac tcgggccgtg tgctcggcca ccccggctcc ctcgtctcgc tcagcgcctg 1680
cggcgccgcc ggcggcctgg ttggcctcat tcagcttggg caggagcagg tgctaatcca 1740
gcccctcaac aactcccagg gcccattcag tggacgagaa catctgatca ggcgcaaatg 1800
gtccttgacc cccagccctt ctgctgaggc ccagagacct gagcagctct gcaaggttct 1860
aacagttcca cagtgtctgg gcctcacctg ggaggacttg aaatctggag gctggagtga 1920
tctggaggtg cctcattcat gtgtctggcc tggaggtgga tgacttgaag acaaggacaa 1980
caacgtggag cgtctacctg tggcctctgc agcttggcgt ccataccttg gtggcagaca 2040
tacttcttct atggccacca gggctcccaa tgcaagagtt cccgcaagcc cagcaggagc 2100
tgtgctgcct ttgaggatca gcctcagaaa tcctagagca tcactctgaa ggtactctgt 2160
tggctgaagc ggttagaaac ctacccaggt tcaagggcag agagatagac cccaccgctc 2220
aatgtcaaag aatttggggg gc 2242
<210> 55
<211> 3751
<212> DNA
<213> Homo Sapiens
<220>
<221> misc feature
98/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<223> Incyte ID No: 3534918CB1
<400> 55
ttcatggagc atggagcgct tggcagcctt ggggaacatg cagcgaaagt tgtgggaaag 60
gtactcagac aagagcaaga ctttgtaata acccaccacc agcgtttggt gggtcctact 120
gtgatggagc agaaacacag atgcaagttt gcaatgaaag aaattgtcca attcatggca 180
agtgggcgac ttgggccagt tggagtgcct gttctgtgtc atgtggagga ggtgccagac 240
agagaacaag gggctgctcc gaccctgtgc cccagtatgg aggaaggaaa tgcgaaggga 300
gtgatgtcca gagtgatttt tgcaacagtg acccttgccc aagtgagtgt tggaaatacc 360
catggtaact ggagtccttg gagtggctgg ggaacatgca gccggacgtg taacggaggg 420
cagatgcggc ggtaccgcac atgtgataac cctcctccct ccaatggggg aagagcttgt 480
gggggaccag actcccagat ccagaggtgc aacactgaca tgtgtcctgt ggatggaagt 540
tggggaagct ggcatagttg gagccagtgc tctgcctcct gtggaggagg tgaaaagact 600
cggaagcggc tgtgcgacca tcctgtgcca gttaaaggtg gccgtccctg tcccggagac 660
actactcagg tgaccaggtg caatgtacaa gcatgtccag gtgggcccca gcgagccaga 720
ggaagtgtta ttggaaatat taatgatgtt gaatttggaa ttgctttcct taatgccaca 780
ataactgata gccctaactc tgatactaga ataatacgtg ccaaaattac caatgtacct 840
cgtagtcttg gttcagcaat gagaaagata gtttctattc taaatcccat ttattggaca 900
acagcaaagg aaataggaga agcagtcaat ggctttaccc tcaccaatgc agtcttcaaa 960
agagaaactc aagtggaatt tgcaactgga gaaatcttgc agatgagtca tattgcccgg 1020
ggcttggatt ccgatggttc tttgctgcta gatatcgttg tgagtggcta tgtcctacag 1080
cttcagtcac ctgctgaagt cactgtaaag gattacacag aggactacat tcaaacaggt 1140
cctgggcagc tgtacgccta ctcaacccgg ctgttcacca ttgatggcat cagcatccca 1200
tacacatgga accacaccgt tttctatgat caggcacagg gaagaatgcc tttcttggtt 1260
gaaacacttc atgcatcctc tgtggaatct gactataacc agatagaaga gacactgggt 1320
tttaaaattc atgcttcaat atccaaagga gatcgcagta atcagtgccc ctccgggttt 1380
accttagact cagttggacc tttttgtgct gatgaggatg aatgtgcagc agggaatccc 1440
tgctcccata gctgccacaa tgccatgggg acttactact gctcctgccc taaaggcctc 1500
accatagctg cagatggaag aacttgtcaa gatattgatg agtgtgcttt gggtaggcat 1560
acctgccacg ctggtcagga ctgtgacaat acgattggat cttatcgctg tgtggtccgt 1620
tgtggaagtg gctttcgaag aacctctgat gggctgagtt gtcaagatat taatgaatgt 1680
caagaatcca gcccctgtca ccagcgctgt ttcaatgcca taggaagttt ccattgtgga 1740
tgtgaacctg ggtatcagct caaaggcaga aaatgcatgg atgtgaacga gtgtagacaa 1800
aatgtatgca gaccagatca gcactgtaag aacacccgtg gtggctataa gtgcattgat 1860
ctttgtccaa atggaatgac caaggcagaa aatggaacct gtattgatat tgatgaatgt 1920
aaagatggga cccatcagtg cagatataac cagatatgtg agaatacaag aggcagctat 1980
cgttgtgtat gcccaagagg ttatcggtct,caaggagttg gaagaccctg catggatatt 2040
gatgaatgtg aaaatacaga tgcctgccag catgagtgta agaatacctt tggaagttat 2100
cagtgcatct gcccacctgg ctatcaactc acacacaatg gaaagacatg ccaagatatc 2160
gatgaatgtc tggagcagaa tgtgcactgt ggacccaatc gcatgtgctt caacatgaga 2220
ggaagctacc agtgcatcga tacaccctgt ccacccaact accaacggga tcctgtttca 2280
gggttctgcc tcaagaactg tccacccaat gatttggaat gtgccttgag cccatatgcc 2340
ttggaataca aactcgtctc cctcccattt ggaatagcca ccaatcaaga tttaatccgg 2400
ctggttgcat acacacagga tggagtgatg catcccagga caactttcct catggtagat 2460
gaggaacaga ctgttccttt tgccttgagg gatgaaaacc tgaaaggagt ggtgtataca 2520
acacgaccac tacgagaagc agagacctac cgcatgaggg tccgagcctc atcctacagt 2580
gccaatggga ccattgaata tcagaccaca ttcatagttt atatagctgt gtccgcctat 2640
ccatactaag gaactctcca aagcctattc cacatattta aaccgcatta atcatggcaa 2700
tcaagccccc ttccagatta ctgtctcttg aacagttgca atcttggcag cttgaaaatg 2760
gtgctacact ctgttttgtg tgccttcctt ggtacttctg aggtattttc atgatcccac 2820
catggtcata tcttgaagta tggtctagaa aagtccctta ttattttatt tattacactg 2880
gagcagttac ttcccaaaga ttattctgaa catctaacag gacatatcag tgatggttta 2940
cagtagtgta gtacctaaga tcattttcct gaaagccaaa ccaaacaacg aaaaacaaga 3000
acaactaatt cagaatcaaa tagagttttt gagcatttga ctatttttag aatcataaaa 3060
ttagttacta agtattttga tcaaagctta taaaataact tacggagatt tttgtaagta 3120
ttgatacatt ataataggac ttgcctattt tcatttttaa gaagaaaaac accactcatt 3180
99/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ttataaaata tagtacagct actataaggc ttgtttgatc ccaaatggtg cttatcttga 3240
ttgaacattc agaacaagga tattattttc agtgattttg tgagatcagc tgaaccactt 3300
atgataataa taataaaaaa gactgctttg ccctcacgtc agttgtacat ggcatggaac 3360
tttaaaaatt ttaatataaa ctttcatcca gttagcttca taacttttac gttccagaat 3420
tttgtttatt ttcctgtcaa tgaaagcaat ttttaaagat accagtggga caggtttggt 3480
tttttaaaaa tctcatgtgt tcaaattaac ataaatatta cacgtcaata cactgtacat 3540
ggtggtaata gactctaagc aattgccaag atgtattcta tttttatgaa gtgtatatat 3600
attaccttag tgtgcatttt ctatataata tcttgatgga ctcttttata aaattatttt 3660
ataaaaaaca atgttacact aaaatcagcc taaataaatt ttcacaactt tttttcataa 3720
ccaaaaacaa caaacaacaa aaccggggcc g 3751
<210> 56
<211> 3579
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 2428715CB1
<400> 56
gggtcgacca cgcgtcgggg caggtggcga gcagcgagca gcgcctgcgg gagcggcc,gg 60
tcggtcgggt ccccgcgccc cgcacgcccg cacgcccagc ggggcccgca ttgagcatgg 120
gcgcggcggc cgtgcgctgg cacttgtgcg tgctgctggc cctgggcaca cgcgggcggc 180
tggccggggg cagcgggctc ccagggtcag tcgacgtgga tgagtgctca gagggcacag 240
atgactgcca catcgatgcc atctgtcaga acacgcccaa gtcctacaaa tgcctctgca 300
agccaggcta caagggggaa ggcaagcagt gtgaagacat tgacgagtgt gagaatgact 360
actacaatgg gggctgtgtc cacgagtgca tcaacatccc ggggaactac aggtgtacct 420
gctttgatgg cttcatgctg gcacacgatg gacacaactg cctggatgtg gacgagtgtc 480
aggacaataa tggtggctgc cagcagatct gcgtcaatgc catgggcagc tacgagtgtc 540
agtgccacag tggcttcttc cttagtgaca accagcatac ctgcatccac cgctccaatg 600
agggtatgaa ctgcatgaac aaagaccatg gctgtgccca catctgccgg gagacgccca 660
aaggtggggt ggcctgcgac tgcaggcccg gctttgacct tgcccaaaac cagaaggact 720
gcacactaac ctgtaattat ggaaacggag gctgccagca cagctgtgag gacacagaca 780
caggccccac gtgtggttgc caccagaagt acgccctcca ctcagacggt cgcacgtgca 840
tcgagaagga tgaggctgca attgagcgct ctcagttcaa tgccacgtca gtagctgatg 900
tggacaagcg ggtgaaacgg cggctactca tggagacgtg cgcagtcaat aacggaggct 960
gcgaccggac atgcaaggac acagccactg gcgtgcgatg cagctgcccc gttggattca 1020
cactgcagcc ggacgggaag acatgcaaag acatcaacga gtgcctggtc aacaacggag 1080
gctgcgacca cttctgccgc aacaccgtgg gcagcttcga gtgcggctgc cggaagggct 1140
acaagctgct caccgacgag cgcacctgcc aggacatcga cgagtgctcc ttcgagcgga 1200
cctgtgacca catctgcatc aactccccgg gcagcttcca gtgcctgtgt caccgcggct 1260
acatcctcta cgggacaacc cactgcggag atgtggacga gtgcagcatg agcaacggga 1320
gctgtgacca gggctgcgtc aacaccaagg gcagctacga gtgcgtctgt cccccgggga 1380
ggcggctcca ctggaaccgg aaggattgcg tggagacagg caagtgtctt tctcgtgcca 1440
agacctcccc ccgggcccag ctgtcctgca gcaaggcagg cggtgtggag agctgcttcc 2500
tttcctgccc ggctcacaca ctcttcgtgc cagatgcccc caccaccccc atcaaacaga 1560
aggcccgctt caagatccga gatgccaagt gccacctccg gccccacagc caggcacgag 1620
caaaggagac cgccaggcag ccgctgctgg accactgcca tgtgactttc gtgaccctca 1680
agtgtgactc ctccaagaag aggcgccgtg gccgcaagtc cccatccaag gaggtgtccc 1740
acatcacagc agagtttgag atcgagacaa agatggaaga ggcctcagac acatgcgaag 1800
cggactgctt gcggaagcga gcagaacaga gcctgcaggc cgccatcaag accctgcgca.1860
agtccatcgg ccggcagcag ttctatgtcc aggtctcagg cactgagtac gaggtagccc 1920
agaggccagc caaggcgctg gaggggcagg gggcatgtgg cgcaggccag gtgctacagg 1980
acagcaaatg cgttgcctgt gggcctggca cccacttcgg tggtgagctc ggccagtgtg 2040
tgccatgtat gccaggaaca taccaggaca tggaaggcca gctcagttgc acaccgtgcc 2100
100/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ccagcagcga cgggcttggt ctgcctggtg cccgcaacgt gtcggaatgt ggaggccagt 2160
gttctccagg cttcttctcg gccgatggct tcaagccctg ccaggcctgc cccgtgggca 2220
cgtaccagcc tgagcccggg cgcaccggct gcttcccctg tggagggggt ttgctcacca 2280
aacacgaagg caccacctcc ttccaggact gcgaggctaa agtgcactgc tcccccggcc 2340
accactacaa caccaccacc caccgctgca tccgctgccc cgtcggcacc taccagcccg 2400
agtttggcca gaaccactgc atcacctgtc cgggcaacac cagcacagac ttcgatggct 2460
ccaccaacgt cacacactgc aaaaaccagc actgcggcgg cgagcttggt gactacaccg 2520
gctacatcga gtcccccaac taccctggcg actacccagc caacgctgaa tgcgtctggc 2580
acatcgcacc tcccccaaag cgcaggatcc tcatcgtggt ccctgagatc ttcctgccca 2640
tcgaggatga gtgcggcgat gttctggtca tgaggaagag tgcctctccc acgtccatca 2700
ccacctatga gacctgccag acctacgaga ggcccatcgc cttcacctcc cgctcccgca 2760
agctctggat ccagttcaaa tccaatgaag gcaacagcgg caaaggcttc caagtgccct 2820
atgtcaccta cgatgaggac taccagcaac tcatagagga catcgtgcgc gatgggcgcc 2880
tgtacgcctc ggagaaccac caggaaattt tgaaagacaa gaagctgatc aaggccctct 2940
tcgacgtgct ggcgcatccc cagaaccgcg gcttagtttc ctcatgttaa aagaaaatac 3000
ttatcctccc tgtggcacag ggttttgttt aaaagattag acaagatgat acaaccattt 3060
tggaaataat ttggcagctt cttataaaca tatactttac aggtaagcca gcaattgcac 3120
tcctagctgc acccacgaga aatgaaaata tgtccataca aagatttata cacaaatgtt 3180
tatagcagct ttattcataa taatcaaaaa ctgaaaacaa ctcaaacatc catcaacagg 3240
cagatggata aacaaattat ggtatgtcca tgcaacggaa tacaactcac tgatgaaaag 3300
gaataaacca caaatgcctg caacgccatg atgaatctca aaacatgctg agtgtagaga 3360
agccagacac aagagtagat actcctatac aattccactt acatggaaat ctagaaaaga 3420
caattcgaat atatagtggc aaaaagcaga agagtggttg cctggaacca gggtgggaat 3480
gaagattaac tgcccagagg cataaaaaat ggggtggtgg gggcggtgat ggaaaagtgc 3540
tatgccttca ctgtaccttt gtcaaaactt gttgaactg 3579
<210> 57
<211> 5178
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 3351332CB1
<400> 57
gggaacccag aaccagcccg agccgcctgc cccgtcgccc ggccgccggc ttagggcgca 60
gcgcggttgg tcctcgcccc ctcccgcccg ccggcctacc aggccatggg ggcgtcccgg 120
gaccgcgggc tggccgcgct ctggtgcctt gggctcctgg ggggcctggc gcgcgtcgcg 180
ggcacgcact accgctacct ctggaggggc tgctacccat gtcacctggg ccaggccggc 240
taccccgtga gcgccggtga ccagaggcca gatgtggacg aatgccgaac ccacaacggt 300
ggctgccagc accggtgcgt gaacacccca ggctcctacc tctgtgagtg caagcccggc 360
ttccggctcc acactgacag caggacctgc ctggccatta actcctgcgc cctgggcaat 420
ggcggctgcc agcaccactg tgtccagctc acaatcactc ggcatcgctg ccagtgccgg 480
cccgggttcc agctccagga ggacggcagg cattgtgtcc gtagaagccc gtgtgccaac 540
aggaacggca gctgcatgca caggtgccag gtggtccggg gcctcgcccg ctgtgagtgc 600
cacgtgggct atcagctagc agcggacggc aaggcctgtc cagatgtgga cgaatgtgcc 660
gcagggctgg cccagtgtgc ccatggctgc ctcaacaccc aggggtcctt caagtgcgtg 720
tgtcacgcgg gctatgagct gggcgccgat ggccggcagt gctaccggat tgagatggaa 780
atcgtgaaca gctgtgaggc caacaacggc ggctgctccc atggctgcag ccacaccagt 840
gctgggcccc tgtgcacatg tccccgcggc tacgagctgg acacagatca gaggacctgc 900
