CA2320799A1

CA2320799A1 - Secreted proteins and polynucleotides encoding them

Info

Publication number: CA2320799A1
Application number: CA002320799A
Authority: CA
Inventors: Kenneth Jacobs; John M. Mccoy; Edward R. Lavallie; Lisa A. Collins-Racie; David Merberg; Maurice Treacy; Michael J. Agostino; Robert J. Ii Steininger
Original assignee: Individual
Current assignee: Genetics Institute LLC
Priority date: 1998-02-18
Filing date: 1999-02-18
Publication date: 1999-08-26
Also published as: AU2685599A; WO1999042470A1; JP2002504488A; EP1056764A1; EP1056764A4

Abstract

Novel polynucleotides and the proteins encoded thereby are disclosed.

Description

SECRETED PROTEINS AND POLYNUCLEOTIDES ENCODING THEM
This application is a continuation-in-part of provisional application Ser. No.
60/075,038, filed February 18,1998, which is incorporated by reference herein.
FIELD OF THE INVENTION
The present invention provides novel.polynucleotides and proteins encoded by such polynucleotides, along with therapeutic, diagnostic and research utilities for these polynucleotides and proteins.
BACKGROUND OF THE INVENTION

2 0 Technology aimed at the discovery of protein factors (including e.g., cytokines, such as lymphokines, interferons, CSFs and interleukins) has matured rapidly over the past decade. The now routine hybridization cloning and expression cloning techniques clone novel polynucleotides "directly" in the sense that they rely on information directly related to the discovered protein (i.e., partial DNA/amino acid sequence of the protein 2 5 in the case of hybridization cloning; activity of the protein in the case of expression cloning). More recent "indirect" cloning techniques such as signal sequence cloning, which isolates DNA sequences based on the presence of a now well-recognized secretory leader sequence motif, as well as various PCR-based or low stringency hybridization cloning techniques, have advanced the state of the art by making available large numbers of 3 0 DNA/amino acid sequences for proteins that are known to have biological activity by virtue of their secreted nature in the case of leader sequence cloning, or by virtue of the cell or tissue source in the case of PCR-based techniques. It is to these proteins and the polynucleotides encoding them that the present invention is directed.

SUMMARY OF THE INVENTI(,~N
In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:I;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:1 from nucleotide 185 to nucleotide 1678;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:1 from nucleotide 482 to nucleotide 1678;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone co821 31 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone co821 31 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone co821 31 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone co821_31 deposited under accession number ATCC 98663;
2 0 (h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID N0:2;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:2 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:2;
2 5 (j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(g) above;
(k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above ;
(1) a polynucleotide that hybridizes under stringent conditions to any 3 0 one of the polynucleotides specified in (a)-(i); and (m) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i) and that has a length that is at least 25% of the length of SEQ ID N0:1.

Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
N0:1 from nucleotide 185 to nucleotide 1678; the nucleotide sequence of SEQ ID
NO:1 from nucleotide 482 to nucleotide 1678; the nucleotide sequence of the full-length protein coding sequence of clone co821 31 deposited under accession number ATCC 98663;
or the nucleotide sequence of a mature protein coding sequence of clone co821 31 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone co821 31 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:2 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:2, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:2 having biological activity, the fragment comprising the amino acid sequence from amino acid 244 to amino acid 253 of SEQ ID N0:2.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID NO:1.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
2 0 (a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID NO:1, but excluding the poly(A) tail at the 2 5 3' end of SEQ ID NO:1; and (ab) the nucleotide sequence of the cDNA insert of clone co821 31 deposited under accession number ATCC 98663;
(ii) hybridizing said probes} to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and 3 0 (iii) isolating the DNA polynucleotides detected with the probes};
and (b) a process comprising the steps of:

(i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID NO:1, but excluding the poly(A) tail at the 3' end of SEQ ID NO:1; and (bb) the nucleotide sequence of the cDNA insert of clone co821 31 deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID NO:1, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ ID
NO:1 to a nucleotide sequence corresponding to the 3' end of SEQ ID NO:1 , but excluding the poly(A} tail at the 3' end of SEQ ID NO:1. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID NO:1 from nucleotide I85 to nucleotide 1678, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of 2 0 SEQ ID NO:1 from nucleotide 185 to nucleotide 1678, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID NO:1 from nucleotide 185 to nucleotide 1678. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID
NO:1 from nucleotide 482 to nucleotide 1678, and extending contiguously from a 2 5 nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
NO:1 from nucleotide 482 to nucleotide 1678, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID NO:1 from nucleotide 482 to nucleotide 1678.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group 3 0 consisting of:
(a) the amino acid sequence of SEQ ID N0:2;
{b) a fragment of the amino acid sequence of SEQ ID N0:2, the fragment comprising eight contiguous amino acids of SEQ ID N0:2; and (c) the amino acid sequence encoded by the cDNA insert of clone co821 31 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID N0:2. In further preferred embodiments, the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID N0:2 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:2, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:2 having biological activity, the fragment comprising the amino acid sequence from amino acid 244 to amino acid 253 of SEQ ID N0:2.
In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:3;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:3 from nucleotide 176 to nucleotide 754;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:3 from nucleotide 425 to nucleotide 754;
(d) a polynucleotide comprising the nucleotide sequence of the full-2 0 length protein coding sequence of clone dk329_1 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone dk329_1 deposited under accession number ATCC 98663;
(f} a polynucleotide comprising the nucleotide sequence of a mature 2 5 protein coding sequence of clone dk329_1 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone dk329_1 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid 3 0 sequence of SEQ ID N0:4;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:4 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:4;

(j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(g) above;
(k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above ;
(1) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a}-(i); and (m) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a~(i) and that has a length that is at least 25% of the length of SEQ ID N0:3.
Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
N0:3 from nucleotide 176 to nucleotide 754; the nucleotide sequence of SEQ ID
N0:3 from nucleotide 425 to nucleotide 754; the nucleotide sequence of the full-length protein coding sequence of clone dk329_1 deposited under accession number ATCC 98663; or the nucleotide sequence of a mature protein coding sequence of clone dk329_1 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone dk329_1 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:4 having biological 2 0 activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:4, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:4 having biological activity, the fragment comprising the amino acid sequence from amino acid 91 to amino acid 100 of SEQ ID NO:4.
2 5 Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID N0:3.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
3 0 (i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:3, but excluding the poly(A) tail at the 3' end of SEQ ID N0:3; and WO 99!42470 PCT/US99/03458 (ab) the nucleotide sequence of the cDNA insert of clone d1c329 1 deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the probe(s);
and (b) a process comprising the steps of:
(i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID N0:3, but excluding the poly(A) tail at the 3' end of SEQ ID N0:3; and (bb) the nucleotide sequence of the cDNA insert of clone dk329_1 deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
2 0 Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:3, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ ID
N0:3 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:3 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:3. Also preferably the polynucleotide isolated 2 5 according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:3 from nucleotide 176 to nucleotide 754, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ iD N0:3 from nucleotide 176 to nucleotide 754, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:3 from nucleotide 176 to 3 0 nucleotide 754. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID
N0:3 from nucleotide 425 to nucleotide 754, and extending contiguously from a nucleotide sequence corresponding to the S' end of said sequence of SEQ ID
NO:3 from nucleotide 425 to nucleotide 754, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:3 from nucleotide 425 to nucleotide 754.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID N0:4;
(b) a fragment of the amino acid sequence of SEQ ID N0:4, the fragment comprising eight contiguous amino acids of SEQ ID N0:4; and (c) the amino acid sequence encoded by the cDNA insert of clone dk329_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID N0:4. In further preferred embodiments, the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID N0:4 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:4, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:4 having biological activity, the fragment comprising the amino acid sequence from amino acid 91 to amino acid 100 of SEQ ID N0:4.
In one embodiment, the present invention provides a composition comprising an 2 0 isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:5;
(b) a polvnucleotide comprising the nucleotide sequence of SEQ ID
N0:5 from nucleotide 190 to nucleotide 1449;
2 5 {c) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:5 from nucleotide 913 to nucleotide 1449;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone fx317_ll deposited under accession number ATCC 98663;
3 0 (e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone fx317_ll deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone fx317_11 deposited under accession number ATCC 98663;

(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone fx317 11 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID N0:6;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:6 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:6;
(j) a polynucleotide which is an allelic variant of a polynucleotide of (a}-(g) above;
(k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above ;
(1) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i); and (m) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i) and that has a length that is at least 25% of the length of SEQ ID N0:5.
Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
N0:5 from nucleotide 190 to nucleotide 1449; the nucleotide sequence of SEQ ID
N0:5 from nucleotide 913 to nucleotide 1449; the nucleotide sequence of the full-length protein 2 0 coding sequence of clone fx317_11 deposited under accession number ATCC
98663; or the nucleotide sequence of a mature protein coding sequence of clone (x317 11 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone fx317_11 deposited under accession number ATCC 98663. In further preferred 2 5 embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:6 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:6, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:6 having 3 0 biological activity, the fragment comprising the amino acid sequence from amino acid 205 to amino acid 214 of SEQ ID N0:6.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID N0:5.

Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:5, but excluding the poly{A} tail at the 3' end of SEQ ID N0:5; and (ab) the nucleotide sequence of the cDNA insert of clone fx317_ll deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the probe(s);
and (b) a process comprising the steps of:
(i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
2 0 (ba) SEQ ID N0:5, but excluding the poly(A} tail at the 3' end of SEQ ID N0:5; and (bb) the nucleotide sequence of the cDNA insert of clone fx317_ll deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in 2 5 conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID NO:S, and extending 3 0 contiguously from a nucleotide sequence corresponding to the 5' end of SEQ
ID N0:5 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:5 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:5. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:5 from nucleotide 190 to nucleotide 1449, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:5 from nucleotide 190 to nucleotide 1449, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:5 from nucleotide 190 to nucleotide 1449. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID
N0:5 from nucleotide 913 to nucleotide 1449, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
N0:5 from nucleotide 913 to nucleotide 1449, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:5 from nucleotide 913 to nucleotide 1449.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID N0:6;
(b) a fragment of the amino acid sequence of SEQ ID N0:6, the fragment comprising eight contiguous amino acids of SEQ ID N0:6; and (c} the amino acid sequence encoded by the cDNA insert of clone fx317_l l deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID N0:6. In further preferred 2 0 embodiments, the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID N0:6 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:6, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:6 having biological activity, the fragment comprising the amino acid sequence from 2 5 amino acid 205 to amino acid 214 of SEQ ID N0:6.
In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:7;
3 0 (b) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:7 from nucleotide 51 to nucleotide 1202;
(c) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone 1p547 4 deposited under accession number ATCC 98663;

WO 99/42470 PCT/US9910345$
(d) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone 1p547 4 deposited under accession number ATCC 98663;
(e) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone Ip547 4 deposited under accession number ATCC 98663;
(f) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone 1p547 4 deposited under accession number ATCC 98663;
(g} a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID N0:8;
(h) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:8 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:8;
(i) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(f) above;
(j) a polynucleotide which encodes a species homologue of the protein of (g) or (h) above ;
(k) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(h); and {1) a polynucleotide that hybridizes under stringent conditions to any 2 0 one of the polynucleotides specified in (a)-{h) and that has a length that is at least 25% of the length of SEQ ID N0:7.
Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
N0:7 from nucleotide 51 to nucleotide 1202; the nucleotide sequence of the full-length protein coding sequence of clone 1p547_4 deposited under accession number ATCC
98663;
2 5 or the nucleotide sequence of a mature protein coding sequence of clone 1p547 4 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone Ip547_4 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein 3 0 comprising a fragment of the amino acid sequence of SEQ ID NO:B having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID NO:8, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:8 having i2 biological activity, the fragment comprising the amino acid sequence from amino acid 187 to amino acid 196 of SEQ ID N0:8.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID N0:7.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:7, but excluding the poly(A) tail at the 3' end of SEQ ID N0:7; and (ab) the nucleotide sequence of the cDNA insert of clone 1p547_4 deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the probe(s);
and 2 0 (b) a process comprising the steps of:
(i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID N0:7, but excluding the poly(A) tail at the 2 5 3' end of SEQ ID N0:7; and (bb) the nucleotide sequence of the cDNA insert of clone 1p547 4 deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
3 0 {iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:7, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ ID
N0:7 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:7 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:7. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:7 from nucleotide 51 to nucleotide 1202, and extending S contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:7 from nucleotide 51 to nucleotide 1202, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:7 from nucleotide 51 to nucleotide 1202.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID N0:8;
(b) a fragment of the amino acid sequence of SEQ . ID N0:8, the fragment comprising eight contiguous amino acids of SEQ ID N0:8; and (c) the amino acid sequence encoded by the cDNA insert of clone 1p547 4 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:B. In further preferred embodiments, the present invention provides a protein comprising a fragment of the 2 0 amino acid sequence of SEQ ID N0:8 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:8, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:8 having biological activity, the fragment comprising the amino acid sequence from amino acid 187 to amino acid 196 of SEQ ID N0:8.
2 5 In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:9;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
3 0 N0:9 from nucleotide 61 to nucleotide 2559;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:9 from nucleotide 904 to nucleotide 2559;