atcgatgtcg acgactgtgc agacagcccg tgctgccagc aggtgtgcac caacaaccct 960
ggcgggtacg agtgcggctg ctacgccggc taccggctca gtgccgatgg ctgcggctgt 1020
gaggatgtgg atgagtgcgc ctccagccgt ggcggctgcg agcaccactg caccaacctg 1080
gccggctcct tccagtgctc ctgcgaggcc ggctaccggc tgcacgagga ccgtaggggc 1140
tgcagccccc tggaggagcc gatggtggac ctggacggcg agctgccttt cgtgcggccc 1200
1011123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ctgccccaca ttgccgtgct ccaggacgag ctgccgcaac tcttccagga tgacgacgtc 1260
ggggccgatg aggaagaggc agagttgcgg ggcgaacaca cgctcacaga gaagtttgtc 1320
tgcctggatg actcctttgg ccatgactgc agcttgacct gtgatgactg caggaacgga 1380
gggacctgcc tcctgggcct ggatggctgt gattgccccg agggctggac tgggctcatc 1440
tgcaatgaga cttgtcctcc ggacaccttt gggaagaact gcagcttctc ctgcagctgt 1500
cagaatggtg ggacctgcga ctctgtcacg ggggcctgcc gctgcccccc gggtgtcagt 1560
ggaactaact gtgaggatgg ctgccccaag ggctactatg'gcaagcactg tcgcaagaaa 1620
tgcaactgtg ccaaccgggg ccggtgccac cgcctctacg gggcctgcct ctgcgaccca 1680
gggctctacg gccgcttctg ccacctcacc tgcccgccgt gggcctttgg gccgggctgc 1740
tcggaggagt gccagtgtgt gcagccccac acgcagtcct gtgacaagag ggatggcagc 1800
tgctcctgca aggctggctt ccggggcgag cgctgtcagg cagagtgtga gctgggctac 1860
tttgggccgg ggtgctggca ggcatgcacc tgcccagtgg gcgtggcctg tgactccgtg 1920
agcggcgagt gtgggaagcg gtgtcctgct ggcttccagg gagaggactg tggccaagag 1980
tgcccggtgg ggacgtttgg cgtgaactgc tcgagctcct gctcctgtgg gggggccccc 2040
tgccacgggg tcacggggca gtgccggtgt ccgccgggga ggactgggga agactgtgag 2100
gcagattgtc ccgagggccg ctgggggctg ggctgccagg agatctgccc agcatgccag 2160
cacgctgccc gctgcgaccc tgagaccgga gcctgcctgt gcctccctgg cttcgtcggc 2220
agccgctgcc aggacgtgtg cccagcaggc tggtatggtc ccagctgcca gacaaggtgc 2280
tcttgtgcca atgatgggca ctgccaccca gccaccggac actgcagctg tgcccccggg 2340
tggaccggct ttagctgcca gagagcctgt gatactgggc actggggacc tgactgcagc 2400
cacccctgca actgcagcgc tggccacggg agctgtgatg ccatcagcgg cctgtgtctg 2460
tgtgaggctg gctacgtggg cccgcggtgc gagcagcagt gtccccaggg ccactttggg 2520
cccggctgtg agcagctgtg ccagtgtcag catggagcag cctgtgacca cgtcagcggg 2580
gcctgcacct gcccggccgg ctggaggggc accttctgcg agcatgcctg cccggccggc 2640
ttctttggat tggactgtcg cagtgcctgc aactgcaccg ccggagctgc ctgtgatgcc 2700
gtgaatggct cctgcctctg ccccgctggc cgccggggcc cccgctgtgc cgagacctgc 2760
ccagcccaca cctacgggca caattgcagc caggcctgtg cctgctttaa cggggcctcc 2820
tgtgaccctg tccacgggca gtgccactgt gcccctggct ggatggggcc ctcctgcctg 2880
caggagtgcc tcccccggga cgtcagagct ggctgccggc acagcggcgg ttgcctcaac 2940
gggggcctgt gtgacccgca cacgggccgc tgcctctgcc cagccggctg gactggggac 3000
aagtgtcaga gcccctgcct gcggggctgg tttggagagg cctgtgccca gcgctgcagc 3060
tgcccgcctg gcgctgcctg ccaccacgtc actggggcct gccgctgtcc ccctggcttc 3120
actggctccg gctgcgagca ggcctgccca cccggcagct ttggggagga ctgtgcgcag 3180
atgtgccagt gtcccggtga gaacccggcc tgccaccctg ccaccgggac ctgctcatgt 3240
gctgctggct accacggccc cagctgccag caacgatgtc cgcccgggcg gtatgggcca 3300
ggctgtgaac agctgtgtgg gtgtctcaac gggggctcct gtgatgcggc cacgggggcc 3360
tgccgctgcc ccactgggtt cctcgggacg gactgcaacc tcacctgtcc gcagggccgc 3420
ttcggcccca actgcaccca cgtgtgtggg tgtgggcagg gggcggcctg cgaccctgtg 3480
accggcacct gcctctgccc cccggggaga gccggcgtcc gctgtgagcg aggctgcccc 3540
cagaaccggt ttggcgtggg ctgcgagcac acctgctcct gcagaaatgg gggcctgtgc 3600
cacgccagca acggcagctg ctcctgtggc ctgggctgga cggggcggca ctgcgagctg 3660
gcctgtcccc ctgggcgcta cggagccgcc tgccatctgg agtgctcctg ccacaacaac 3720
agcacgtgtg agcctgccac gggcacctgc cgctgcggcc ccggcttcta tggccaggcc 3780
tgcgagcacc cctgtccccc tggcttccac ggggctggct gccaggggtt gtgctggtgt 3840
caacatggag ccccctgcga ccccatcagt ggccgatgcc tctgccctgc cggcttccac 3900
ggccacttct gtgagagggg gtgtgagcca ggttcatttg gagagggctg ccaccagcgc 3960
tgtgactgtg acgggggggc accctgtgac cctgtcaccg gtctctgcct ttgcccacca 4020
gggcgctcag gagccacctg taacctggat tgcagaaggg gccagtttgg gcccagctgc 4080
accctgcact gtgactgcgg gggtggggct gactgcgacc ctgtcagtgg gcagtgtcac 4140
tgtgtggatg gctacatggg gcccacgtgc cgggaaggtg ggcccctccg gctccccgag 4200
aacccgtcct tagcccaggg ctcagcgggc acactgcccg cctccagcag acccacatcc 4260
cggagcggtg gaccagcgag gcactagtag aggcagtccc gtggagcccg cctctccagt 4320
cccagccaga ggggaccctg gcctttggtg accactgaga aggacacttc acgggcccag 4380
agctcctggt actgcccttc ctttgagggc cgtggagggc tgtggacagc ccagcaacct 4440
gtcgctcttg gaggctggtg tggccttgag gagggaagcc tcgcatggcc gctggaagag 4500
aggcgcctcc tggcctggct ctgcagaacc caggggcacg ctctgggcct gggctgagga 4560
102/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
agtcccgctc tccccgcggc tctgagttgg actgaggaca ggtgtgggcg ccagtgtggg 4620
tgcaggcgca ggtgcaggca cagggccact gtcctccagg caggcttttt ggtgctaggc 4680
cctgggactg gaagtcgccc agcccgtatt tatgtaaagg tatttatggg ccactgcaca 4740
tgcccgctgc agccctggga tcagctggaa gctgcctgtc atctcctgcc caatccccag 4800
aaaccctgat tcaggtctgc aggctcctgc gggctcacca ggctgctggc tccggtacca 4860
tgtaaaccta ggaaggtaaa ggagcaggca acctcctcgt ggcctgtgtg tttgctgtgt 4920
tacgtggact ctgtgtgggc tcctccctgg ggcccggcca gcataacggt gcacccaggg 4980
acctcccagt gcacccgggg ccctttgcag gggtgggggt gccacacaag tgaagaagtt 5040
gggactcatc tcagttccca gtgctattga ggagaacgct ggggctgcat tcattaccgc 5100
tgagacccag agactggctg ttcccagaga atggcccagg gggaggaggg ctggtgtgga 5160
agggcaactt ggactgag 5178
<210> 58
<211> 11367
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 6382722CB1
<400> 58
atggcgaagc ggctctgcgc ggggagcgca ctgtgtgttc gcggcccccg gggccccgcg 60
ccgctgctgc tggtcgggct ggcgctgctg ggcgcggcgc gggcgcggga ggaggcgggc 120
ggcggcttca gcctgcaccc gccctacttc aacctggccg agggcgcccg catcgccgcc 180
tccgcgacct gcggagagga ggccccggcg cgcggctccc cgcgccccac cgaggacctt 240
tactgcaagc tggtaggggg ccccgtggcc ggcggcgacc ccaaccagac catccggggc 300
cagtactgcg acatctgcac ggctgccaac agcaacaagg cacaccccgc gagcaatgcc 360
atcgatggca cggagcgctg gtggcagagt ccaccgctgt cccgcggcct ggagtacaac 420
gaggtcaacg tcaccctgga cctgggccag gtcttccacg tggcctacgt cctcatcaag 480
tttgccaact caccccggcc ggacctctgg gtgctggagc ggtccatgga cttcggccgc 540
acctaccagc cctggcagtt ctttgcctcc tctaagaggg actgtctgga gcggttcggg 600
ccacagacgc tggagcgcat cacacgggac gacgcggcca tctgcaccac cgagtactca 660
cgcatcgtgc ccctggagaa cggagagatc gtggtgtccc tggtgaacgg acgtccgggc 720
gccatgaatt tctcctactc gccgctgcta cgtgagttca ccaaggccac caacgtccgc 780
ctgcgcttcc tgcgtaccaa cacgctgctg ggccatctca tggggaaggc gctgcgggac 840
cccacggtca cccgccggta ttattacagc atcaaggata tcagcatcgg aggccgctgt 900
gtctgccacg gccacgcgga tgcctgcgat gccaaagacc ccacggaccc gttcaggctg 960
cagtgcacct gccagcacaa cacctgcggg ggcacctgcg accgctgctg ccccggcttc 1020
aatcagcagc cgtggaagcc tgcgactgcc aacagtgcca acgagtgcca gtcctgtaac 1080
tgctacggcc atgccaccga ctgttactac gaccctgagg tggaccggcg ccgcgccagc 1140
cagagcctgg atggcaccta tcagggtggg ggtgtctgta tcgactgcca gcaccacacc 1200
gccggcgtca actgtgagcg ctgcctgccc ggcttctacc gctctcccaa ccaccctctc 1260
gactcgcccc acgtctgccg ccgctgcaac tgcgagtccg acttcacgga tggcacctgc 1320
gaggacctga cgggtcgatg ctactgccgg cccaacttct ctggggagcg gtgtgacgtg 1380
tgtgccgagg gcttcacggg cttcccaagc tgctacccga cgccctcgtc ctccaatgac 1440
accagggagc aggtgctgcc agctggccag attgtgaatt gtgactgcag cgcggcaggg 1500
acccagggca acgcctgccg gaaggaccca agggtgggac gctgtctgtg caaacccaac 1560
ttccaaggca cccattgtga gctctgcgcg ccagggttct acggccccgg ctgccagccc 1620
tgccagtgtt ccagccctgg agtggccgat gaccgctgtg accctgacac aggccagtgc 1680
aggtgccgag tgggcttcga gggggccaca tgtgatcgct gtgcccccgg ctactttcac 1740
ttccctctct gccagttgtg tggctgcagc cctgcaggaa ccttgcccga gggctgcgat 1800
gaggccggcc gctgcctatg ccagcctgag tttgctggac ctcattgtga ccggtgccgc 1860
cctggctacc atggtttccc caactgccaa gcatgcacct gcgaccctcg gggagccctg 1920
gaccagctct gtggggcggg aggtttgtgc cgctgccgcc ccggctacac aggcactgcc 1980
tgccaggaat gcagccccgg ctttcacggc ttccccagct gtgtcccctg ccactgctct 2040
103/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gctgaaggct ccctgcacgc agcctgtgac ccccggagtg ggcagtgcag ctgccggccc 2100
cgtgtgacgg ggctgcggtg tgacacgtgt gtgcccggtg cctacaactt cccctactgc 2160
gaagctggct cttgccaccc tgccggtctg gccccagtgg atcctgccct tcctgaggca 2220
caggttccct gtatgtgccg ggctcacgtg gaggggccga gctgtgaccg ctgcaaacct 2280
gggttctggg gactgagccc cagcaacccc gagggctgta cccgctgcag ctgcgacctc 2340
aggggcacac tgggtggagt tgctgagtgc cagccgggca ccggccagtg cttctgcaag 2400
ccccacgtgt gcggccaggc ctgcgcgtcc tgcaaggatg gcttctttgg actggatcag 2460
gctgactatt ttggctgccg cagctgccgg tgtgacattg gcggtgcact gggccagagc 25.20
tgtgaaccga ggacgggcgt ctgccggtgc cgccccaaca cccagggccc cacctgcagc 2580
gagcctgcga gggaccacta cctcccggac ctgcaccacc tgcgcctgga gctggaggag 2640
gctgccacac ctgagggtca cgccgtgcgc tttggcttca accccctcga gttcgagaac 2700
ttcagctgga ggggctacgc gcagatggca cctgtccagc ccaggatcgt ggccaggctg 2760
aacctgacct cccccgacct tttctggctc gtcttccgat acgtcaaccg gggggccatg 2820
agtgtgagcg ggcgggtctc tgtgcgagag gagggcaggt cggccgcctg tgccaactgc 2880
acagcacaga gtcagcccgt ggccttccca cccagcacgg agcctgcctt catcaccgtg 2940
ccccagaggg gcttcggaga gccctttgtg ctgaaccctg gcacctgggc cctgcgtgtg 3000
gaggccgaag gggtgctcct ggactacgtg gttctgctgc ctagcgcata ctacgaggcg 3060
gcgctcctgc agctgcgggt gactgaggcc tgcacatacc gtccctctgc ccagcagtct 3120
ggcgacaact gcctcctcta cacacacctc cccctggatg gcttcccctc ggccgc.cggg 3180
ctggaggccc tgtgtcgcca ggacaacagc ctgccccggc cctgccccac ggagcagctc 3240
agcccgtcgc acccgccact gatcacctgc acgggcagtg atgtggacgt ccagcttcaa 3300
gtggcagtgc cacagccagg ccgctatgcc ctagtggtgg agtacgccaa tgaggatgcc 3360
cgccaggagg tgggcgtggc tgtgcacacc ccacagcggg ccccccagca ggggctgctc 3420
tccctgcacc cctgcctgta cagcaccctg tgccggggca ctgcccggga tacccaggac 348,0
cacctggctg tcttccacct ggactcggag gccagcgtga ggctcacagc cgagcaggca 3540
cgcttcttcc tgcacggggt cactctggtg cccattgagg agttcagccc ggagttcgtg 3600
gagccccggg tcagctgcat cagcagccac ggcgcctttg gccccaacag tgccgcctgt 3660
ctgccctcgc gcttcccaaa gccgccccag cccatcatcc tcagggactg ccaggtgatc 3720
ccgctgccgc ccggcctccc gctgacccac gcgcaggatc tcactccagc cacgtcccca 3780
gctggacccc gacctcggcc ccccaccgct gtggaccctg atgcagagcc caccctgctg 3840
cgtgagcccc aggccaccgt ggtcttcacc acccatgtgc ccacgctggg ccgctatgcc 3900
ttcctgctgc acggctacca gccagcccac cccaccttcc ccgtggaagt cctcatcaac 3960
gccggccgcg tgtggcaggg ccacgccaac gccagcttct gtccacatgg ctacggctgc 4020
cgcaccctgg tggtgtgtga gggccaggcc ctgctggacg tgacccacag cgagctcact 4080
gtgaccgtgc gtgtgcccga gggccggtgg ctctggctgg attatgtact cgtggtccct 4140
gagaacgtct acagctttgg ctacctccgg gaggagcccc tggataaatc ctatgacttc 4200
atcagccact gcgcagccca gggctaccac atcagcccca gcagctcatc cctgttctgc 4260
cgaaacgctg ctgcttccct ctccctcttc tataacaacg gagcccgtcc atgtggctgc 4320
cacgaagtag gtgctacagg ccccacgtgt gagcccttcg ggggccagtg tccctgccat 4380
gcccatgtca ttggccgtga ctgctcccgc tgtgccaccg gatactgggg cttccccaac 4440
tgcaggccct gtgactgcgg tgcccgcctc tgtgacgagc tcacgggcca gtgcatctgc 4500
ccgccacgca ccatcccgcc cgactgcctg ctgtgccagc cccagacctt tggctgccac 4560
cccctggtcg gctgtgagga gtgtaactgc tcagggcccg gcatccagga gctcacagac 4620
cctacctgtg acacagacag cggccagtgc aagtgcagac ccaacgtgac tgggcgccgc 4680
tgtgatacct gctctccggg cttccatggc tacccccgct gccgcccctg tgactgtcac 4740
gaggcgggca ctgcgcctgg cgtgtgtgac cccctcacag ggcagtgcta ctgtaaggag 4800
aacgtgcagg gccccaaatg tgaccagtgc agccttggga ccttctcact ggatgctgcc 4860
aaccccaaag gttgcacccg ctgcttctgc tttggggcca cggagcgctg ccggagctcg 4920
tcctacaccc gccaggagtt cgtggatatg gagggatggg tgctgctgag cactgaccgg 4980
caggtggtgc cccacgagcg gcagccaggg acggagatgc tccgtgcaga cctgcggcac 5040
gtgcctgagg ctgtgcccga ggctttcccc gagctgtact ggcaggcccc accctcctac 5100
ctgggggacc gggtgtcatc ctacggtggg accctccgtt atgaactgca ctcagagacc 5160
cagcggggag atgtctttgt ccccatggag agcaggccgg atgtggtgct gcagggcaac 5220
cagatgagca tcacattcct ggagccggca taccccacgc ctggccacgt tcaccgtggg 5280
cagctgcagc tggtggaggg gaacttccgg catacggaga ctcgcaacac tgtgtcccgc 5340
gaggagctca tgatggtgct ggccagcctg gagcagctgc agatccgtgc cctcttctca 5400
104/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
cagatctcct cggctgtctc cctgcgcagg gtggcactgg aggtggccag cccagcaggc 5460
cagggggccc tggccagcaa tgtggagctg tgcctgtgcc ccgccagcta ccggggggac 5520
tcatgccagg aatgtgcccc cggcttctat cgggacgtca aaggtctctt cctgggccga 5580
tgtgtccctt gtcagtgcca tggacactca gaccgctgcc tccctggctc tggcgtctgt 5640
gtggactgcc agcacaacac cgaaggggcc cactgtgagc gctgccaggc tggcttcatg 5700
agcagcaggg acgaccccag cgccccctgt gtcagctgcc cctgccccct ctcagtgcct 5760
tccaacaact tcgccgaggg ctgtgtcctg cgaggcggcc gcacccagtg cctctgcaaa 5820
cctggttatg caggtgcctc ctgcgagcgg tgtgcgcccg gattctttgg gaacccactg 5880
gtgctgggca gctcctgcca gccatgcgac tgcagcggca acggtgaccc caacttgctc 5940
ttcagcgact gcgaccccct gacgggcgcc tgccgtggct gcctgcgcca caccactggg 6000
ccccgctgcg agatctgtgc ccccggcttc tacggcaacg ccctgctgcc cggcaactgc 6060
acccggtgcg actgtacccc atgtgggaca gaggcctgcg acccccacag cgggcactgc 6120
ctgtgcaagg cgggcgtgac tgggcggcgc tgtgaccgct gccaggaggg acattttggt 6180
ttcaatggct gcgggggctg ccgcccgtgt gcttgtggac cggccgccga gggctccgag 6240
tgccaccccc agagcggaca gtgccactgc cgaccaggga ccatgggacc ccagtgccgc 6300
gagtgtgccc ctggctactg ggggctccct gagcagggct gcaggcgctg ccagtgccct 6360
gggggccgct gtgaccctca cacgggccgc tgcaactgcc ccccggggct cagcggggag 6420
cgctgcgaca cctgcagcca gcagcatcag gtgcctgttc caggcgggcc tgtgggccac 6480
agcatccact gtgaagtgtg tgaccactgt gtggtcctgc tcctggatga cctggaacgg 6540
gccggcgccc tcctccccgc cattcacgag caactgcgtg gcatcaatgc cagctccatg 6600
gcctgggccc gtctgcacag gctgaacgcc tccatcgctg acctgcagag ccagctccgg 6660
agccccctgg gcccccgcca tgagacggca cagcagctgg aggtgctgga gcagcagagc 6720
acaagcctcg ggcaggacgc acggcggcta ggcggccagg ccgtggggac ccgagaccag 6780
gcgagccaat tgctggccgg caccgaggcc acactgggcc atgcgaagac gctgttggcg 6840
gccatccggg ctgtggaccg caccctgagc gagctcatgt cccagacggg ccacctgggg 6900
ctggccaatg cctcggctcc atcaggtgag cagctgctcc ggacactggc cgaggtggag 6960
cggctgctct gggagatgcg ggcccgggac ctgggggccc cgcaggcagc agctgaggct 7020
gagttggctg cagcacagag attgctggcc cgggtgcagg agcagctgag cagcctctgg 7080
gaggagaacc aggcactggc cacacaaacg~cgcgaccggc tggcccagca cgaggccggc 7140
ctcatggacc tgcgagaggc tttgaaccgg gcagtggacg ccacacggga ggcccaggag 7200
ctcaacagcc gcaaccagga gcgcctggag gaagccctgc aaaggaagca ggagctgtcc 7260
cgggacaatg ccaccctgca ggccactctg catgcggcta gggacaccct ggccagcgtc 7320
ttcagattgc tgcacagcct ggaccaggct aaggaggagc tggagcgcct cgccgccagc 7380
ctggacgggg ctcggacccc actgctgcag aggatgcaga ccttctcccc ggcgggcagc 7440
aagctgcgtc tagtggaggc cgccgaggcc cacgcacagc agctgggcca gctggcactc 7500
aatctgtcca gcatcatcct ggacgtcaac caggaccgcc tcacccagag ggccatcgag 7560
gcctccaacg cctacagccg catcctgcag gccgtgcagg ctgccgagga tgctgctggc 7620
caggccctgc agcaggcgga ccacacgtgg gcgacggtgg tgcggcaggg cctggtggac 7680
cgagcccagc agctcctggc caacagcact gcactagaag aggccatgct ccaggaacag 7740
cagaggctgg gccttgtgtg ggctgccctc cagggtgcca ggacccagct ccgagatgtc 7800
cgggccaaga aggaccagct ggaggcgcac atccaggcgg cgcaggccat gcttgccatg 7860
gacacagacg agacaagcaa gaagatcgca catgccaagg ctgtggctgc tgaagcccag 7920
gacaccgcca cccgtgtgca gtcccagctg caggccatgc aggagaatgt ggagcggtgg 7980
cagggccagt acgagggcct gcggggccag gacctgggcc aggcagtgct tgacgcaggc 8040
cactcagtgt ecaccctgga gaagacgctg ccccagctgc tggccaagct gagcatcctg 8100
gagaaccgtg gggtgcacaa cgccagcctg gccctgtccg ccagcattgg ccgcgtgcga 8160
gagctcattg cccaggcccg gggggctgcc agtaaggtca aggtgcccat gaagttcaac 8220
gggcgctcag gggtgcagct gcgcacccca cgggatcttg ccgaccttgc tgcctacact 8280
gccctcaagt tctacctgca gggcccagag cctgagcctg ggcagggtac cgaggatcgc 8340
tttgtgatgt acatgggcag ccgccaggcc actggggact acatgggtgt gtctctgcgt 8400
gacaagaagg tgcactgggt gtatcagctg ggtgaggcgg gccctgcagt cctaagcatc 8460
gatgaggaca ttggggagca gttcgcagct gtcagcctgg acaggactct ccagtttggc 8520
cacatgtccg tcacagtgga gagacagatg atccaggaaa ccaagggtga cacggtggcc 8580
cctggggcag aggggctgct caacctgcgg ccagacgact tcgtcttcta cgtcgggggg 8640
taccccagta ccttcacgcc ccctcccctg cttcgcttcc ccggctaccg gggctgcatc 8700
gagatggaca cgctgaatga ggaggtggtc agcctctaca acttcgagag gaccttccag 8760
105/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ctggacacgg ctgtggacag gccttgtgcc cgctccaagt cgaccgggga cccgtggctc 8820
acggacggct cctacctgga cggcaccggc ttcgcccgca tcagcttcga cagtcagatc 8880
agcaccacca agcgcttcga gcaggagctg cggctcgtgt cctacagcgg ggtgctcttc 8940
ttcctgaagc agcagagcca gttcctgtgc ttggccgtgc aagaaggcag cctcgtgctg 9000
ttgtatgact ttggggctgg cctgaaaaag gccgtcccac tgcagccccc accgcccctg 9060
acctcggcca gcaaggcgat ccaggtgttc ctgctggggg gcagccgcaa gcgtgtgctg 9120
gtgcgtgtgg agcgggccac ggtgtacagc gtggagcagg acaatgatct ggagctggcc 9180
gacgcctact acctgggggg cgtgccgccc gaccagctgc ccccgagcct gcgacggctc 9240
ttccccaccg gaggctcagt ccgtggctgc gtcaaaggca tcaaggccct gggcaagtat 9300
gtggacctca agcggctgaa cacgacaggc gtgagcgccg gctgcaccgc cgacctgctg 9360
gtggggcgcg ccatgacttt ccatggccac ggcttccttc gcctggcgct ctcgaacgtg 9420
gcaccgctca ctggcaacgt ctactccggc ttcggcttcc acagcgccca ggacagtgcc 9480
ctgctctact accgggcgtc cccggatggg ctatgccagg tgtccctgca gcagggccgt 9540
gtgagcctac agctcctgag gactgaagtg aaaactcaag cgggcttcgc cgatggtgcc 9600
ccccattacg tcgccttcta cagcaatgcc acgggagtct ggctgtatgt cgatgaccag 9660
ctccagcaga tgaagcccca ccggggacca ccccccgagc tccagccgca gcctgagggg 9720
cccccgaggc tcctcctggg agg.cctgcct gagtctggca ccatttacaa cttcagtggc 9780
tgcatcagca acgtcttcgt gcagcggctc ctgggcccac agcgcgtatt tgatctgcag 9840
cagaacctgg gcagcgtcaa tgtgagcacg ggctgtgcac ccgccctgca agcccagacc 9900
ccgggcctgg ggcctagagg actgcaggcc accgcccgga aggcctcccg ccgcagccgt 9960
cagcccgccc ggcatcctgc ctgcatgctg cccccacacc tcaggaccac ccgagactcc 10020
taccagtttg ggggttccct gtccagtcac ctggagtttg tgggcatcct ggcccgacat 10080
aggaactggc ccagtctctc catgcacgtc ctcccgcgaa gctcccgagg cctcctcctc 20140
ttcactgccc gtctgaggcc cggcagcccc tccctggcgc tcttcctgag caatggccac 10200
ttcgttgcac agatggaagg cctcgggact cggctccgcg cccagagccg ccagcgctcc 10260
cggcctggcc gctggcacaa ggtctccgtg cgctgggaga agaaccggat cctgctggtg 10320
acggacgggg cccgggcctg gagccaggag gggccgcacc ggcagcacca gggggcagag 10380
cacccccagc cccacaccct ctttgtgggc ggcctcccgg ccagcagcca cagctccaaa 10440
cttccggtga ccgtcgggtt cagcggctgt gtgaagagac tgaggctgca cgggaggccc 10500
ctgggggccc ccacacggat ggcaggggtc acaccctgca tcttgggccc cctggaggcg 10560
ggcctgttct tcccaggcag cgggggagtt atcactttag acctcccagg agctacactg 10620
cctgatgtgg gcctggaact ggaggtgcgg cccctggcag tcaccggact gatcttccac 10680
ttgggccagg cccggacgcc cccctacttg cagttgcagg tgaccgagaa gcaagtcctg 10740
ctgcgggcgg atgacggagc aggggagttc tccacgtcag tgacccgccc ctcagtgctg 10800
tgtgatggcc agtggcaccg gctagcggtg atgaaaagcg ggaatgtgct ccggctggag 10860
gtggacgcgc agagcaacca caccgtgggc cccttgctgg cggctgcagc tggtgcccca 10920
gcccctctgt acctcggggg cctgcctgag cccatggccg tgcagccctg gccccccgcc 10980
tactgcggct gcatgaggag gctggcggtg aaccggtccc ccgtcgccat gactcgctct 11040
gtggaggtcc acggggcagt gggggccagt ggctgcccag ccgcctagga cacagccaac 11100
cccggcccct ggtcaggccc ctgcagctgc ctcacaccgc cccttgtgct cgcctcatag 11160
gtgtctattt ggactctaag ctctacgggt gacagatctt gtttctgaag atggtttaag 11220
ttatagcttc ttaaacgaaa gaataaaata ctgcaaaatg tttttatatt tggcccttcc 11280
acccattttt aattgtgaga gatttgtcac caatcatcac tggttcctcc ttaaaaatta 11340
aaaagtaact tctgtgtaaa aaaaaaa 11367
<210> 59
<211> 4255
<212> DNA
<213> Homo Sapiens
<220>
<221> misc feature
<223> Incyte ID No: 55022490CB1
<400> 59
gcggcacaga cccagctctg aattctgggt caaccatgga ccaactgtga cccttcggac 60
106/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
aagtcccttc gcctctctgg agctggccta taagagggaa aaggaacccc tgtggagagg 120
gtctatttat cctggcgaag atcgcctgaa gtgatcttct aacaggagtg tttccagagg 180
aggggctggg ccgggagagg tgtggacagc tggggaccgc tctgagcagc gcagccccgg 240
gcgccccaca ccaccacatg gtccggggag gaaggtggga gcaggcacac aagaaggaac 300
ctctgggggt ctgggggccc ctgccatgtg tgaggggtgc ccaggggacc cttggggaca 360
ggaacggggg cacgggtggg tggcggcact ggggagggtg tgagggtatg cccatgccct 420
cctcctcgca gaatgtctgc acaaactctg gtgcatctgt ggggaccacc tgtcactcca 480
agetggatgc agctgtggac ggcacccggt gtggggagaa taagtggtgt ctcagtgggg 540
agtgcgtacc cgtgggcttc cggcccgagg ccgtggatgg tggctggtct ggctggagcg 600
cctggtccat ctgctcacgg agctgtggca tgggcgtaca gagcgccgag cggcagtgca 660
cgcagcctac gcccaaatac aaaggcagat actgtgtggg tgagcgcaag cgcttccgcc 720
tctgcaacct gcaggcctgc cctgctggcc acccctcctt ccgccacgtc cagtgcagcc 780
actttgacgc tatgctctac aagggccagc tgcacacatg ggtgcccgtg gtcaatgacg 840
tgaacccctg cgagctgcac tgccggcccg cgaatgagta ctttgccgag aagctgcggg 900
acgccgtggt cgatggcacc ccctgctacc aggtccgagc cagccgggac ctctgcatca 960
acggcatctg taagaacgtg ggctgtgact tcgagattga ctccggtgct atggaggacc 1020
gctgtggtgt gtgccacggc aacggctcca cctgccacac cgtgagcggg accttcgagg 1080
aggccgaggg cctggggtat gtggatgtgg ggctgatccc agccggcgca cgcgagatcc 1140
gcatccaaga ggttgccgag gctgccaact tcctggcact gcggagtgag gacccggaga 1200
agtacttcct caatggtggc tggaccatcc agtggaacgg ggactaccag gtggcaggga 1260
ccaccttcac atacgcacgc aggggcaact gggagaacct cacgtccccg ggtcccacca 1320
aggagcctgt ctggatccag ctgctgttcc aggagagcaa ccctggggtg cactacgagt 1380
acaccatcca cagggaggca ggtggccacg acgaggtccc gccgcccgtg ttctcctggc 1440
attatgggcc ctggaccaag tgcacagtca cctgcggcag aggtgtgcag aggcagaatg 1500
tgtactgctt ggagcggcag gcagggcccg tggacgagga gcactgtgac cccctgggcc 1560
ggcctgatga ccaacagagg aagtgcagcg agcagccctg ccctgccagg tggtgggcag 1620
gtgagtggca gctgtgctcc agctcctgcg ggcctggggg cctctcccgc cgggccgtgc 1680
tctgcatccg cagcgtgggg ctggatgagc agagcgccct ggagccaccc gcctgtgaac 1740
accttccccg gccccctact gaaacccctt gcaaccgcca tgtaccctgt ccggccacct 1800
gggctgtggg gaactggtct cagtgctcag tgacatgtgg ggagggcact cagcgccgaa 1860
atgtcctctg caccaatgac accggtgtcc cctgtgacga ggcccagcag ccagccagcg 1920
aagtcacctg ctctctgcca ctctgtcggt ggcccctggg cacactgggc cctgaaggct 1980
caggcagcgg ctcctccagc cacgagctct tcaacgaggc tgacttcatc ccgcaccacc 2040
tggccccacg cccttcaccc gcctcatcac ccaagccagg caccatgggc aacgccattg 2100
aggaggaggc tccagagctg gacctgccgg ggcccgtgtt tgtggacgac ttctactacg 2160
actacaattt catcaatttc cacgaggatc tgtcctacgg gccctctgag gagcccgatc 2220