(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone 1v310_7 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone 1v310_7 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone 1v310_7 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone 1v310_7 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:10;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:10 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:10;
(j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(g) above;
(k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above ;
2 0 (I) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i); and (m) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in {a)-(i) and that has a length that is at least 25% of the length of SEQ ID N0:9.
2 5 Preferably, such polynucleotide comprises the nucleotide sequence of SEQ
ID
N0:9 from nucleotide 61 to nucleotide 2559; the nucleotide sequence of SEQ ID
N0:9 from nucleotide 904 to nucleotide 2559; the nucleotide sequence of the full-length protein coding sequence of clone 1v310_7 deposited under accession number ATCC 98663;
or the nucleotide sequence of a mature protein coding sequence of clone Iv310_7 deposited 3 0 under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone 1v310_7 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:10 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID NO:10, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:10 having biological activity, the fragment comprising the amino acid sequence from amino acid 411 to amino acid 420 of SEQ ID NO:10.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID N0:9.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:9, but excluding the poly{A) tail at the 3' end of SEQ ID N0:9; and (ab) the nucleotide sequence of the cDNA insert of clone 1v310_7 deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and 2 0 (iii) isolating the DNA polynucleotides detected with the probe(s);
and (b) a process comprising the steps of:
(i) preparing one or more polynucleotide primers that 2 5 hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID N0:9, but excluding the poly(A) tail at the 3' end of SEQ ID N0:9; and (bb) the nucleotide sequence of the cDNA insert of clone 3 0 1v310_7 deposited under accession number ATCC 98663;
{ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).

Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:9, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ ID
N0:9 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:9 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:9. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:9 from nucleotide 61 to nucleotide 2559, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:9 from nucleotide 61 to nucleotide 2559, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:9 from nucleotide 61 to nucleotide 2559. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID
N0:9 from nucleotide 904 to nucleotide 2559, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
N0:9 from nucleotide 904 to nucleotide 2559, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:9 from nucleotide 904 to nucleotide 2559.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
2 0 (a) the amino acid sequence of SEQ ID N0:10;
(b) a fragment of the amino acid sequence of SEQ ID NO:10, the fragment comprising eight contiguous amino acids of SEQ ID N0:10; and (c) the amino acid sequence encoded by the cDNA insert of clone 1v310_7 deposited under accession number ATCC 98663;
2 S the protein being substantially free from other mammalian proteins.
Preferably such protein comprises the amino acid sequence of SEQ ID N0:10. In further preferred embodiments; the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID NO:10 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids 3 0 of SEQ TD NO:10, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:10 having biological activity, the fragment comprising the amino acid sequence from amino acid 411 to amino acid 420 of SEQ ID NO:10.
In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:

(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:11;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:11 from nucleotide 389 to nucleotide 1330;
(c} a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:11 from nucleotide 1286 to nucleotide 1330;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone nq34_12 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone nq34_12 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone nq34 12 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone nq34_12 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID N0:12;
(i) a polynucleotide encoding a protein comprising a fragment of the 2 0 amino acid sequence of SEQ ID NO:12 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:12;
(j) a polynucieotide which is an allelic variant of a polynucleotide of (a)-{g) above;
(k) a polynucleotide which encodes a species homologue of the protein 2 5 of (h) or (i) above ;
(1) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a}-(i); and (m) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a}-(i) and that has a length that is at least 3 0 25% of the length of SEQ ID N0:11.
Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
NO:11 from nucleotide 389 to nucleotide 1330; the nucleotide sequence of SEQ
ID N0:11 from nucleotide 1286 to nucleotide 1330; the nucleotide sequence of the full-length protein coding sequence of clone nq34_12 deposited under accession number ATCC