tagacctggc ggggacaggg gaccggacac ccccaccaca cagccgtcct gctgcgccct 2280e
ccacgggtag ccctgtgcct gccacagagc ctcctgcagc caaggaggag ggggtactgg 2340
gaccttggtc cccgagccct tggcctagcc aggccggccg ctccccaccc ccaccctcag 2400
agcagacccc tgggaaccct ttgatcaatt tcctgcctga ggaagacacc cccatagggg 2460
ccccagatct tgggctcccc agcctgtcct ggcccagggt ttccactgat ggcctgcaga 2520
cacctgccac ccctgagagc caaaatgatt tcccagttgg caaggacagc cagagccagc 2580
tgccccctcc atggcgggac aggaccaatg aggttttcaa ggatgatgag gaacccaagg 2640
gccgcggagc accccacctg cccccgagac ccagctccac gctgccccct ttgtcccctg 2700
ttggcagcac ccactcctct cctagtcctg acgtggcgga gctgtggaca ggaggcacag 2760
tggcctggga gccagctctg gagggtggcc tggggcctgt ggacagtgaa ctgtggccca 2820
ctgttggggt ggcttctctc cttcctcctc ccatagcccc tctgccagag atgaaggtca 2880
gggacagttc cctggagccg gggactccct ccttcccaac cccaggacca ggctcatggg 2940
acctgcagac tgtggcagtg tgggggacct tcctccccac aaccctgact ggcctcgggc 3000
acatgcctga gcctgccctg aacccaggac ccaagggtca gcctgagtcc ctcagccctg 3060
aggtgcccct gagctctagg ctgctgtcca caccagcttg ggacagcccc gccaacagcc 3120
acagagtccc tgagacccag ccgctggctc ccagcctggc tgaagcgggg ccccccgcgg 3180
acccgttggt tgtcaggaac gccagctggc aagcgggaaa ctggagcgag tgctctacca 3240
cctgtggcct gggtgcggtc tggaggccgg tgcgctgtag ctccggccgg gatgaggact 3300
gcgcccccgc tggccggccc cagcctgccc gccgctgcca cctgcggccc tgtgccacct 3360
ggcactcagg caactggagt aagtgctccc gcagctgcgg cggaggttcc tcagtgcggg 3420
107/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
acgtgcagtg tgtggacaca cgggacctcc ggccactgcg gcccttccat tgtcagcccg 3480
ggcctgccaa gccgcctgcg caccggccct gcggggccca gccctgcctc agctggtaca 3540
catcttcctg gagggagtgc tccgaggcct gtggcggtgg tgagcagcag cgtctagtga 3600
cctgcccgga gccaggcctc tgcgaggagg cgctgagacc caacaccacc cggccctgca 3660
acacccaccc ctgcacgcag tgggtggtgg ggccctgggg ccagtgctca gccccctgtg 3720
gtggtggtgt ccagcggcgc ctggtcaagt gtgtcaacac ccagacaggg ctgcccgagg 3780
aagacagtga ccagtgtggc cacgaggcct ggcctgagag ctcccggccg tgtggcaccg 3840
aggattgtga gcccgtcgag cctccccgct gtgagcggga ccgcctgtcc ttcgggttct 3900
gcgagacgct gcgcctactg ggccgctgcc agctgcccac catccgcacc cagtgctgcc 3960
gctcgtgctc tccgcccagc cacggcgccc cctcccgagg ccatcagcgg gttgcccgcc 4020
gctgactgtg ccaggatgca cagaccgacc gacagacctc agtgcccacc acgggctgtg 4080
gcggagctcc cgccccctgc gccctaatgg tgctaacccc ctctcactac ccagcagcag 4140
gctggggacc tcctccccct caaaaaaggt atttttttat tctaacagtt tgtgtaacat 4200
ttattatgat tttacataaa tgagcatcta ccattccaaa aaaaaaaaaa aaaaa 4255
<210> 60
<211> 3438
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 6755002CB1
<400> 60
tgtgcgccgg gagggccggc gccctcttcc gaatgtcctg cggccccagc ctctcctcac 60
gctcgcgcag tctccgccgc agtctcagct gcagctgcag gactgagccg tgcacccgga 120
ggagaccccc ggaggaggcg acaaacttcg cagtgccgcg acccaacccc agccctgggt 180
agcctgcagc atggcccagc tgttcctgcc cctgctggca gccctggtcc tggcccaggc 240
tcctgcagct ttagcagatg ttctggaagg agacagctca gaggaccgcg cttttcgcgt 300
gcgcatcgcg ggcgacgcgc cactgcaggg cgtgctcggc ggcgccctca ccatcccttg 360
ccacgtccac tacctgcggc caccgccgag ccgccgggct gtgctgggct ctccgcgggt 420
caagtggact ttcctgtccc ggggccggga ggcagaggtg ctggtggcgc ggggagtgcg 480
cgtcaaggtg aacgaggcct accggttccg cgtggcactg cctgcgtacc cagcgtcgct 540
caccgacgtc tccctggcgc tgagcgagct.gcgccccaac gactcaggta tctatcgctg 600
tgaggtccag cacggcatcg atgacagcag cgacgctgtg gaggtcaagg tcaaaggggt 660
cgtctttctc taccgagagg gctctgcccg ctatgctttc tccttttctg gggcccagga 720
ggcctgtgcc cgcattggag cccacatcgc caccccggag cagctctatg ccgcctacct 780
tgggggctat gagcaatgtg atgctggctg gctgtcggat cagaccgtga ggtatcccat 840
ccagacccca cgagaggcct gttacggaga catggatggc ttccccgggg tccggaacta 900
tggtgtggtg gacccggatg acctctatga tgtgtactgt tatgctgaag acctaaatgg 960
agaactgttc ctgggtgacc ctccagagaa gctgacattg gaggaagcac gggcgtactg 1020
ccaggagcgg ggtgcagaga ttgccaccac gggccaactg tatgcagcct gggatggtgg 1080
cctggaccac tgcagcccag ggtggctagc tgatggcagt gtgcgctacc ccatcgtcac 1140
acccagccag cgctgtggtg ggggcttgcc tggtgtcaag actctcttcc tcttccccaa 1200
ccagactggc ttccccaata agcacagccg cttcaacgtc tactgcttcc gagactcggc 1260
ccagccttct gccatccctg aggcctccaa cccagcctcc aacccagcct ctgatggact 1320
agaggctatc gtcacagtga cagagaccct ggaggaactg cagctgcctc aggaagccac 1380
agagagtgaa tcccgtgggg ccatctactc catccccatc atggaggacg gaggaggtgg 1440
aagctccact ccagaagacc cagcagaggc ccctaggacg ctcctagaat ttgaaacaca 1500
atccatggta ccgcccacgg ggttctcaga agaggaaggt aaggcattgg aggaagaaga 1560
gaaatatgaa gatgaagaag agaaagagga ggaagaagaa gaggaggagg tggaggatga 1620
ggctctgtgg gcatggccca gcgagctcag cagcccgggc cctgaggcct ctctccccac 1680
tgagccagca gcccaggaga agtcactctc ccaggcgcca gcaagggcag tcctgcagcc 1740
tggtgcatca ccacttcctg atggagagtc agaagcttcc aggcctccaa gggtccatgg 1800
accacctact gagactctgc ccactcccag ggagaggaac ctagcatccc catcaccttc 1860
108/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
cactctggtt gaggcaagag aggtggggga ggcaactggt ggtcctgagc tatctggggt 1920
ccctcgagga gagagcgagg agacaggaag ctccgagggt gccccttccc tgcttccagc 1980
cacacgggcc cctgagggta ccagggagct ggaggccccc tctgaagata attctggaag 2040
aactgcccca gcagggacct cagtgcaggc ccagccagtg ctgcccactg acagcgccag 2100
ccgaggtgga gtggccgtgg tccccgcatc aggtgactgt gtccccagcc cctgccacaa 2160
tggtgggaca tgcttggagg aggaggaagg ggtccgctgc ctatgtctgc ctggctatgg 2220
gggggacctg tgcgatgttg gcctccgctt ctgcaacccc ggctgggacg ccttccaggg.2280
cgcctgctac aagcactttt ccacacgaag gagctgggag gaggcagaga cccagtgccg 2340
gatgtacggc gcgcatctgg ccagcatcag cacacccgag gaacaggact tcatcaacaa 2400
ccggtaccgg gagtaccagt ggatcggact caacgacagg accatcgaag gcgacttctt 2460
gtggtcggat ggcgtccccc tgctctatga gaactggaac cctgggcagc ctgacagcta 2520
cttcctgtct ggagagaact gcgtggtcat ggtgtggcat gatcagggac aatggagtga 2580
cgtgccctgc aactaccacc tgtcctacac ctgcaagatg gggctggtgt cctgtgggcc 2640
gccaccggag ctgcccctgg ctcaagtgtt cggccgccca cggctgcgct atgaggtgga 2700
cactgtgctt cgctaccggt gccgggaagg actggcccag cgcaatctgc cgctgatccg 2760
atgccaagag aacggtcgtt gggaggcccc ccagatctcc tgtgtgccca gaagacctgc 2820
ccgagctctg cacccagagg aggacccaga aggacgtcag gggaggctac tgggacgctg 2880
gaaggcgctg ttgatccccc cttccagccc catgccaggt ccctaggggg caaggccttg 2940
aacactgccg gccacagcac tgccctgtca cccaaatttt ccctcacacc ctgcgctccc 3000
gccaccacag gaagtgacaa catgacgagg ggtggtgctg gagtccaggt gacagttcct 3060
gaaggggctt ctgggaaata cctaggaggc tccagcccag cccaggccct ctccccctac 3120
cctgggcacc agatcttcca tcagggccgg agtaaatccc taagtgcctc aactgccctc 3180
tccctggcag ccatcttgtc ccctctattc ctctagggag cactgtgccc actctttctg 3240
ggttttccaa gggaatgggc ttgcaggatg gagtgtctgt aaaatcaaca ggaaataaaa 3300
ctgtgtatga gcccagggta gggggagagg gcctgggctg ggctggagcc tcctaggtat 3360
ttcccagaag ccccttcagg aactgtcacc tggactccag caccacccct cgtcatgttg 3420
tcacttcctg tggtggcg 3438
<210> 61
<221> 1683
<212> DNA
<213> Homo sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7350907CB1
<400> 61
ggcgtgggga cacgagccag gcgccgccgc cggagccagc ggagccgggg ccagagccgg 60
agcgcgtccg cgtccacgca gccgccggcc ggccagcacc cagggccctg catgccaggt 120
cgttggaggt ggcagcgaga catgcacccg gcccggaagc tcctcagcct cctcttcctc 180
atcctgatgg gcactgaact cactcaagtg ctgcccacca accctgagga gagctggcag 240
gtgtacagct ctgcccagga cagcgagggc aggtgtatct gcacagtggt cgccccacag 300
cagaccatgt gttcacggga tgcccgcaca aaacagctga ggcagctact.ggagaaggtg 360
cagaacatgt ctcaatccat agaggtcttg gacaggcgga cccagagaga cttgcagtac 420
gtggagaaga tggagaacca aatgaaagga ctggagtcca agttcaaaca ggtggaggag 480
agtcataagc aacacctggc caggcagttt aaggcgataa aagcgaaaat ggatgaactt 540
aggcctttga tacctgtgtt ggaagagtac aaggccgatg ccaaattggt attgcagttt 600
aaagaggagg tccagaatct gacgtcagtg cttaacgagc tgcaagagga aattggcgcc 660
tatgactacg atgaacttca gagcagagtg tccaatcttg aagaaaggct ccgtgcatgc 720
atgcaaaaac tagcttgcgg gaagttgacg ggcatcagtg accccgtgac tgtcaagacc 7'80
tccggctcga ggttcggatc ctggatgaca gaccctctcg cccctgaagg cgataaccgg 840
gtgtggtaca tggacggcta tcacaacaac cgcttcgtac gtgagtacaa gtccatggtt 900
gacttcatga acacggacaa tttcacctcc caccgtctcc cccacccctg gtcgggcacg 960
gggcaggtgg tctacaacgg ttctatctac ttcaacaagt tccagagcca catcatcatc 1020
aggtttgacc tgaagacaga gaccatcctc aagacccgca gcctggacta tgccggttac 1080
109/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
aacaacatgt accactacgc ctggggtggc cactcggaca tcgacctcat ggtggacgag 1140
agcgggctgt gggccgtgta cgccaccaac cagaacgctg gcaacatcgt ggtcagtagg 1200
ctggaccccg tgtccctgca gaccctgcag acctggaaca cgagctaccc caagcgcagc 1260
gccggggagg ccttcatcat ctgcggcacg ctgtacgtca ccaacggcta ctcagggggt 1320
accaaggtcc actatgcata ccagaccaat gcctccacct atgaatacat cgacatccca 1380
ttccagaaca aatactccca catctccatg ctggactaca accccaagga ccgggccctg 1440
tatgcctgga acaacggcca ccagatcctc tacaacgtga ccctcttcca cgtcatccgc 1500
tccgacgagt tgtagctccc tcctcctgga agccaagggc ccacgtcctc accacaaagg 1560
gactcctgtg aaactgctgc caaaaagata ccaataacac taacaatacc gatcttgaaa 1620
aatcatcagc agtgcggatt ctgacatcga gggatggcat tacctccgtg tttctccctt 1680
tcg 1683
<210> 62
<211> 6886
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 7474411CB1
<400> 62
cggggcacag cgggagcccg tgcaggcggg cgcggggcgg ctgggcggcg gtggcggccg 60
tccatgcggc ggcgctcggg gctgcccggc gccgggaacc acgcgggggc gaggcgaggc 120
gaggcggccg ccggtcgctc cgggacgcgg accgccagga cttgaacgca actcccaatt 180
gcagaaaatt ggcaacgtct ctgaagagcc cttgcttttg cctggacccc cagcatcatg 240
gtttcccatt tcatggggtc tctcagtgtc ctgtgtttcc ttctgctgct tggattccag 300
ttcgtctgcc cacagccctc cactcaacac aggaaggtcc cgcagcggat ggcggcggag 360
ggcgcccccg aggacgacgg cggcggcggc gccccgggag tgtggggcgc ctggggcccc 420
tggtcggcct gctcgcgtag ctgcagcggc ggcgtgatgg agcagacgcg gccctgcctg 480
ccccgctcct accgcctgcg cggcggccag cggcctggcg cccctgcgcg cgccttcgcg 540
gaccacgtgg tgtcggcggt gcgcacgtcg gtgccactgc accggagccg cgacgagacg 600
ccagcgctgg ccggtacgga cgccagccgc cagggcccca cggtgctgcg aggcagccgg 660
cacccacagc cccagggcct cgaagtcact ggggacagaa ggagcaggac ccgtggtacc 720
attggccctg gcaagtatgg ctatggtaag gccccatata tcttaccact gcagacagac 780
actgcacaca cgccacagag gctccggaga cagaagctct catcccgcca ttccaggtcc 840
cagggagcat cttctgctag gcatggctac agttcaccag cccaccaggt cccccaacat 900
gggcctttgt accaaagtga cagtggccct cgctctggac tgcaggctgc ggaggccccc 960
atctaccagc tacctttgac ccatgatcaa ggctaccctg cagcttcaag tctctttcac 1020
agcccagaaa caagcaacaa ccacggtgtg gggacccatg gggcaactca gagcttctct 1080
cagcctgccc gatctacagc aatctcatgc atcggggcct atcggcagta caagctgtgc 1140
aacaccaacg tatgtccaga aagcagtaga agtatccggg aggtacagtg tgcatcctac 1200
aacaacaagc cattcatggg ccggttttat gagtgggaac catttgcaga agtaaaaggc 1260
aatcgcaaat gtgagttgaa ctgccaggca atgggctacc gcttctatgt acggcaagct 1320
gagaaagtca tcgatggcac cccctgtgac cagaacggca cggccatctg tgtgtctggg 1380
cagtgcaaga gcattggctg tgatgactac ttaggctccg acaaagtcgt ggacaaatgt 1440
ggggtgtgtg gaggagacaa cacgggctgt caggttgtgt cgggcgtgtt taagcatgcc 1500
ctcaccagcc tgggctacca ccgcgtcgtg gagattcccg agggagccac gaaaatcaac 1560
atcacggaga tgtacaagag caacaactat ttggccctga gaagtcgttc tggacgctcc 1620
atcatcaatg ggaactgggc aattgatcga ccaggaaaat acgagggcgg agggaccatg 1680