98663; or the nucleotide sequence of a mature protein coding sequence of clone nq34_12 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone nq34_12 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:12 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:12, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:12 having biological activity, the fragment comprising the amino acid sequence from amino acid 152 to amino acid 161 of SEQ ID N0:12.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID NO:11.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
2 0 (aa) SEQ ID NO:11, but excluding the poly(A) tail at the 3' end of SEQ ID NO:11; and (ab) the nucleotide sequence of the cDNA insert of clone nq34_12 deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in 2 5 conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the probe{s);
and (b) a process comprising the steps of:
3 0 (i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID N0:11, but excluding the poly(A) tail at the 3' end of SEQ ID N0:11; and (bb) the nucleotide sequence of the cDNA insert of clone nq34_12 deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID NO:11, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ
ID NO:11 to a nucleotide sequence corresponding to the 3' end of SEQ ID NO:11 , but excluding the poly(A) tail at the 3' end of SEQ ID NO:11. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:11 from nucleotide 389 to nucleotide 1330, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:11 from nucleotide 389 to nucleotide 1330, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID NO:11 from nucleotide 389 to nucleotide 1330. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID
NO:11 from nucleotide 1286 to nucleotide 1330, and extending contiguously from a 2 0 nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
NO:11 from nucleotide 128b to nucleotide 1330, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID NO:11 from nucleotide 1286 to nucleotide 1330.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group 2 5 consisting of:
(a) the amino acid sequence of SEQ ID N0:12;
(b) a fragment of the amino acid sequence of SEQ ID N0:12, the fragment comprising eight contiguous amino acids of SEQ ID N0:12; and (c) the amino acid sequence encoded by the cDNA insert of clone 3 0 nq34 12 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID N0:12. In further preferred embodiments, the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID N0:12 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:12, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:12 having biological activity, the fragment comprising the amino acid sequence from amino acid 152 to amino acid 161 of SEQ ID N0:12.
In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:13;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:13 from nucleotide 1026 to nucleotide 1226;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:13 from nucleotide 1101 to nucleotide 1226;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone pj154_1 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone pj154_1 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone pj154_1 deposited under accession number 2 0 ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone pj154_1 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID N0:14;
2 5 (i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:14 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:14;
(j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(g) above;
3 0 (k) a polynucleotide which encodes a species homologue of the protein of (h) or (i} above ;
(1) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i); and (m) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i) and that has a length that is at least 2S% of the length of SEQ ID N0:13. ' Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
N0:13 from nucleotide 1026 to nucleotide 1226; the nucleotide sequence of SEQ
ID N0:13 from nucleotide 1101 to nucleotide 1226; the nucleotide sequence of the full-length protein coding sequence of clone pj154_1 deposited under accession number ATCC
98663;
or the nucleotide sequence of a mature protein coding sequence of clone pj154_1 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone pj154_1 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:14 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:14, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:14 having biological activity, the fragment comprising the amino acid sequence from amino acid 28 to amino acid 37 of SEQ ID N0:14.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
2 0 ID N0:13.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize 2 5 in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:13, but excluding the poly(A) tail at the 3' end of SEQ ID N0:13; and (ab) the nucleotide sequence of the cDNA insert of clone 3 0 pj154_1 deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the probe(s);

and (b) a process comprising the steps of:
(i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID N0:13, but excluding the poly(A) tail at the 3' end of SEQ ID N0:13; and (bb) the nucleotide sequence of the cDNA insert of clone pj154_1 deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:13, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ
ID N0:13 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:13 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:13. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence 2 0 corresponding to the cDNA sequence of SEQ ID N0:13 from nucleotide 1026 to nucleotide 2226, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:13 from nucleotide 1026 to nucleotide 1226, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:13 from nucleotide 1026 to nucleotide 1226. Also preferably the polynucleotide isolated according to the 2 5 above process comprises a nucleotide sequence corresponding to the cDNA
sequence of SEQ ID N0:13 from nucleotide 1101 to nucleotide 1226, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
N0:13 from nucleotide 1101 to nucleotide 1226, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:13 from nucleotide 1101 to nucleotide 1226.
3 0 In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID N0:14;

{b) a fragment of the amino acid sequence of SEQ ID N0:14, the fragment comprising eight contiguous amino acids of SEQ ID N0:14; and (c) the amino acid sequence encoded by the cDNA insert of clone pj154_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID N0:14. In further preferred embodiments, the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID N0:14 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:14, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:14 having biological activity, the fragment comprising the amino acid sequence from amino acid 28 to amino acid 37 of SEQ ID N0:14.
In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:15;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:15 from nucleotide 478 to nucleotide 651;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
2 0 N0:15 from nucleotide 562 to nucleotide 651;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone pk147_1 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the 2 5 cDNA insert of clone pk147_1 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone pk147_1 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
3 0 insert of clone pk147_1 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:16;

WO 99/42470 PC'TIUS99/03458 (i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:16 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:16;
(j) a polynucleotide which is an allelic variant of a polynucleotide of S (a)-(g) above;
(k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above ;
(1) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i); and (m} a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-{i) and that has a length that is at least 25% of the length of SEQ ID N0:15.
Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
N0:15 from nucleotide 478 to nucleotide 651; the nucleotide sequence of SEQ ID
N0:15 from nucleotide 562 to nucleotide 651; the nucleotide sequence of the full-length protein coding sequence of clone pk147_1 deposited under accession number ATCC 98663;
or the nucleotide sequence of a mature protein coding sequence of clone pk147_1 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert 2 0 of clone pk147_1 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:16 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:16, or a polynucleotide encoding 2 5 a protein comprising a fragment of the amino acid sequence of SEQ ID N0:16 having biological activity, the fragment comprising the amino acid sequence from amino acid 24 to amino acid 33 of SEQ ID N0:16.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID N0:15.
3 0 Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:

(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:15, but excluding the poly(A) tail at the 3' end of SEQ ID N0:15; and (ab) the nucleotide sequence of the cDNA insert of clone pk147_1 deposited under accession number ATCC 98663;
(ii) hybridizing said probes} to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the probe(s);
and (b) a process comprising the steps of:
(i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID N0:15, but excluding the poly(A) tail at the 3' end of SEQ ID N0:15; and (bb) the nucleotide sequence of the cDNA insert of clone 2 0 pk147_1 deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
2 5 Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:15, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ
ID N0:15 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:15 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:15. Also preferably the 3 0 polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:15 from nucleotide 478 to nucleotide 651, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:15 from nucleotide 478 to nucleotide 651, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:15 from nucleotide 478 to nucleotide 651. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID
N0:15 from nucleotide 562 to nucleotide 651, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
N0:15 from nucleotide 562 to nucleotide 651, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:15 from nucleotide 562 to nucleotide 651.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:16;
(b) a fragment of the amino acid sequence of SEQ ID N0:16, the fragment comprising eight contiguous amino acids of SEQ ID N0:16; and (c) the amino acid sequence encoded by the cDNA insert of clone pk147_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID N0:16. In further preferred embodiments, the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID N0:16 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids 2 0 of SEQ ID N0:16, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:16 having biological activity, the fragment comprising the amino acid sequence from amino acid 24 to amino acid 33 of SEQ ID N0:16.
In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
2 5 (a) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:17;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:17 from nucleotide 1129 to nucleotide 1896;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
3 0 N0:17 from nucleotide 1189 to nucleotide 1896;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone pt127_1 deposited under accession number ATCC 98663;

(e} a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone pt127_1 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone pt127_1 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone pt127_1 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:18;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:18 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:18;
(j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-(g) above;
(k) a polynucleotide which encodes a species homologue of the protein of (h} or (i) above ;
(1) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-{i); and (m) a polynucleotide that hybridizes under stringent conditions to any 2 0 one of the polynucleotides specified in (a)-(i) and that has a length that is at least 25% of the length of SEQ ID N0:17.
Preferably, such polynucleotide comprises the nucleotide sequence of SEQ ID
N0:17 from nucleotide 1129 to nucleotide 1896; the nucleotide sequence of SEQ
ID N0:17 from nucleotide 1189 to nucleotide 1896; the nucleotide sequence of the full-length 2 5 protein coding sequence of clone pt127_1 deposited under accession number ATCC 98663;
or the nucleotide sequence of a mature protein coding sequence of clone pt127_1 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone pt127_1 deposited under accession number ATCC 98663. In further preferred 3 0 embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:18 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:18, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:18 having biological activity, the fragment comprising the amino acid sequence from amino acid 123 to amino acid 132 of SEQ ID N0:18.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID N0:17.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:17, but excluding the poly(A) tail at the 3' end of SEQ ID N0:17; and (ab) the nucleotide sequence of the cDNA insert of clone pt127_1 deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the probe(s);
and 2 0 (b) a process comprising the steps of:
(i) preparing one or more polynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(ba) SEQ ID N0:17, but excluding the poly(A) tail at the 2 5 3' end of SEQ ID N0:17; and (bb) the nucleotide sequence of the cDNA insert of clone pt127_1 deposited under accession number ATCC 98663;
(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
3 0 (iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:17, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ

ID N0:17 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:17 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:17. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:17 from nucleotide 1129 to nucleotide 1896, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:17 from nucleotide 1129 to nucleotide 1896, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID NO:I7 from nucleotide 1129 to nucleotide 1896. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA
sequence of SEQ ID NO:17 from nucleotide 1189 to nucleotide 1896, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
N0:17 from nucleotide 1189 to nucleotide 1896, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:17 from nucleotide 1189 to nucleotide 1896.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
{a) the amino acid sequence of SEQ ID N0:18;
(b) a fragment of the amino acid sequence of SEQ ID N0:18, the fragment comprising eight contiguous amino acids of SEQ ID N0:18; and 2 0 (c) the amino acid sequence encoded by the cDNA insert of clone pt127_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such protein comprises the amino acid sequence of SEQ ID NO:18. In further preferred embodiments, the present invention provides a protein comprising a fragment of the 2 5 amino acid sequence of SEQ ID N0:18 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:18, or a protein comprising a fragment of the amino acid sequence of SEQ
ID N0:18 having biological activity, the fragment comprising the amino acid sequence from amino acid 123 to amino acid 132 of SEQ ID N0:18.
3 0 In one embodiment, the present invention provides a composition comprising an isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:19;

(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:19 from nucleotide 172 to nucleotide 1041;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
N0:19 from nucleotide 295 to nucleotide 1041;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone qo115_13 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone qo115_13 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of a mature protein coding sequence of clone qo115_13 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding a mature protein encoded by the cDNA
insert of clone qo115_13 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID N0:20;
(i) a polynudeotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:20 having biological activity, the fragment comprising eight contiguous amino acids of SEQ ID N0:20;
2 0 (j) a polynucleotide which is an allelic variant of a polynucleotide of (a)-{g) above;
(k) a polynucleotide which encodes a species homologue of the protein of (h) or (i) above ;
(1) a polynucieotide that hybridizes under stringent conditions to any 2 5 one of the polynucleotides specified in (a)-(i); and (m) a polynucleotide that hybridizes under stringent conditions to any one of the polynucleotides specified in (a)-(i) and that has a length that is at least 25% of the length of SEQ ID N0:19.
Preferably, such poiynucleotide comprises the nucleotide sequence of SEQ ID
3 0 N0:19 from nucleotide 172 to nucleotide 1041; the nucleotide sequence of SEQ ID N0:19 from nucleotide 295 to nucleotide 1041; the nucleotide sequence of the full-length protein coding sequence of clone qo115_13 deposited under accession number ATCC 98663;
or the nucleotide sequence of a mature protein coding sequence of clone qo115_13 deposited under accession number ATCC 98663. In other preferred embodiments, the polynucleotide encodes the full-length or a mature protein encoded by the cDNA
insert of clone qo115 13 deposited under accession number ATCC 98663. In further preferred embodiments, the present invention provides a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:20 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:20, or a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID N0:20 having biological activity, the fragment comprising the amino acid sequence from amino acid 140 to amino acid 149 of SEQ ID N0:20.
Other embodiments provide the gene corresponding to the cDNA sequence of SEQ
ID N0:19.
Further embodiments of the invention provide isolated polynucleotides produced according to a process selected from the group consisting of:
(a) a process comprising the steps of:
(i) preparing one or more polynucleotide probes that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from the group consisting of:
(aa) SEQ ID N0:19, but excluding the poly(A) tail at the 3' end of SEQ ID N0:19; and 2 0 (ab) the nucleotide sequence of the cDNA insert of clone qo115_13 deposited under accession number ATCC 98663;
(ii) hybridizing said probes) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C; and (iii) isolating the DNA polynucleotides detected with the 2 5 probe(s);
and (b) a process comprising the steps of:
(i) preparing one or more poiynucleotide primers that hybridize in 6X SSC at 65 degrees C to a nucleotide sequence selected from 3 0 the group consisting of:
(ba) SEQ ID N0:19, but excluding the poly(A) tail at the 3' end of SEQ ID N0:19; and (bb) the nucleotide sequence of the cDNA insert of clone qo115_13 deposited under accession number ATCC 98663;