ttcacctaca agcgtccaaa tgagatttcg agcactgccg gagagtcctt tttggcggaa 1740
ggtcccacca acgagatctt ggatgtctac atgatacacc agcagccaaa cccaggcgtg 1800
cactacgagt acgtgatcat ggggaccaac gccatcagcc cccaggtgcc accccacagg 1860
agaccagggg aacccttcaa tggccagatg gtgacagaag gcaggagcca ggaggaggga 1920
gaacagaaag ggaggaacga ggagaaggaa gacttgcgtg gggaggcccc tgagatgttc 1980
acctcagaat cggcacagac cttcccagtc aggcatccag acagattttc tccccatcga 2040
110/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
ccggacaact tggtgccacc agcaccgcag cccccacggc gcagccggga tcacaactgg 2100
aagcagcttg ggacaacaga atgttccacg acctgtggga aaggatcgca gtaccctatt 2160
ttccgctgtg tgcacagaag cactcatgaa gaggctcctg agagttactg tgactccagc 2220
atgaagccga cccccgagga ggagccctgc aacatcttcc cttgcccagc cttctgggac 2280
atcggggagt ggtctgagtg cagcaagacc tgtggcctgg gcatgcagca ccgccaggtt 2340
ctgtgccgcc aggtgtacgc caaccgcagc ctgacggtgc agccctaccg ctgccagcac 2400
ctggagaaac ctgagaccac cagcacctgc caactcaaga tctgcagcga gtggcagatc 2460
cggaccgact ggacctcgtg ctcggtgccc tgtggcgtgg gacagaggac ccgtgatgtg 2520
aagtgtgtga gcaacattgg ggatgtggtt gacgatgagg aatgcaacat gaagctccgg 2580
ccgaatgaca ttgagaactg cgacatggga ccctgtgcca agagctggtt cctcaccgag 2640
tggagcgaaa ggtgctcagc ggagtgtggg gccggagtgc ggacacgctc ggtggtgtgc 2700
atgaccaacc atgtcagcag cctgcccctg gagggctgtg ggaacaaccg gccggcagag 2760
gccaccccat gtgacaacgg accctgcacg ggcaaggtgg agtggtttgc cgggagctgg 2820
agtcagtgtt ccatcgagtg tgggagcggg acgcaacaga gggaggtgat ttgtgttaga 2880
aagaatgcag acacctttga agtgttggac ccctctgaat gttctttcct ggagaaaccc 2940
cccagccagc aatcctgcca cctcaagcct tgcggagcca aatggtttag caccgaatgg 3000
agcatgtgtt ccaagagctg ccagggtggc tttcgggtcc gggaagtgcg gtgtctgtct 3060
gatgacatga ctctaagtaa cctctgtgac cctcagttga aaccagaaga gagagaatct 3120
tgtaaccctc aggactgtgt ccctgaagtt gatgaaaact gcaaggacaa gtactacaac 3180
tgcaacgtgg tggtccaggc aagactctgt gtctacaact actacaagac cgcctgctgt 3240
gcctcctgca cccgtgtggc caacaggcag acgggcttcc tggggagcag ataacactcc 3300
tgcaccccca tcagtagggc agcatcactg ccttcccggg ggcttcagca gtgcgcctgg 3360
ctggctgctg ctccaccacg ggccccctgg cccaggcgct gccaaccaac ttagtcacca 3420
cccctgcctc cggtgaatgc accccgtggt acccaggggc tttttacaca agatgtttga 3480
aagccacagt cagtccttta agcatcacca tgtactgatg atcccctcct tggacctggc 3540
atctgctaat ggtgcccttt gaaagtcaag cagtgggaag tacatggagc tctcagccct 3600
gctcccatct ggcaccttca agtcagcaga tgggccactg actgagcact gccccgtccc 3660
tggtgctact ggtctttcta aacttagcac cctggagagt ccaaggaggc agcgccccca 3720
acccagcgcc ccactaagcc ttgctgacac gcgtgcatcc ctctgtgacc tcagcccaga 3780
tgtgcctgtt ttcattctca aagacattag actgttttcc tgccctatga cacagatagc 3840
tcacatgaat attgtgcttt atttagcagg tgtactcaca gatactagct ccttagcagc 3900
tcacaacatc ccagaatggg aggcaggggg tgactcatta tccccatttt actgacaggg 3960
aaactgaggc tcaacttaag taattgacct gccaggtata ttcaeccatc cagtggaaga 4020
gctgagtccc cgccccagtc atctaccagt atccagcctg gggcctgtac ttagatgtga 4080
aaggtgctgc ttcatttctg accaagagac tgagaagttt cccagaatgc aaacaaagcc 4140
caggcccctg aaatctttcc ggtcaagcct ttatcccagc actcagttgt tttggatgtc 4200
tgttcctact tgcccttacc cccaaagtta cagatcctag ttacaggact ctgccagctt 4260
tgttaaactg tccgtgagac aagaaagcca ttggggaaac caggtgattg cctgaaattc 4320
ttactccgtt ccaagtgctg ttcctcccag gaaatcaaag gccagggtcc ttatggccgt 4380
ggagccttcc cgaccacaga gccaacttgt gaagcacaca gctctgcagc ctgggctctg 4440
ccctgcctca gccgcctccc ccacgctctt caccacgttc ctggagagtc cggccaacct 4500
gtcccagcca aaacactgct gtattagaaa aagtctcttt ctggtctttc tggttttgtt 4560
tatgaatttc cctctgtggc cacaaattcc tcccctcccc catgactcac agtccatatg 4620
gcccaccccc agacttgagc accaagctct gcattaatgc agttggcctg cgacaaggag 4680
ctgtggaccc ttccccatct cttccaattc actttcccca actatccagt tccagaggcc 4740
gcaggcctgg aaggatgcag tgcatattga aaggtggacc ctctgaaaac agttaagagg 4800
aatatatgta tgttttgccc attaagaaaa aatggcaagc taaacaaatg ttaaacttac 4860
agaaaatttg tcttatggtc ctgagcatat ttccctttta gagcaagcct ggattcttag 4920
caaagtgttt cccccatttg ctcttttagc tgacaaatct gccactgtga tgatggtttg 4980
cagcttttgg aagcagtatg gcaacctggc ctgacatgct ctttaggctt ccactaacct 5040
ggggctttca gaaattctat ttggcctttc tgtgggtagc tttccagctt ctcttctagg 5100
gagccccagg catcatttcc caaaagcatc cccatctcct gattctcttg gaactcctac 5160
agataagcat cctggcagag gcccaggctc ccaaaccgac aaagtgaaaa gagaccagag 5220
aggccaagca tattgactgg tgctgttcag ggcctgctct tttccactca ccacttgttt 5280
tgctgcttgt cacgaggaga gttgttcctg tatgtggctg ctctcagatc tttccaagca 5340
agccagtcat ttgaagaggt tttcttttca tgctggaggg caggctaaga tcaatgagtg 5400
111/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gaagagagaa aggctgtttt agctcaagtt aaaggaacac cttctagcca tcaaagccgc 5460
ccaacagagg caagggccac cacacatgag agagcgctct gtccttaaag ggaattctct 5520
gttgagtggg aggtgaacac cctggttctt ccaactcagg aattctcgtg gctgggctgg 5580
gtcagtgatg gctttgtctc tttatgtcta aagtgcccta tggctgctga aggttaccta 5640
accattcttt aaaaggagaa tgaccctcca tgggaatggc cagcctgcca actgtgcaat 5700
tgaagaagac ccgatggatc aaccccatgt ctcccttggg gagaaagtgc ataaaccagg 5760
ggtctctttt tttttttttt caacaaacca ttgagctgtt cttggagttc atctctggag 5820
aggttataca ttattagaag tttgattatt attatagttt gatcaattta tttgtcttag 5880
agatccaatt tttactaatt ccctagtttt ttatttcagc atctgaatgt ctttctccct 5940
agcacagtgc atacaatcag ggccttgggt atttccagtg ataactttcc ttggagagga 6000
tctaagaaaa gcccagattt cggtagccat ctccctccaa atatgtctct ttctgctttc 6060
ttagtgccca ttatttcccc ttctcctttc ttctgtcact gccatctcct tcttggtctt 6120
cccattgttc tttaactggc tgtaatgtgg aattgatatt tacattttga tacggttttt 6180
ttcttggcct gtgtacggga ttgcctcatt tcctgctctg aattttaaaa ttagatatta 6240
aagctgtcat atggtttcct cacaaaagtc aacaaagtcc aaacaaaaat agtttgccgt 6300
tttactttca tccattgaaa aaggaaattg tgcctcttgc agcctaggca aaggacattt 6360
agtactatcg attctttcca ccctcacgat gacttgcggt tctctctgta gaaaagggat 6420
ggcctaagaa atacaactaa aaaaacaaac aaaaacacca aaagaaaaaa aaaagccatt 6480
taaagccagc cactagaggg agtcagttca gttccgtaaa ggtatgctca gtgcccgctg 6540
cctgcaagct gttggggacc ccagggaggg caaggcagcc tgtccccgcc cccagggaac 6600
tagaacatga caagaattct ccgcactgtg cctacctgtc cctttaactt acctctctgg 6660
cccagagttc ttggagggta aaccttctat ttctcttatg tactcatcta cttattctca 6720
aagtatttag cattcaacac tcttttggct ttaaaaagaa tgggccttac aaagggacag 6780
aacacgagaa gacacgagct aggtgtattt catcaagtat gtggcacgag aaatccagat 6840
attaccagga cctgtctaac caatgtgggg ttactttcat cggatg 6886
<210> 63
<211> 4457
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 4755911CB1
<400> 63
atggggaagg agcaggagct ggtgcaggcg gtgaaggcgg aggacgtagg gaccg'cgcag 60
aggctgctgc agaggccgcg gcccgggaag gccacgcgta gcctccctgg gggccgccgg 120
agatggatgg atgggcgtgt ggaccagccg cgtgtgcggc tgcgcacgta tagccgtgtc 180
agtgtgtcag ggcacctgtg cgggcacgga cagggctctg cagagctcct gggttccacc 240
aagaagatca atgtcaactt ccaggacccg gatggggttg ggtttggggt caagggtcag 300
ctcccagcat cccctcgccc cccaggcatg cggccgctgc actatgcggc ctggcagggc 360
cggaaggagc ccatgaagct ggtgctgaag gcgggctcgg ccgtgaacat cccgtctgat 420
gagggccaca tccccctgca cctggcggcc cagcatggtc actatgatgt gtctgagatg 480
ctgctacagc accagtctaa cccgtgcatg gtggacaact cggggaagac gcccctggac 540
ctggcctgcg agttcggccg cgttggggtg gtccagctgc tcctcagcag caatatgtgt 600
gcggcgctgc tggagccccg gccgggagac gccaccgacc ccaacggcac cagccctttg 660
cacctcgcag ctaaaaacgg ccacatcgac atcatcaggc tcctcctcca agccggcatc 720
gacattaacc gccagaccaa gtccggcacg gccctgcacg aggctgcgct ctgcggaaag 780
acagaggtgg tgcggctgct gctggatagc gggatcaatg cccacgtgag gaacacctac 840
agccagacag ccctggacat cgtgcaccag ttcaccacgt cccaggccag cagggagatc 900
aagcagctgt tgcgagaggc ctcagcggcc ctgcaggtcc gggcgaccaa ggattattgc 960
aacaattacg acctgaccag cctcaacgtg aaggcagggg acatcatcac agtcctcgag 1020
cagcatccgg atggccggtg gaagggctgc atccatgaca accggacggg caatgaccgg 1080
gtgggctact tcccgtcctc cctgggcgag gccattgtca agcgagcagg ttcccgagca 1140
ggcactgaac caagcctgcc ccagggaagc agctcatcgg gaccctctgc acccccagag 1200
112/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gagatctggg tgctgaggaa gccttttgca ggtggggacc gaagcggcag cattagcggc 1260
atggctggcg gccggggcag cgggggtcac gccctacacg cgggctctga aggcgtcaag 1320
ctcctggcaa cggtgctttc ccagaagtcc gtctctgagt ccggcccggg ggacagcccc 1380
gccaagcctc cggaaggctc tgcaggtgtg gcccggtccc agcctccagt ggcccacgcc 1440
gggcaggtct atggggagca gccgcccaag aagctggagc cagcatcgga gggcaagagc 1500
tctgaggccg tgagccagtg gctcaccgcg ttccagctgc agctctacgc ccccaacttc 1560
atcagcgccg gctacgacct gcccaccatc agccgcatga ctcccgagga cctcacggcc 1620
attggtgtca ccaagccggg ccaccggaag aagatcgcgg cagagatcag cggcctaagc 1680
atccctgact ggctgcctga gcacaaaccc gctaacctgg ccgtgtggct gtccatgatc 1740
ggcctggccc agtactacaa ggtgttggtg gacaatggct acgagaacat tgatttcatc 2800
accgacatca cctgggagga cctgcaggag atcggcatca ccaagctggg gcaccagaag 1860
aagctgatgc tcgctgtgag gaagctggca gagctgcaga aggctgaata cgccaagtat 1920
gaggggggcc ccctgcgccg gaaggcgccc cagtctcttg aagtgatggc catcgagtcg 1980
ccgcccccgc ctgagcccac accggccgac tgccagtccc ctaaaatgac caccttccag 2040
gacagcgagc tcagtgacga gctgcaggct gccatgactg gcccggctga ggtggggccc 2100
accactgaga agccctccag ccacctgcca cccaccccga gggccaccac gcggcaggac 2160
tccagcctgg gtggtcgggc acggcacatg agcagctcgc aggagctgct gggagatggg 2220
ccccctgggc ccagcagccc catgtctcga agccaggagt acctcctgga tgagggcccc 2280
gcccccggca ccccgcccag ggaggcccgg cccggccgcc acggccacag catcaagagg 2340
gccagcgtgc cccccgtgcc tggcaagcca cggcaggtcc tcccaccagg cactagccac 2400
ttcacgcccc cccagacgcc caccaaaacc cgaccaggct ctccccaggc ccttggggga 2460
cctcatggtc cagccccagc tacggccaag gtgaagccca ccccgcagct gctgccgccg 2520
acagagcgcc ccatgtcacc ccgctccctg cctcagtcac cgacgcaccg cggctttgcc 2580
tacgtgctgc cccagcccgt ggagggcgag gtggggccgg ctgccccggg gcctgcgccc 2640
ccacccgtgc cgacggctgt gcccacactg tgcctgcccc ctgaggccga cgcggagccg 2700
gggcggccca agaagcgggc ccacagcctg aatcgctatg cggcgtccga cagcgagccg 2760
gagcgggacg agctgctggt gcctgcggct gccggcccct atgccacggt ccagcggcgc 2820
gtgggccgca gccactcagt gagggcgccc gcaggtgccg acaagaacgt caaccgcagc 2880
cagtcctttg ccgtgcggcc ccgaaagaag gggcccccgc cgcccccacc caagcgctcc 2940
agctcggccc tggctagtgc caacctggcg gatgagccgg tgcctgacgc cgagcctgag 3000
gatggcctgc tgggggtccg ggcacagtgc cggcgggcca gtgacctggc cggcagcgtg 3060
gacacgggta gtgccggcag tgtgaagagc atcgcggcca tgctggagct gtcctccatt 3120
gggggtgggg gccgggctgc ccgcaggcct cctgagggec accccactcc ccgccctgcc 3180
agcccagagc cgggccgggt ggccaccgtg ctggcctcag tgaaacacaa agaggccatc 3240
gggcctggcg gggaggtggt gaaccggcgc cgcacgctca gcgggccagt caccggactt 3300
ctggccactg cccgccgggg gcctggggag tcggcagacc caggcccctt tgtggaggat 3360
ggcactggcc ggcagcggcc tcggggtccc tccaagggcg aggcgggtgt cgaaggcccg 3420
cccttggcca aggtggaagc cagcgccaca ctcaagaggc gcatccgggc caagcagaac 3480
cagcaggaga acgtcaagtt catcctgacc gagtctgaca cggtcaagcg caggcccaag 3540
gccaaggagc gggaggccgg gcctgagcca ccaccgccac tgtccgtgta ccataatggc 3600
actggcaccg tgcgccgccg accggcctcg gagcaggctg ggcctccgga gctgcctcca 3660
ccgcccccgc ctgccgaacc cccgcccacc gacctggcgc acctaccccc attgcccccg 3720