(ii) hybridizing said primers) to human genomic DNA in conditions at least as stringent as 4X SSC at 50 degrees C;
(iii) amplifying human DNA sequences; and (iv) isolating the polynucleotide products of step (b)(iii).
Preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:19, and extending contiguously from a nucleotide sequence corresponding to the 5' end of SEQ
ID N0:19 to a nucleotide sequence corresponding to the 3' end of SEQ ID N0:19 , but excluding the poly(A) tail at the 3' end of SEQ ID N0:19. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID N0:19 from nucleotide 172 to nucleotide 1041, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID N0:19 from nucleotide 172 to nucleotide 1041, to a nucleotide sequence corresponding to the 3' end of said sequence of SEQ ID N0:19 from nucleotide 172 to nucleotide 1041. Also preferably the polynucleotide isolated according to the above process comprises a nucleotide sequence corresponding to the cDNA sequence of SEQ ID
NO:19 from nucleotide 295 to nucleotide 1041, and extending contiguously from a nucleotide sequence corresponding to the 5' end of said sequence of SEQ ID
N0:19 korn nucleotide 295 to nucleotide 1041, to a nucleotide sequence corresponding to the 3' end 2 0 of said sequence of SEQ ID N0:19 from nucleotide 295 to nucleotide 1041.
In other embodiments, the present invention provides a composition comprising a protein, wherein said protein comprises an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID N0:20;
2 5 (b) a kagment of the amino acid sequence of SEQ ID N0:20, the fragment comprising eight contiguous amino acids of SEQ ID N0:20; and (c) the amino acid sequence encoded by the cDNA insert of clone qo115_13 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins. Preferably such 3 0 protein comprises the amino acid sequence of SEQ ID N0:20. In further preferred embodiments, the present invention provides a protein comprising a fragment of the amino acid sequence of SEQ ID N0:20 having biological activity, the fragment preferably comprising eight (more preferably twenty, most preferably thirty) contiguous amino acids of SEQ ID N0:20, or a protein comprising a fragment of the amino acid sequence of SEQ

ID N0:20 having biological activity, the fragment comprising the amino acid sequence from amino acid 140 to amino acid 149 of SEQ ID N0:20.
In certain preferred embodiments, the polynucleotide is operably linked to an expression control sequence. The invention also provides a host cell, including bacterial, yeast, insect and mammalian cells, transformed with such poiynucleotide compositions.
Also provided by the present invention are organisms that have enhanced, reduced, or modified expression of the genes) corresponding to the polynucleotide sequences disclosed herein.
Processes are also provided for producing a protein, which comprise:
2 0 (a) growing a culture of the host cell transformed with such polynucleotide compositions in a suitable culture medium; and (b) purifying the protein from the culture.
The protein produced according to such methods is also provided by the present invention.
Protein compositions of the present invention may further comprise a pharmaceutically acceptable carrier. Compositions comprising an antibody which specifically reacts with such protein are also provided by the present invention.
Methods are also provided for preventing, treating or ameliorating a medical condition which comprises administering to a mammalian subject a therapeutically 2 0 effective amount of a composition comprising a protein of the present invention and a pharmaceutically acceptable carrier.
BRIEF DESCRIPTION OF THE 'DRAWINGS
Figures lA and 18 are schematic representations of the pED6 and pNOTs vectors, 2 5 respectively, used for deposit of clones disclosed herein.
DETAILED DESCRIPTION
ISOLATED PROTEINS AND POLYNUCLEOTIDES
Nucleotide and amino acid sequences, as presently determined, are reported 3 0 below for each clone and protein disclosed in the present application. The nucleotide sequence of each clone can readily be determined by sequencing of the deposited clone in accordance with known methods. The predicted amino acid sequence (both full-length and mature forms) can then be determined from such nucleotide sequence. The amino acid sequence of the protein encoded by a particular clone can also be determined by expression of the clone in a suitable host cell, collecting the protein and determining its sequence. For each disclosed protein applicants have identified what they have determined to be the reading frame best identifiable with sequence information available at the time of filing.
As used herein a "secreted" protein is one which, when expressed in a suitable host cell, is transported across or through a membrane, including transport as a result of signal sequences in its amino acid sequence. "Secreted" proteins include without limitation proteins secreted wholly (e.g., soluble proteins) or partially (e.g. , receptors) from the cell in which they are expressed. "Secreted" proteins also include without limitation proteins which are transported across the membrane of the endoplasmic reticulum.
Clone "co821 31"
A polynucleotide of the present invention has been identified as clone "co821_31".
co821_31 was isolated from a human adult brain cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amine acid sequence of the encoded protein. co821 31 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "co821 31 protein').
2 0 The nucleotide sequence of co821 31 as presently determined is reported in SEQ
ID NO:1, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the co821 31 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID N0:2.
Amino acids 87 to 99 of SEQ ID N0:2 are a predicted leader/signal sequence, with the predicted 2 5 mature amino acid sequence beginning at amino acid 100. Due to the hydrophobic nature of the predicted Ieader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the co821 31 protein.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone 3 0 co821 31 should be approximately 2400 bp.
The nucleotide sequence disclosed herein for co821 31 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. co821 31 demonstrated at least some similarity with sequences identified as AA488906 (aa55a02.r1 NCI_CGAP_GCB1 Homo Sapiens cDNA clone 1MAGE:824810 5' similar to TR:G607003 6607003 BETA TRANSDUC1N-LIKE PROTEIN), L26690 (Mus musculus expressed sequence tag EST F101), N30002 (yx82e02.s1 Homo Sapiens cDNA clone 268250 3'), 882926 (EST23j22 Clontech adult human fat cell library HL1108A Homo sapiens cDNA clone 23j22), T20673 (Human gene signature HUMGS01889), and W44749 (zb98b11.s1 Soares parathyroid tumor NbHPA Homo sapiens cDNA clone 320829 3'). The predicted amino acid sequence disclosed herein for co821 31 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted co821 31 protein demonstrated at least some similarity to sequences identified as U51030 (Ydr267cp [Saccharomyces cerevisiae]).
The predicted co82I 31 protein also demonstrated at least some similarity to (general transcriptional repressor Tupl [Schizosaccharomyces pombe]), L28125 (beta transducin-like protein (het-el) [Podospora anserina]), and other proteins containing WD-40 motifs. Based upon sequence similarity, co821 31 proteins and each similar protein or peptide may share at least some activity.
Clone "dk329 1"
A polynucleotide of the present invention has been identified as clone "dk329_1".
dk329_1 was isolated from a human fetal kidney cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was 2 0 identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. dk329_1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "dk329_1 protein').
The nucleotide sequence, of dk329_1 as presently determined is reported in SEQ
2 5 ID N0:3, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the dk329_1 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID N0:4.
Amino acids 71 to 83 of SEQ ID N0:4 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 84. Due to the hydrophobic nature 3 0 of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the dk329_1 protein.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone dk329_1 shauld be approximately 1300 bp.

The nucleotide sequence disclosed herein for dk329_1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. dk329_1 demonstrated at least some similarity with sequences identified as AA147429 (zo39g07.r1 Stratagene endothelial cell 937223 Homo sapiens cDNA clone 589308 5' similar to WP T14G10.6 CE06452 LEUCOCYTE SURFACE
ANTIGEN CD53 LINE), AA190572 (zp42hO8.r1 Stratagene muscle 937209 Homo Sapiens cDNA clone 612159 5' similar to WP T14G10.6 CE06452 LEUCOCYTE SURFACE
ANTIGEN CD53 LINE), AA234042 (zr51a05.s1 Soares NhHMPu Sl Homo sapiens cDNA
clone 666896 3' similar to WP:T24G10.6 CE06452 LEUCOCYTE SURFACE ANTIGEN
CD53 LINE), AA236262 (zr51a05:r1 Soares NhHMPu S1 Homo Sapiens cDNA clone 666896 5' similar to WP:T14G10.6 CE06452 LEUCOCYTE SURFACE ANTIGEN CD53 LINE), N72328 (yv31f12.r1 Homo sapiens cDNA clone 244367 5' similar to SW
A15_HUMAN P41732 CELL SURFACE GLYCOPROTEllV A15), and W50192 (mbO8d07.r1 Life Tech mouse brain Mus musculus cDNA clone 319597 5' similar to SW:CD53 FiLIMAN
P19397 LEUKOCYTE SURFACE ANTIGEN CD53). The predicted amino acid sequence disclosed herein for dk329_1 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted dk329_1 protein demonstrated at least some similarity to sequences identified as 268880 (T14G10.6 [Caenorhabditis elegans]) and a variety of membrane proteins involved in immune 2 0 function. Based upon sequence similarity, dk329_1 proteins and each similar protein or peptide may share at least some activity. The TopPredII computer program predicts three potential transmembrane domains within the dk329_1 protein sequence, centered around amino acids 31, 71, and 103 of SEQ ID N0:4, respectively.
dk329_1 protein was expressed in a COS cell expression system, and an expressed 2 5 protein band of approximately 18 kDa was detected in membrane fractions using SDS
polyacrylamide gel electrophoresis.
Clone "fx317 11"
A polynucleotide of the present invention has been identified as clone "fx317_11".
3 0 fx317_l l was isolated from a human fetal brain cDNA library using methods which are selective for cDNAs encoding secreted proteins {see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. fx317_ll is a full-length WO 99142470 PCTIlJS99103458 clone, including the entire coding sequence of a secreted protein (also referred to herein as "fx317_ll protein').
The nucleotide sequence of (x317_11 as presently determined is reported in SEQ
ID N0:5, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the fx317_11 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID N0:6.
Amino acids 229 to 241 of SEQ ID N0:6 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 242. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the fx317_ll protein.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone fx317_I1 should be approximately 1900 bp.
The nucleotide sequence disclosed herein for fx317_ll was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. fx317_ll demonstrated at least some similarity with sequences identified as AA505600 (nh93hll.sl NCI_CGAP_Br2 Homo sapiens cDNA clone IMAGE:966117), N47450 (yy89c09.r1 Homo Sapiens cDNA clone 280720 5' similar to contains element PTR5 repetitive element), T64549 (Human activated platelet protein-2 2 0 APP-2 cbNA}, and W52611 (zc49e02.r1 Soares senescent fibroblasts NbHSF
Homo Sapiens cDNA clone 325658 5'). The predicted amino acid sequence disclosed herein for fx317_11 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted fx317_11 protein demonstrated at least some similarity to sequences identified as W15413 {Human activated platelet protein-2 APP-2) 2 5 and W 15414 (Human activated platelet protein-2 APP-2 alternatively spliced variant).
APP-2 protein is expressed on activated human platelets. Based upon sequence similarity, fx317_ll proteins and each similar protein or peptide may share at least some activity.
Clone "1p547 4"
3 0 A polynucleotide of the present invention has been identified as clone "1p547 4".
1p547 4 was isolated from a human adult blood (peripheral blood mononuclear cells treated in vivo with granulocyte-colony stimulating factor) cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No.
5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. 1p547_4 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "1p547 4 protein").
The nucleotide sequence of 1p547 4 as presently determined is reported in SEQ
ID
N0:7, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the 1p547 4 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID N0:8.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone 1p547 4 should be approximately 1800 bp.
The nucleotide sequence disclosed herein for 1p547 4 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. 1p547 4 demonstrated at least some similarity with sequences identified as AA442560 (zv75g07.r1 Soares total fetus Nb2HF8 9w Homo sapiens cDNA
clone 759516 5' similar to TR:G4369416436941 PHORBOLIN I). The predicted amino acid sequence disclosed herein for 1p547 4 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted 1p547_4 protein demonstrated at least some similarity to sequences identified as 858704 (Apo-B
RNA editing protein), U03891 (phorbolin I [Homo sapiens]), and U21951 (apolipoprotein B mRNA-editing component 1 [Mus musculus]). U03891 protein (phorbolin I} is 2 0 upregulated in psoriatic keratinocytes. The predicted 1p547 4 protein also contains a cytidine and deoxycytidylate deaminases zinc-binding region signature. Based upon sequence similarity,1p547 4 proteins and each similar protein or peptide may share at least some activity. The TopPredII computer program predicts a potential transmembrane domain within the 1p547_4 protein sequence, centered around amino acid 290 of SEQ ID
N0:8; amino acids 278 to 290 are also a possible leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 291.
1p547 4 protein was expressed in a COS cell expression system, and an expressed protein band of approximately 41 kDa was detected in conditioned medium and membrane fractions using SDS polyacrylamide gel electrophoresis.
Clone "1v310 7"
A polynucleotide of the present invention has been identified as clone "1v310_7".
Clones were first isolated from a human adult thyroid cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No.
5,536,637), or were identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. Probes derived from these cDNAs were then used to isolate 1v310_7 from a human adult brain cDNA library.
1v310_7 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "1v310_7 protein") The nucleotide sequence of 1v310_7 as presently determined is reported in SEQ
ID
N0:9, and includes a poly(A} tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the 1v310_7 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID
NO:10. Amino acids 269 to 281 of SEQ ID NO:10 are a predicted Ieader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 282. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted Ieader/signal sequence not be separated from the remainder of the 1v3I0_7 protein.
Another possible 1v310_7 reading frame and predicted amino acid sequence, encoded by base pairs 1619 to 2188 of SEQ ID N0:9, is reported in SEQ ID
N0:31.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone 1v310_7 should be approximately 3650 bp.
The nucleotide sequence disclosed herein for 1v310_7 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. 1v310_7 demonstrated at least some similarity with sequences identified as N3700I (yy40a01.s1 Homo sapiens cDNA clone 273672 3'), 856228 (yg90dOl.s1 Homo sapiens cDNA clone 40958 3'), and 856310 (yg90dOl.r1 Homo sapiens cDNA clone 40958 5'). The predicted amino acid sequence disclosed herein for 1v310_7 2 5 was searched against the GenPept and GeneSeq amino acid sequence databases using the BLASTX search protocol. The predicted 1v310_7 protein demonstrated at least some similarity to sequences identified as U24223 (alpha-CPl [Homo sapiens]}. Based upon sequence similarity,1v3I0_7 proteins and each similar protein or peptide may share at least some activity. The TopPredII computer program predicts 10 potential 3 0 transmembrane domains within the 1v310_7 protein sequence, centered around amino acids 100,130,160, 210, 280, 490, 520, 600, 690, and 750 of SEQ ID NO:10, respectively.