cccgagggcg aagcccggaa gccggccaag ccgcctgtct ctcccaagcc cgtcctgacg 3780
cagcctgtgc ccaagctcca gggctcgccc acacccacct ccaagaaggt gccgctgcca 3840
ggccctggca gcccagaggt gaagcgcgcc cacggcacgc caccgcccgt gtctcccaag 3900
ccgccgccgc cgcccacagc gcccaagccc gtcaaggcgg tcgcggggct gccttcgggc 3960
agcgccggcc cttcacccgc accctcgccc gcgcgacagc cgcccgccgc cctcgccaag 4020
ccgcccggta cgccgccctc gctgggcgcc agccccgcca agcccccgtc ccccggcgcg 4080
cccgcgctgc acgtgcccgc caagcccccg cgagccgccg ccgccgccgc cgccgccgcc 4140
gccgcgcccc ccgccccgcc cgaaggcgcc tcgccagggg acagcgcccg gcagaaactg 4200
gaggagacaa gcgcgtgcct ggccgcggcg ctgcaggcgg tggaggagaa gatccggcag 4260
gaggacgcgc agggcccgcg cgactcggcg gcggaaaaga gcactggcag catcctggac 4320
gacatcggca gcatgttcga cgacctggcc gaccagctgg atgccatgct ggagtgaacg 4380
ccgcctggcc gggccctccc gcgccgcccg ggccctcccc gcacactgac ctatacctca 4440
ggatgggcgc gtctggg 4457
113/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<210> 64
<211> 1943
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 379766CB1
<400> 64
ggcggcggcg actgcggcgc cgcgggctgg aggccggcgt cggggaaggt cctggtgccg 60
gattccgcac gaggtgttga cgggcggctt ctgccaactt ctccccagcg cgcgccgagc 120
ccgcgcggcc ccggggctgc acgtcccaga tacttctgcg gcgcaaggct acaactgaga 180
cccggaggag actagacccc atggcttcct ggacgagccc ctggtgggtg ctgataggga 240
tggtcttcat gcactctccc ctcccgcaga ccacagctga gaaatctcct ggagcctatt 300
tccttcccga gtttgcactt tctcctcagg gaagttttct ggaagacaca acaggggagc 360
agttcctcac ttatcgctat gatgaccaga cctcaagaaa cactcgttca gatgaagaca 420
aagatggcaa ctgggatgct tggggcgact ggagtgactg ctcccggacc tgtgggggag 480
gagcatcata ttctctgcgg agatgtttga ctggaaggaa ttgtgaaggg cagaacattc 540
ggtacaagac atgcagcaat catgactgcc ctccagatgc agaagatttc agagcccagc 600
agtgctcagc ctacaatgat gtccagtatc aggggcgtta ctatgaatgg cttccacgat 660
ataatgatcc tgctgccccg tgtgcactca agtgtcatgc acaaggacaa aacttggtgg 720
tggagctggc acctaaggta ctggatggaa ctcgttgcaa cacggactcc ttggacatgt 780
gtatcagtgg catctgtcag gcagtgggct gcgatcggca actgggaagc aatgccaagg 840
aggacaactg tggagtctgt gccggcgatg gctccacctg caggcttgta cggggacaat 900
caaagtcaca cgtttctcct gaaaaaagag aagaaaatgt aattgctgtt cctttgggaa 960
gtcgaagtgt gagaattaca gtgaaaggac ctgcttatcc tgtggcctgg gctttagcca 1020
tctcttccaa taccaattgc ctagtgttat tatgtaaagc taatttggcc agctctggtc 1080
cttattttgc actcattcca gtaaacccaa ccactatggc acttaatact gccattgtca 1140
gtcagtctgc agtattgatt gactgccttt agagctctct tttgtgtgcc ttgtccactc 1200
ttcagtcact gagagagaga ccaaagaaca gagaccaaca ccctgtactt ggcatggcca 1260
ttagtcactg gagttagatg aatcacactg tatctaagag agaagactca gggagaaggg 1320
cttagcacaa cacagaaaag ctttaaacac tcttaccttt gactggaatt acacacacac 1380
acacacacac acacacatac acacacacac atacacacac acacactaag gctttcccac 1440
aaagccatga tgcatcctta aaaataacac acagctctga aaagtgaatg tcgggggtga 1500
agagagccct cctacactccattttcctagt gatgacaagg ttgtgggggc atggctgact 1560
gtgaggagca gaagatgaga gggagatatc attttacttc tttgtactgc aataataaaa 1620
agaacagata gaatggaagg aagaggccag gggcagtggc tcatacctgt aatcccagca 1680
ctttgggagg ctgaggcagg tggatcacct gaggtcagga gttcgagacc agcctggcca 1740
acatggagaa actccgtctc tattaagaat acaaaaatta gccaggcgtg gtggtgggca 1800
cctataatca cagctacccg ggaggttgag gcaggagaat cacttgaact tgtggggcgg 1860
aggtcgcagt gagccaagat tgcaccactt cactccagcc tgggcgagaa agtgaactct 1920
gtctcaaaaa aaaaaaaaaa aaa 1943
<210> 65
<211> 4111
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 553744CB1
<400> 65
gcgatctagg gcggggcaac tgtacagatg aacaatctgg aatattaaat tcaactcaca 60
gagtggcaac aaacaatact ggagagctgg gcatgaatcc tggaaagcct tgtatggccc 120
114/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
tgcaagggaa gccatgttct gaaagctcct atgaggggga ctgactgact ctagataagt 180
agattgaaag aattagaggt aaagtcagtg cagcagcact aatcacaatt aaaataaatg 240
ctttaatttt taaaaagcgg aaaaacatga aaggacactt cgcaagcttc tcaaaacttc 300
ctgtgatttg gagggctatt ttgagcagag tctagacgaa aactggatct gactggctcc 360
agagtaaaga tctgagaaat ggaacccagc aatttagata ttacaagagc ctgttatact 420
tgtcattttt tatttggtat ttgttaaata ttacaaaaat ggttatgctt tttaattcaa 480
aatttgacgt ttcagcatga tgatacattc ttgccttttt tcccccttcc atatagcatt 540
ttccacccca gcaagtcaac tcttttctcc tcatggttct aatccttcaa cacctgctgc 600
aactcctgtt cctactgcat ccccagtcaa ggcaattaat catccatcag catcagcagc 660
tgccaccgtt tctggaatga acctgctgaa tactgtcctt cctgtgttcc cagggcaggt 720
ctcctcagcc gttcacacac ctcagccatc aataccaaac ccaacagtta tcagaacccc 780
ttcattgccc actgcacctg ttacatccat ccacagtaca accaccactc ctgttccttc 840
cattttttct ggcctagtgt cactgccagg tccttctgcc actcctaccg cagccactcc 900
taccccagga cctacaccac ggtccactct tggttccagt gaagcatttg cttctacttc 960
tgcacctttc actagcctcc ccttttccac cagctcttct gctgcttcta ccagcaaccc 1020
aaattctgct tcattgtcat cagtttttgc agggctccct ttgcccttac caccaacatc 1080
ccaaggccta tccaacccga ctcctgtaat tgctggtggc tctactccca gcgttgccgg 1140
tccacttggt gtgaacagtc catcttttgt ctgcgttaaa aggttttctg acatccaatg 1200
acaccaattt aatcaactcc tctgctttat cctctgctgt cacaagtggg ctggcttcac 1260
tatcttctct tactcttcag aactctgact cttctgcttc agcccctaac aagtgctatg 1320
ccccatcagc catccctacc ccacagagga cttccactcc agggttggcc ctgttcccag 1380
gcctgccgtc tcccgtggct aactcaactt ccactcccct gacattgcct gtacagtctc 1440
ctttagccac tgctgcatca gcttccacgt cagtgccagt tagctgtggc tcctcagcct 1500
cccttttgcg tggcccccac ccaggtacct cagatctgca tatttcatct acccctgctg 1560
caacaactct tcctgttatg atcaaaactg agcccacaag tcctactccc tcggccttca 1620
aaggtccatc tcattctggg aatccctctc atggcacttt aggtttgtca gggacattgg 1680
gccgtgcata tacttcaaca tccgtgccca tcagtttatc tgcttgcctt aatcctgcat 1740
tgtcaggtct ctccagcttg agtactcctt taaatggttc aaatcctctt tcctctattt 1800
cccttccacc acatggttcc tccactccca ttgcaccagt attcactgct cttccttctt 1860
ttacttcttt gaccaacaat tttcctttaa ctggcaaccc atctcttaat ccgtcagtat 1920
ctctcccagg gtcattaata gccacctcat ctaccgctgc cacctccaca tctctccctc 1980
atcctagctc aacggcagct gttctctcag ggctttctgc ttcagcacca gtctcagcag 2040
cacctttccc cctcaacctg tccactgctg ttccctcact tttctctgtt actcaaggac 2100
ctctgtcatc ttcaaatccc tcctatccag gcttttctgt ctctaatacc ccaagcgtta 2160
cccctgctct tccctcattc ccggggctgc aggcgccctc tacagtcgca gctgtcacac 2220
cactacctgt ggctgccaca gccccatccc cagctccagt cctcccagga ttcgcctcag 2280
cattcagttc caatttcaac tccgctcttg ttgcacaagc cggtttatca tctggacttc 2340
aagctgcagg cagttctgtt tttccaggcc ttttgtccct cccgggtatc cctgggtttc 2400
ctcagaatcc ttcacaatca tccttgcaag aattacagca taatgcggct gcgcagtcag 2460
cattgttaca gcaggtccat tcagcttcgg ctctggaaag ctatccagct cagcctgatg 2520
ggtttcctag ttatccttca gcgccaggaa caccattttc tttgcaacca agcctgtccc 2580
agagtgggtg gcagtgaata cttttaactt ttattctcct tcagagcaac atcagaattg 2640
cctgagaact gcaatgaaca atctgacaaa tgtgaagctg gccaaaagtc ggaaaatgag 2700
aatgagggta atcctggaga aattgtgaca acaatttgaa aattgtggtt gcattttaaa 2760
gtgtgaacac tcccctatgt aaatatgctg acaataaatt gtatggagaa tggtatttaa 2820
aaagtgtttg gagacttttc acctgtccta taaaattttg aattgtgtat gtgatctaca 2880
tagaaagaat attaaagagt aggttgaact ctttatagcc gaatacagcc ttaaatatgc 2940
ttgtatagca tccactggca gaagtaatag ttgtgcctca gacttggggg ttgcatgtgg 3000
ccctggggga gttactaccc ttggtatgca tgagcggttc ctattagcat cagtgggaac 3060
tcagtactct gtatgtatcc acaaaaggga acttgagacc cacagttatt cttaatttct 3120
gatattaaca accgtacata ctgctgaatt taactcaaaa tatttcaggt aagtgaaagt 3180
ggtgcttaat gtagactata gaatgacttt caggtgtttt caactgaaag tatatatcca 3240
gaactgcatc cttatagaaa tacaagtaag acttaggata atttgecttc aaaacagttt 3300
tcctaatctc agcagtatcc agtgagtgaa gaacacttga ctgactcttg ggccacctct 3360
gttacttact gtactatgga agctcctggt gaatgtttac aattatggga tgtagtattt 3420
ctatttgtac tttaagtcaa atgcttatat gaaatatgtg acaacaaata gagaagactg 3480
115/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gctctgttag taattatgca gtatgtactc tatttaagga tctgtggtag tataacatga 3540
gtgaatgtca ttaattttga agtaataact gccacatgtg ggaagtaggg gagtaaggag 3600
aatgaattcc aatctgtgat taaaagtgta aactatagac tctactgtag tacatttcag 3660
gatctagaag ttttactttt ataaagatgg tgtccggaag atgttgctaa tgtattttac 3720
ttcaacatag ggaacaaact ttttaagtat attaataaac ctgtatggtt agtttttaac 3780
agttttttaa aataaactat ggatatgaca aatattctgt gttttactaa gtgcttggat 3840
aggctttcta attttgtata cgtgctagag ttaattattg aacattttta tccaaattta 3900
gttgtaactc tgtttatact actgattgct cattcgttta aatgatattt taatgtaaaa 3960
gtcataacca acatatgaac agacagattt atgtctttaa acacagaatg taagctatag 4020
tttaatctga taccagttgc tggaagttgc catttgtttt tcttaaatct atacccataa 4080
aacttctttt aagattaaaa aaaaaaaaaa a 4111
<210> 66
<211> 1604
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 1825473CB1
<400> 66
gatcttaaat ctaatagatt tcctatttcc aaaaagctcg actggagtgt tataaaacct 60
gaaaattctc ttgtgctttc tcttcttttg cttctagtta ccatcctcaa aggattggct 120
aaaagcaagc aactggattg aacaccctaa gaagaaagat tcacactgca ccaggagaca 180
tcagaaagaa tgaaaactct gccgctgttt gtgtgcatct gtgcactgag tgcttgcttc 240
tcgttcagtg aaggtcgaga aagggatcat gaactacgtc acagaaggca tcatcaccaa 300
tcacccaaat ctcactttga attaccacat tatcctggac tgctagctca ccagaagccg 360
ttcattagaa agtcctataa atgtctgcac aaacgctgta ggcctaagct tccaccttca 420
cctaataacc cccccaaatt cccaaatcct caccagccac ctaaacatcc agataaaaat 480
agcagtgtgg tcaaccctac cttagtggct acaacccaaa ttccatctgt gactttccca 540
tcagcttcca ccaaaattac tacccttcca aatgtgactt ttcttcccca gaatgccacc 600
accatatctt caagagaaaa tgttaacaca agctcttctg tagctacatt agcaccagtg 660
aattccccag ctccacaaga caccacagct gccccaccca caccttctgc aactacacca 720
gctccaccat cttcctcagc tccaccagag accacagctg ccccacccac accttctgca 780
actacacaag ctccaccatc ttcctcagct ccaccagaga ccacagctgc cccacccaca 840
cctcctgcaa ctacaccagc tccaccatct tcctcagctc caccagagac cacagctgcc 900
ccacccacac cttctgcaac tacaccagct ccactatctt cctcagctcc accagagacc 960
acagctgtcc cacccacacc ttctgcaact accctagacc catcatccgc ctcagctcca 1020
ccagagacca cagctgcccc acccacacct tctgcaacta caccagctcc accgtcttcc 1080
ccagctccac aagagaccac agctgcccca attaccacac ctaattcttc cccaactact 1140
cttgcacctg acacttctga aacttcagct gcacccacac accagactac tacttcggtc 1200
actactcaaa ctactactac taaacaacca acttcagctc ctggccaaaa taaaatttct 1260
cgatttcttt tatatatgaa gaatctacta aacagaatta ttgacgacat ggtggagcaa 1320
tagtatattg tatgttgtaa agtgttctgt catttacaag atgtgattca tgagtgcaga 1380
actaccacct ttcttttagc accaatccca acatgaaatt atattactca gatttaaagc 1440
actatcatta atctttcaat ctaattattc accaccacaa gacctattaa caagacaaaa 1500
tgcctctatc ccacaagcca gatgcaggtc tggggttcaa aataactctt tggatcctac 1560
agagatagcc tactgagggc agagaaagtc cttagataaa gaga 1604
<210> 67
<211> 2646
<212> DNA
<213> Homo sapiens
<220>
116/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<221> misc_feature
<223> Incyte ID No: 7950094CB1
<400> 67
gcgagcgcgg gcaggcggcg acgcgggggc aggggtggac ggcggtcaga gccgaacgcg 60
agggcggcgc ccggggactg gagctgcgcg caataggaca gctggcctga agctcagagc 120
cggggcgtgc gccatggccc cacactgggc tgtctggctg ctggcagcaa ggctgtgggg 180
cctgggcatt ggggctgagg tgtggtggaa ccttgtgccg cgtaagacag tgtcttctgg 240
ggagctggcc acggtagtac ggcggttctc ccagaccggc atccaggact tcctgacact 300
gacgctgacg gagcccactg ggcttctgta cgtgggcgcc cgagaggccc tgtttgcctt 360
cagcatggag gccctggagc tgcaaggagc gatctcctgg gaggcccccg tggagaagaa 420
gactgagtgt atccagaaag ggaagaacaa ccagaccgag tgcttcaact tcatccgctt 480
cctgcagccc tacaatgcct cccacctgta cgtctgtggc acctacgcct tccagcccaa 540
gtgcacctac gtcaacatgc tcaccttcac tttggagcat ggagagtttg aagatgggaa 600
gggcaagtgt ccctatgacc cagctaaggg ccatgctggc cttcttgtgg atggtgagct 660
gtactcggcc acactcaaca acttcctggg cacggaaccc attatcctgc gtaacatggg 720
gccccaccac tccatgaaga cagagtacct ggccttttgg ctcaacgaac ctcactttgt 780
aggctctgcc tatgtacctg agagtgtggg cagcttcacg ggggacgacg acaaggtcta 840
cttcttcttc agggagcggg cagtggagtc cgactgctat gccgagcagg tggtggctcg 900
tgtggcccgt gtctgcaagg gcgatatggg gggcgcacgg accctgcaga ggaagtggac 960
cacgttcctg aaggcgcggc tggcatgctc tgccccgaac tggcagctct acttcaacca 1020
gctgcaggcg atgcacaccc tgcaggacac ctcctggcac aacaccacct tctttggggt 1080
ttttcaagca cagtggggtg acatgtacct gtcggccatc tgtgagtacc agttggaaga 1140
gatccagcgg gtgtttgagg gcccctataa ggagtaccat gaggaagccc agaagtggga 1200
ccgctacact gaccctgtac ccagccctcg gcctggctcg tgcattaaca actggcatcg 1260
gcgccacggc tacaccagct ccctggagct acccgacaac atcctcaact tcgtcaagaa 1320
gcacccgctg atggaggagc aggtggggcc tcggtggagc cgccccctgc tcgtgaagaa 1380
gggcaccaac ttcacccacc tggtggccga ccgggttaca ggacttgatg gagccaccta 1440
tacagtgctg ttcattggca caggagacgg ctggctgctc aaggctgtga gcctggggcc 1500
ctgggttcac ctgattgagg agctgcagct gtttgaccag gagcccatga gaagcctggt 1560
gctatctcag agcaagaagc tgctctttgc cggctcccgc tctcagctgg tgcagctgcc 1620
cgtggccgac tgcatgaagt atcgctcctg tgcagactgt gtcctcgccc gggaccccta 1680
ttgcgcctgg agcgtcaaca ccagccgctg tgtggccgtg ggtggccact ctggatctct 1740
actgatccag catgtgatga cctcggacac ttcaggcatc tgcaacctcc gtggcagtaa 1800
gaaagtcagg cccactccca aaaacatcac ggtggtggcg ggcacagacc tggtgctgcc 1860
ctgccacctc tcctccaact tggcccatgc ccgctggacc tttgggggcc gggacctgcc 1920
tgcggaacag cccgggtcct tcctctacga tgcccggctc caggccctgg ttgtgatggc 1980
tgcccagccc cgccatgccg gggcctacca ctgcttttca gaggagcagg gggcgcggct 2040
ggctgctgaa ggctaccttg tggctgtcgt ggcaggcccg tcggtgacct tggaggcccg 2100
ggcccccctg gaaaacctgg ggctggtgtg gctggcggtg gtggccctgg gggctgtgtg 2160
cctggtgctg ctgctgctgg tgctgtcatt gcgccggcgg ctgcgggaag agctggagaa 2220
aggggccaag gctactgaga ggaccttggt gtaccccctg gagctgccca aggagcccac 2280
cagtcccccc ttccggccct gtcctgaacc agatgagaaa ctttgggatc ctgtcggtta 2340
ctactattca gatggctccc ttaagatagt acctgggcat gcccggtgcc agcccggtgg 2400
ggggccccct tcgccacctc caggcatccc aggccagcct ctgccttctc caactcggct 2460
tcacctgggg ggtgggcgga actcaaatgc caatggttac gtgcgcttac aactaggagg 2520
ggaggaccgg ggagggctcg ggcaccccct gcctgagctc gcggatgaac tgagacgcaa 2580
actgcagcaa cgccagccac tgcccgactc caaccccgag gagtcatcag tatgagggga 2640
accccc 2646
<210> 68
<211> 3876
<222> DNA
<213> Homo sapiens
<220>
117/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
<221> misc_feature
<223> Incyte ID No: 7479484CB1
<400> 68
atgttccgac caaccacggt ggctgtagac gaggatggtg gagaagagga taaagatgag 60
tcatcaacca acagtggtgc aagtgctgtt tcttcttgtg gctttggagc cgacttctcc 120
acagataaag ggggctcctt cacgtcagta cagatcacta ataccactgg actgtcacag 180
gctcctggct tagcctccca aggtattagc tttggcatta agaataatct gggaccccca 240
ctgcagaaat tgggagtatc attttccttt gccaagaaag ctcccgtcaa acttgaatca 300
atagcatccg ttttcaagga ccatgcagag gaagggagct cagaagatgg aacgaaggct 360
gatgagaaga gctctgacca aggggtgcag aaggtgggag atactgatgg cactggtaat 420
cttgatggaa agaaagaaga tgaagaccct caggatggag ggtcccttgc ctcaacactg 480
tccaagttga aaaggatgaa acgggaagaa ggaacagggg ctacagagcc agaatattac 540
cactacatcc ccccagcaca ctgcaaggtc aaacctaatt tccccttctt actctttatg 600
agagccagtg aacagatgga aggggatcat agtgcacact caaagagtgc ccccgagaac 660
agaaaaagca gctctcccaa gccgcaaggc tgtagtaaga cagcagcaag cccaggggca 720
gaaagaacag tgagtgaagc ttctgagctg caaaaggaag ccgctgtggc tgggccttca 780
gagcctggag gtaaaactga aacaaagaaa ggctccggag gaggggaaga tgagcagagt 840
gtagagagta gggagacgtc agagagcccg atgtgtgagt ccaatcctaa agacatttct 900
caggccaccc cagcaacaaa agcaggccag ggacccaagc atcctactgg tccattcttt 960
ccagttttaa gcaaggatga aagcactgcc ctccagtggc catcagaact actcattttc 2020
accaaagcag agccttccat ctcctacagt tgtaatcctt tatactttga ctttaaactt 1080
tcaagaaaca aagatgctaa agctaaaggg acagaaaagc caaaagatgt cgcaggctcc 1140
tcaaaggatc atctccagag ccttgatcct agagaaccga ataaaagcca ggaagaggag 1200
caggatgtag tgctctcttc agaaggcaga gtggatgaac ctgcatcagg ggctgcctgt 1260
agcagcctga acaagcagga gcctgggggt agccatatgt cagaaactga agacactggg 1320
agaagccatc ctagcaagaa agaaccatca ggcaagtctc acagacacaa gaagaaaaag 1380
aaacacaaaa aatccagcaa gcacaaacgt aaacacaagg ctgacacgga agagaagagt 1440
tctaaggcag agtctgggga gaaatctaag aagcgcaaga aacgaaaacg gaagaagaac 1500
aaatcatcag ccgcagctga ttctgaacgc ggacccaaat cagaacctcc tggaagcggc 1560
agcccggcac caccgagaag gcggcgccga gctcaagatg attcccagcg gagatccctt 1620
cctgctgaag aaggaaacag tggcaagaag gatgatggtg ggggtggtag cagttgccaa 1680
gatcacagtg ggaggaaaca caaaggtgaa ccaccaactt cctcctgcca gcggagagct 1740
aacaccaaac atagcagccg gtccagccat cggagccaac ccagtagtgg tgatgaggat 1800
agtgatgatg cttcctcaca ccgactgcac cagaagtctc catcccagta cagtgaggag 1860
gaggaagagg aggaggagga agaagaggag gaagatgaag actccggtag tgagcattct 1920
cgtagccgct ctcggtctgg ccatcgccat tcctcacatc gttcctcccg gcgctcttat 1980
tctagcagct ctgatgcctc ttcagaccag agctgctata gtagacagca cagttactct 2040
gatgatagct atagtgacta tagcgaccga tcacgaaggc actctaagcg ctctcacgat 2100
tcagatgatt cagactatac cagctccaaa cacaggtcta aacgacacaa atactcatca 2160
tctgatgatg actatagcct cagttgcagc cagtcccgaa gccgatctcg gagtcataca 2220
agggagcgat caagatcccg gggtcgaagc cgcagtagca gctgtagtcg cagtcgaagc 2280
aagaggagaa gtcgcagcac cacagcccac agctggcagc gaagccgaag ctatagccgg 2340
gaccggagcc gcagcaccag gagcccttct cagagatcag gctccagaaa gggctcatgg 2400
ggtcatgaga gcccagagga aaggcgctct ggccgccggg atttcattcg ttcaaagatc 2460
taccgctctc aatcccccca ctatttccaa tcaggtcggg gagaaggtcc tggaaagaaa 2520
gaagatggca gaggagatga cagtaaagga gcaggcctgc cctcccagaa tagcaatact 2580
ggcacaggaa gggggtcaga aagtgactgc agtcctgaag ataagaattc tgttactgcc 2640
agactgctgc tagagaagat ccagtccagg aaagtggaga ggaaacccaa tgtgtgcgag 2700
gaggtgctgg ccacccctaa taaggctggg ctcaagtaca agaacccccc acaaggttac 2760
tttgggccta agctcccccc gtctcttggt aataagcctg ttcttccaat gatagggaag 2820
cttccagcta cccggaagtc caataagaaa tgtgaagagt ctggcttaga aaggggagaa 2880
gagcaggaac attcagagcc agaagaaggg tccccaagga gtagtgatgc tccatttggg 2940
catcagttct cagaggaagc agctggtccc ttatcagacc ctcccccaga agagccaaag 3000
tctgaagaag ctactgctga tcactctgtg gctccgctag gcaccccagc ccacactgac 3060
tgctaccctg gggatccagc catctcccat aactacctcc cggaccccag tgatggggat 3120
118/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
actctggagt ctctggatag tggcagtcaa ccaggccctg tggaatccag cttgctgcct 3180
atagccccag accttgagca cttccccaat tatgcacctc ccagtgggga acctagtatt 3240
gaatcaacag atgggactga ggatgcctcc ttggctcctc tcgagagcca gcccatcacc 3300
ttcacccctg aggagatgga gaagtacagc aagctccagc aggctgcaca gcagcacatc 3360
cagcagcagc ttctggccaa acaagtgaag gcctttccag cctccaccgc cctagctcca 3420
gccacaccag ccctgcagcc catccacatt cagcagccag ccacagcctc tgccacctcc 3480
atcaccactg ttcagcatgc catcctacag catcatgctg cagccgctgc tgccgccatt 3540
ggcattcacc ctcaccccca ccctcagccg cttgctcaag tacatcatat tccccagccc 3600
catctaaccc ctatttcttt gtcccatctc actcactcaa ttatccctgg ccaccctgcc 3660
acctttcttg ctagccaccc tatccatata attcctgcct cagccatcca tcctgggccc 3720
ttcacctttc atcccgtccc acacgctgcc ctctacccca ccctgcttgc cccacggcct 3780
gctgcagcag ctgccacagc cctccatctt cacccactgc ttcaccccat cttctcaggt 3840
caggacctgc agcaccctcc cagccatggg acttga 3876
<210> 69
<211> 2583
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 6780147CB1
<400> 69
ggtggcgggt ggctggcggt tccgttaggt ctgagggagc gatggcggta cgcgcgttga 60
agctgctgac cacactgctg gctgtcgtgg ccgctgcctc ccaagccgag gtcgagtccg 120
aggcaggatg gggcatggtg acgcctgatc tgctcttcgc cgaggggacc gcagcctacg 180
cgcgcgggga ctggcccggg gtggtcctga gcatggaacg ggcgctgcgc tcccgggcag 240
ccctccgcgc ccttcgcctg cgctgccgca cccagtgtgc cgccgacttc ccgtgggagc 300
tggaccccga ctggtccccc agcccggccc aggcctcggg cgccgccgcc ctgcgcgacc 360
tgagcttctt cgggggcctt ctgcgtcgcg ctgcctgcct gcgccgctgc ctcgggccgc 420
cggccgccca ctcgctcagc gaagagatgg agctggagtt ccgcaagcgg agcccctaca 480
actacctgca ggtcgcctac ttcaagatca acaagttgga gaaagctgtt gctgcagcac 540
acaccttctt cgtgggcaat cctgagcaca tggaaatgca gcagaaccta gactattacc 600
aaaccatgtc tggagtgaag gaggccgact tcaaggatct tgagactcaa ccccatatgc 660
aagaatttcg actgggagtg cgactctact cagaggaaca'gccacaggaa gctgtgcccc 720
acctagaggc ggcgctgcaa gaatactttg~tggcctatga ggagtgccgt gccctctgcg 780
aagggcccta tgactacgat ggctacaact accttgagta caacgctgac ctcttccagg 840
ccatcacaga tcattacatc caggtcctca actgtaagca gaactgtgtc acggagcttg 900
cttcccaccc aagtcgagag aagccctttg aagacttcct cccatcgcat tataattatc 960
tgcagtttgc ctactataac attgggaatt atacacaggc tgttgaatgt gccaagacct 1020
atcttctctt cttccccaat gacgaggtga tgaaccaaaa tttggcctat tatgcagcta 1080
tgcttggaga agaacacacc agatccatcg gcccccgtga gagtgccaag gagtaccgac 1140
agcgaagcct actggaaaaa gaactgcttt tcttcgctta tgatgttttt ggaattccct 1200
ttgtggatcc ggattcatgg actccagaag aagtgattcc caagagattg caagagaaac 1260
agaagtcaga acgggaaaca gccgtacgca tctcccagga gattgggaac cttatgaagg 1320
aaatcgagac ccttgtggaa gagaagacca aggagtcact ggatgtgagc agactgaccc 1380
gggaaggtgg ccccctgctg tatgaaggca tcagtctcac catgaactcc aaactcctga 1440
atggttccca gcgggtggtg atggacggcg taatctctga ccacgagtgt caggagctgc 1500
agagactgac caatgtggca gcaacctcag gagatggcta ccggggtcag acctccccac 1560
atactcccaa tgaaaagttc tatggtgtca ctgtcttcaa agccctcaag ctggggcaag 1620
aaggcaaagt tcctctgcag agtgcccacc tgtactacaa cgtgacggag aaggtgcggc 1680
gcatcatgga gtcctacttc cgcctggata cgcccctcta cttttcctac tctcatctgg 1740
tgtgccgcac tgccatcgaa gaggtccagg cagagaggaa ggatgatagt catccagtcc 1800
acgtggacaa ctgcatcctg aatgccgaga ccctcgtgtg tgtcaaagag cccccagcct 1860
acaccttccg cgactacagc gccatccttt acctaaatgg ggacttcgat ggcggaaact 1920
119/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
tttatttcac tgaactggat gccaagaccg tgacggcaga ggtgcagcct cagtgtggaa 1980
gagccgtggg attctcttca ggcactgaaa acccacatgg agtgaaggct gtcaccaggg 2040
ggcagcgctg tgccatcgcc ctgtggttca ccctggaccc tcgacacagc gagcgggaca 2100
gggtgcaggc agatgacctg gtgaagatgc tcttcagccc agaagagatg gacctctccc 2160
aggagcagcc cctggatgcc cagcagggcc cccccgaacc tgcacaagag tctctctcag 2220
gcagtgaatc gaagcccaag gatgagctat gacagcgtcc aggtcagacg gatgggtgac 2280
tagacccatg gagaggaact cttctgcact ctgagctggc cagcccctcg gggctgcaga 2340
gcagtgagcc tacatctgcc actcagccga ggggaccctg ctcacagcct tctacatggt 2400
gctactgctc ttggagtgga catgaccaga caccgcaccc cctggatctg gctgagggct 2460
caggacacag gcccagccac ccccaggggc ctccacaggc cgctgcataa cagcgataca 2520
gtacttaagt gtctgtgtag acaaccaaag aataaatgat tcatggtttt ttttaaaaaa 2580
aaa 2583
<210> 70
<211> 6147
<212> DNA
<213> Homo sapiens
<220>
<221> misc_~eature
<223> Incyte ID No: 7204554CB1.
<400> 70
tgatatatag ggccatgctt atctagcatg catgctcgag acgcgcgcat atgtgctgga 60
aagggcgggg cgcgccccgg ggcggcgggg ctgaagctcc tggcaccatg atgctcaccc 120
cagcaggacc agagcaccga ggcccaaggc cccagcctgc catgccgctg ccaccgcgga 180
gcctgcaggt gctcctgctg ctgctgctgt tgctgctgct gctgccgggc atgtgggctg 240
aggcaggctt gcccagggca ggcgggggtt cacagccccc cttccgcacc ttctcggcca 300
gcgactgggg cctcacccac ctagtggtgc atgagcagac aggcgaggtg tatgtgggcg 360
cagtgaaccg catctataag ctgtcgggga acctgacact gctgcgggcc cacgtcacgg 420
gccctgtgga ggacaacgag aagtgctacc cgccgcccag cgtgcagtcc tgcccccacg 480
gcctgggcag tactgacaac gtcaacaagc tgctgctgct ggactatgcc gctaaccgcc 540
tgctggcctg tggcagcgcc tcccagggca tctgccagtt cctgcgtctg gacgatctct 600
tcaaactggg tgagccacac caccgtaagg agcactacct gtccagcgtg caggaggcag 660
gcagcatggc gggcgtgctc attgccgggc caccgggcca gggccaggcc aagctcttcg 720
tgggcacacc catcgatggc aagtccgagt acttccccac actgtccagc cgtcggctca 780
tggccaacga ggaggatgcc gacatgttcg gcttcgtgta ccaggatgag tttgtgtcat 840
cacagctcaa gatcccttcg gacacgctgt ccaagttccc ggcctttgac atctactatg 900
tgtacagctt ccgcagcgag cagtttgtct actacctcac gctgcagcta gacacacagc 960
tgacctcgcc tgatgccgcc ggcgagcact tcttcacgtc caagatcgtg cggctctgtg 1020
tggacgaccc caaattctac tcgtacgttg agttccccat tggctgcgag caggcgggtg 1080
tggagtaccg cctggtgcag gatgcctacc tgagccggcc cggccgtgcc ctggcccacc 1140
agctgggcct ggctgaggac gaggacgtgc tgttcactgt gttcgcccag ggccagaaga 1200
accgcgtgaa gccaccaaag gagtcagcac tgtgcctgtt cacgctcagg gccatcaagg 1260
agaagattaa ggagcgcatc cagtcctgct accgtggtga gggcaagctc tccctgccgt 1320
ggctgctcaa caaggagctg ggctgcatca actcgcccct gcagatcgat gacgacttct 1380
gcgggcagga cttcaaccag cccctggggg gcacagtcac cattgagggg acgcccctgt 1440
tcgtggacaa ggatgatggc ctgaccgccg tggctgccta tgactatcgg ggccgcactg 1500
tggtattcgc cggcacgcga agtggccgca tccgcaagat cctggtggac ctctcaaacc 1560
ccggtggccg gcctgccctg gcctacgaga gcgtcgtggc ccaggagggc agccccatcc 1620
tgcgagacct cgtcctcagc cccaaccacc agtacctcta cgccatgacc gagaagcagg 1680
tgacgcgggt gcctgtggag agctgtgtgc agtacacgtc ctgtgagctg tgtctggggt 1740
cacgggaccc ccactgtggc tggtgtgtcc tgcacagcat ctgctcgcgg cgggacgcct 1800
gtgagcgagc agacgagccc cagcgctttg ctgcggacct gctgcagtgt gtgcagctga 1860
ctgtgcagcc ccgcaatgtg tctgtcacca tgtcccaggt eccacttgtg ctgcaggcct 1920
ggaacgtgcc tgacctctca gctggcgtca actgctcctt egaggacttc acggaatctg 1980
120/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
agagcgtcct ggaggatggc cggatccact gccgctcacc ctccgcccgg gaggtggcgc 2040
ccatcacgcg gggccaggga gaccagcggg tggtgaaact ctacctaaag tccaaggaga 2100
cagggaagaa gtttgcgtct gtggacttcg tcttctacaa ctgcagcgtc caccagtcct 2160
gcctgtcctg tgtcaacggc tcctttccct gccactggtg caaataccgc cacgtgtgca 2220
cacacaacgt ggctgactgc gccttcctgg agggccgtgt caacgtgtct gaggactgcc 2280
cacagatcct gccctccacg cagatctacg tgccagtggg agtggtaaaa cccatcaccc 2340
tggccgcacg gaacctgcca cagccacagt caggccagcg tggatatgag tgcctcttcc 2400
acatcccggg cagcccggcc cgtgtcaccg ccctgcgctt caacagctcc agcctgcagt 2460
gccagaattc ctcgtactcc tacgagggga acgatgtcag cgacctgcca gtgaacctgt 2520
cagtcgtgtg gaacggcaac tttgtcattg acaacccaca gaacatccag gcgcacctct 2580
acaagtgccc ggccctgcgc gagagctgcg gcctctgcct caaggccgac ccgcgcttcg 2640
agtgcggatg gtgcgtggcc gagcgccgct gctccctgcg acaccactgc gctgccgaca 2700
cacctgcatc gtggatgcac gcgcgtcacg gcagcagtcg ctgcaccgac cccaagatcc 2760
tcaagctgtc ccccgagacg ggcccgaggc agggcggcac gcggctcact atcacaggcg 2820
agaacctggg cctgcgattc gaagacgtgc gtctgggcgt gcgcgtgggc aaggtgctgt 2880
gcagccctgt ggagagcgag tacatcagtg cggagcagat cgtctgtgag atcggggacg 2940
ecagctccgt gcgtgcccat gacgccctgg tggaggtgtg tgtgcgggac tgctcaccac 3000
actaccgcgc cctgtcaccc aagcgcttca ccttcgtgac accaaccttc taccgtgtga 3060
gcccctcccg tgggcctctg tcagggggca cctggattgg catcgaggga agccacctga 3120
acgcaggcag tgatgtggct gtgtcggtcg gtggccggcc ctgctccttc tcctggagga 3180
actcccgtga gatccggtgc ctgacacccc ccgggcagag ccctggcagc gctcccatca 3240
tcatcaacat caaccgcgcc cagctcacca accctgaggt gaagtacaac tacaccgagg 3300
accccaccat cctgaggatc gaccccgagt ggagcatcaa cagcggtggg accctcctga 3360
cggtcacagg caccaacctg gccactgtcc gtgaaccccg aatccgggcc aagtatggag 3420
gcattgagag ggagaacggc tgcctggtgt acaatgacac caccatggta tgccgcgccc 3480
cgtctgtggc caaccctgtg cgcagcccac cagagctggg ggagcggccg gatgagctgg 3540
gcttcgtcat ggacaacgtg cgctccctgc ttgtgctcaa ctccacctcc ttcctctact 3600
accctgaccc cgtactggag ccactcagcc ccactggcct gctggagctg aagcccagct 3660
ccccactcat cctcaagggc cggaacctct tgccacctgc acccggcaac tcccgactca 3720
actacacggt gctcatcggc tccacaccct gtaccctcac cgtgtcggag acgcaactgc 3780
tgtgcgaggc gcccaacctc actgggcagc acaaggtcac ggtgcgggca ggtggcttcg 3840
agttctcgcc agggacactg caggtgtact cggacagcct gctgacgctg cctgccattg 3900
tgggcattgg cggaggcggg ggtctcctgc tgctggtcat cgtggctgtg ctcatcgcct 3960
acaagcgcaa gtcacgagat gctgaccgca cactcaagcg gctgcagctc cagatggaca 4020
acctggagtc ccgcgtggcc ctcgaatgca aggaagcctt tgcagagctg cagacagaca 4080
tccacgagct gaccaatgac ctggacggtg ccggcatccc cttccttgac taccggacat 4140
atgccatgcg ggtgctcttt cctgggatcg aggaccaccc tgtgctcaag gagatggagg 4200
tgcaggccaa tgtggagaag tcgctgacac tgttcgggca gctgctgacc aagaagcact 4260
tcctgctgac cttcatccgc acgctggagg cacagcgcag cttctccatg cgcgaccgcg 4320
ggaatgtggc ctcgctcatc atgacggccc tgcagggcga gatggaatac gccacaggcg 4380
tgctcaagca gctgctttcc gacctcatcg agaagaacct ggagagcaag aaccacecca 4440
agctgctact gcgccggact gagtcggtgg cagagaagat gctaactaac tggttcacct 4500
tcctcttgta taagttcctc aaggagtgcg ctggggagcc gctgttcatg ctgtactgcg 4560
ccatcaagca gcagatggag aagggcccca ttgacgccat cacgggtgag gcacgctact 4620
ccctgagtga ggacaagctc atccggcagc agattgacta caagacactg accctgaact 4680
gtgtgaaccc tgagaatgag aatgcacctg aggtgccggt gaaggggctg gactgtgaca 4740
cggtcaccca ggccaaggag aagctgctgg acgctgccta caagggcgtg ccctactccc 4800
agcggcccaa ggccgcggac atggacctgg agtggcgcca gggccgcatg gcgcgcatca 4860
tcctgcagga cgaggacgtc accaccaaga ttgacaacga ttggaagagg ctgaacacac 4920
tggctcacta ccaggtgaca gacgggtcct cggtggcact ggtgcccaag cagacgtccg 4980
cctacaacat ctccaactcc tccaccttca ccaagtccct cagcagatac gagagcatgc 5040
tgcgcacggc cagcagcccc gacagcctgc gctcgcgcac gcccatgatc acgcccgacc 5100
tggagagcgg caccaagctg tggcacctgg tgaagaacca cgaccacctg gaecagcgtg 5160
agggtgaccg cggcagcaag atggtctcgg agatctactt gacacggcta ctggccacca 5220
agggcacact gcagaagttt gtggacgacc tgtttgagac catcttcagc acggcacacc 5280
ggggctcagc cctgccgctg gccatcaagt acatgttcga cttcctggat gagcaggccg 5340
121/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
acaagcacca gatccacgat gctgacgtgc gccacacctg gaagagcaac tgcctgcccc 5400
tgcgcttctg ggtgaacgtg atcaagaacc cacagtttgt gttcgacatt cacaagaaca 5460
gcatcacgga cgcctgcttg tcggtggtgg cccagacctt catggactcc tgctccacct 5520
ctgagcacaa gctgggcaag gactcaccct ccaacaagct gctctacgcc aaggacatcc 5580
ccaactacaa gagctgggtg gagaggtact atgcagacat cgccaagatg ccagccatca 5640
gcgaccagga catgagtgcg tatctggctg agcagtcccg cctgcacctg agccagttca 5700
acagcatgag cgccttgcac gagatctact cctacatcac caagtacaag gatgagatcc 5760
tggcagccct ggagaaggat gagcaggcgc ggcggcagcg gctgcggagc aagctggagc 5820
aggtggtgga cacgatggcc ctgagcagct gagccccagc tgtgatcatc cagcatgatg 5880
cagcgtgagg acagctgagc agggaccggg acagccctca ccgcatgcgt gtggagtgtc 5940
cggtggtgct cgggccgccg cagtgcagcg actgcccggc cctccctccc ctgcctcacc 6000
cggtcgggtc ccggctcttc ctgtgtggag gtgatggtac ctgccacacc acagctgcgc 6060
acacagctgc ttgctcaggg gccgggacag cactgggtgc tcaggctggc vaaggacctt 6120
cattgcctgg gcaagagctg cccagtg 6147
<210> 71
<211> 888
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 6833247CB1
<400> 71
cgagcttact tatactggta cctttctaat ctcactacaa tatgtaacat tggtgttcga 60
tctcaagtat ttctgaatat attcccctat ccacagaaat atactctggg ggaaaaaaaa 120
tagaacaaat tcttgccgtc ctgaccattg aacaagagac taattagaca atggggctag 180
aaaaacctca aagtaaactg gaaggaggca tgcatcccca gctgatacct tcggttattg 240
ctgtagtttt catcttactt ctcagtgtct gttttattgc aagttgtttg gtgactcatc 300
acaacttttc acgctgtaag agaggcacag gagtgcacaa gttagagcac catgcaaagc 360
tcaaatgcat caaagagaaa tcagaactga aaagtgctga agggagcacc tggaactgtt 420
gtcctattga ctggagagcc ttccagtcca actgctattt tcctcttact gacaacaaga 480
cgtgggctga gagtgaaagg aactgttcag ggatgggggc ccatctgatg accatcagca 540
cggaagctga gcagaacttt attattcagt ttctggatag acggctttcc tatttccttg 600
gacttagaga tgagaatgcc aaaggtcagt ggcgttgggt ggaccagacg ccatttaacc 660
cacgcagagt attctggcat aagaatgaac ccgacaactc tcagggagaa aactgtgttg 720
ttcttgttta taaccaagat aaatgggcct ggaatgatgt tccttgtaac tttgaagcaa 780
gtaggatttg taaaatacct ggaacaacat tgaactagaa actcagaaag tggtccttgt 840
gatggaaaga gaaaagaaaa accaattaga ataaggcaga atgtacgt 888
<210> 72
<211> 3582
<212> DNA
<213> Homo Sapiens
<220>
<221> misc_feature
<223> Incyte ID No: 4148119CB1
<400> 72
ctggccacac cgaaagagag cccacccaag tctgaggaac cacacccgga gcagttccga 60
aaagcgaggg agacttcccc tgatctggaa agggtgccag gcacttcagc accatcggca 120
gccccagccc ctcacccacg gca~gagagg cagagcggct ctcaccgggt ccagaccggc 180
ccagcccacc ataatggtca aaagaaggcc aagctctgga aggtgggaac aactgaggca 240
gatggggaca gtaaagccag atggaccgcg cttgagcctt catctccacc agggacccag 300
122/123
CA 02413186 2002-12-27
WO 02/02634 PCT/USO1/21067
gccaccttcc cagttccata cctcttcagc ctcaggtccc~tcttgactga gcccagcgtc 360
accgccccca agaaagttcc ccaatcaccc tgtcccacgc tgggccacct gcttccctcc 420
ctgaaggctg tccctaagct gtgggtattt atcctactaa ggaggctggg acagagtcct 480
gacctgcacc catctgttcc caacccacca gccttcaaac aagggggctc ctcctccccg 540
gggcagctct ggcctctgct gggggccagt cgaggcagat agaagggtga gcctaaccaa 600
tgacccaacg cccccttccc aattaactac cgccttccaa cggaatccaa gggaatccct 660
catccccaaa acttcaccgc ggaaggatct gcggggactg acaggcagaa gccaggcaca 720
gggatatccg aacagcctca gtcttgctac ccaactctgc cttcaagaca ttccaatctg 780
atgggaagag tcctgtctgg gaagctccct gtctgatggg agacagccct gtccacatgg 840
~aggtctcagt ctgacggagg aaacagcctg gccagccagg cccaggccga caggggagac 900
acagtccctg cccaaggagc ttccaagcta agggcggaac cacagccaag cccagggagc 960
tcccaggcta agggcggaga ctgtcccagc ccagggagct cccagtcaaa agggggagac 1020
acagcactgc ccttacaaag ctaccagcct cacggagaag gcgcagtccc tgtccacaga 1080
gacacagcct tgccccagtt actgcccacc tgcaagagat ccacatttct gccctccaga 1140
gctcccaaac tgatggggga gagagacatc atcccccagc tctgggagtt tccagtctga 1200
tggaggagac agagcctgct tcggtaactc tcactctgcg ggggaagact cagccctatc 1260
cagggagctc ccacactttc aatggggagg cccacccagt ggccgagcct gctgctgctc 1320
ctgctgttgc cggggccccc gcccgtcgcc ggcttggaag acgctgcctt cccccacctg 1380
ggggagagct tgcagcccct gccccgggcc tgtcccctgc gctgctcctg cccccgagtc 1440
gacactgtgg actgtgatgg cttggacctt cgagtgttcc cggacaacat caccagagcc 1500
gctcagcacc tctccctgca gaacaaccag ctccaggaac tcccctacaa tgagctgtcc 1560
cgcctcagtg gcctgcgaac cctcaacctc cacaacaacc tcatctcctc cgaaggcctg 1620
cctgacgagg ccttcgagtc cctcacccag ctgcagcacc tctgcgtggc tcacaacaag 1680
ctctcagtgg cccctcagtt tctgccccgg tccctccgtg tcgcggatct ggctgccaac 1740
caagtgatgg agatcttccc cctcaccttt ggggagaagc cggtactcag gtccgtgtac 1800
ctccacaaca accagctgag caacgctggc ctgccccccg acgccttccg cggctccgag 1860
gccatcgcca'ccctcagcct ctccaacaac cagctcagct acctgc,cgcc cagcctgccg 1920
ccctcactcg agcggctcca cctgcagaac aatctcatct ccaaggtgcc ccgaggagcc 1980
ctgagccgcc agactcaact ccgtgagctc tacctccagc acaaccagct gacagacagt 2040
ggcctggatg ccaccacctt cagcaagctg catagccttg aatacctgga tctctcccac 2100
aaccagctga ccacagtgcc cgccggcctg ccccggaccc tggctatcct gcacctgggc 2160
cgcaaccgca tccggcaggt ggaggcggct cggctgcacg gggcgcgtgg tctgcgctat 2220
ttgttgctgc agcacaacca gctggggagc tcagggctgc ccgccggggc tctgcggccg 2280
ctgcggggcc tgcacacgct gcacctctat ggcaatgggc tggaccgcgt gcctccagcc 2340
ctgccccgcc gcctgcgtgc cctggtgctg ccccacaacc acgtggccgc gctgggtgcc 2400
cgtgacctgg tcgccacacc gggcctgacg gagcttaacc tggcctataa ccgcctggcc 2460
agcgcccgtg tgcaccaccg ggccttccgc cggttgcgtg ccctgcgcag cctcgacctg 2520
gcagggaatc agctaacccg gctgcccatg ggcctgccca ctggcctgcg caccctgcag 2580
ctgcaacgca accagctgcg gatgctcgag cccgagcctc tggccggcct ggaccaactg 2640
cgggagctca gcctggcgca caaccggctc cgggtcggcg acatcgggcc aggcacctgg 2700
catgagctcc aagccctcca gatgctggac ctcagccaca atgagctgtc ctttgtgccc 2760
ccggacctgc ctgaggccct agaggagctg cacctcgagg gcaaccgcat cggccacgtg 2820
ggccccgagg ccttcctcag cacaccccgc ctgcgtgccc tcttcctcag ggccaacagg 2880
cttcacatga cgagcatcgc ggctgaggcc ttcctggggc tcccaaacct gcgtgtggtg 2940
gacacggcag ggaatccgga gcaggtcctg atccggctgc ctcccaccac cccacgtggg 3000
ccacgggcag ggggcccctg atcctagaga ggcccagcag agcagctcag actcctggga 3060
ctccgctggg ccgtggactg aggagacaac gcccaccagg ggcccttggt ctggctctcc 3120
tgggcctcca gggctgggcc tgctctgcct gccactggcc gagacacaga ggcacacagc 3180
tggcatactc caggctcaca gaccacgccg gcctggcggg acacacccta ccccaaactc 3240
ccaacacaga tggaggcagc aacaataaag ccaaaccctt ccagcactca gcacggacca 3300
ggcacccttc gggggctctg tccacggact cctccccaca accagtccag ctggggaaac 3360
tgaggctctg ggatgctaag tgggtcagga ctgaattttg aggtcttgag gcacacactg 3420
gggtcaccaa acagcaccct gtgcgaccta gccacgtgtg attgcaggga cgcccaaggc 3480
cacccactga aaaaacactg ggtgacagat atagggaccc tcacatgtat ccccccccac 3540
agcaagcatg ggaatgaaat gcatccttca aaaaaaaaaa as 3582
123/223