Clone "nd~4 I2"
A polynucleotide of the present invention has been identified as clone "nq34_12".
nq34_12 was isolated from a human adult blood (erythroleukemia TF-1) cDNA
library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat.
No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein.
nq34_I2 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "nq34 12 protein").
The nucleotide sequence of nq34_12 as presently determined is reported in SEQ
ID NO:11, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the nq34_12 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID
N0:12. Amino acids 287 to 299 of SEQ ID N0:12 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 300. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the nq34_12 protein.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone nq34_12 should be approximately 1700 bp.
2 0 The nucleotide sequence disclosed herein for nq34_22 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. nq34_12 demonstrated at least some similarity with sequences identified as AA126375 (z186c06.r1 Stratagene colon {#937204) Homo sapiens cDNA clone 511498 5'), AA446675 (zw84a08.r1 Soares total fetus Nb2HF8 9w Homo sapiens cDNA
2 5 clone 783638 5'), AA448974 (zx07d05.r1 Soares total fetus Nb2HF8 9w Homo Sapiens cDNA clone 785769 5' similar to SW YNDO_YEAST P40344 HYPOTHETICAL 35.9 KD
PROTEIN IN RPC34-CSE2 IN'TERGENIC REGION), 857902 (F6699 Fetal heart Homo sapiens cDNA clone F6699 5' end), and X07453 (Plasmodium falciparum 11-1 gene part 1). The predicted amino acid sequence disclosed herein for nq34_12 was searched against 3 0 the GenPept and GeneSeq amino acid sequence databases using the BLASTX
search protocol. The predicted nq34_12 protein demonstrated at least some similarity to sequences identified as X77395 (N2040 gene product [Saccharomyces cerevisiae]). Based upon sequence similarity, nq34_12 proteins and each similar protein or peptide may share at least some activity.

nq34_12 protein was expressed in a COS cell expression system, and an expressed protein band of approximately 34 kDa was detected in membrane fractions using SDS
polyacrylarnide gel electrophoresis.
Clone "pj154 1"
A polynucleotide of the present invention has been identified as clone "pj154_1".
pj154_1 was isolated from a human fetal carcinoma (NTD2 cells treated with retinoic acid for 23 days) cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S. Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. pj154_1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "pj154_1 protein').
The nucleotide sequence of pj154_1 as presently determined is reported in SEQ
ID
N0:13, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the pj154_1 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID
N0:14. Amino acids 13 to 25 of SEQ ID N0:14 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 26. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain 2 0 should the predicted leader/signal sequence not be separated from the remainder of the pj154_1 protein.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone pjI54_1 should be approximately 2300 bp.
The nucleotide sequence disclosed herein for pj154_1 was searched against the 2 5 GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. pj154_1 demonstrated at least some similarity with sequences identified as AA223153 (zr07g12.r1 Stratagene NT2 neuronal precursor 937230 Homo Sapiens cDNA clone 650854 5'), AA223170 (zr07g12.s1 Stratagene NT2 neuronal precursor 937230 Homo Sapiens cDNA clone 650854 3' similar to contains Alu repetitive element), 3 0 H16627 (ym26d04.r1 Homo sapiens cDNA clone 49469 5'), and 244660 (H.
sapiens partial cDNA sequence; clone c-26d11). Based upon sequence similarity, pj154_1 proteins and each similar protein or peptide may share at least some activity. The nucleotide sequence of pj154 1 indicates that it may contain an Alu repetitive element.

Clone "pk147 1"
A polynucleotide of the present invention has been identified as clone "pk147_1".
pk147_1 was isolated from a human fetal kidney (293 cell line) cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S.
Pat. No.
S 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein.
pk147_1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "pk147_1 protein').
The nucleotide sequence of pk147_1 as presently determined is reported in SEQ
ID NO:15, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the pk147_1 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID
N0:16. Amino acids 16 to 28 of SEQ ID N0:16 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 29. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the pk147_1 protein.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone pk147_1 should be approximately 1600 bp.
2 0 The nucleotide sequence disclosed herein for pk147_1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. pk147_1 demonstrated at least some similarity with sequences identified as AA126920 (z123hO1.s1 Soares pregnant uterus NbHPU Homo sapiens cDNA
clone 502801 3'), AA406448 (zv12f07.r1 Soares NhHMPu Sl Homo sapiens cDNA
clone 753445 5'), and 851886 (yg78c03.s1 Homo sapiens cDNA clone 39574 3'). Based upon sequence similarity, pk147_1 proteins and each similar protein or peptide may share at least some activity. The TopPredII computer program predicts an additional potential transmembrane domain within the pk147_1 protein sequence centered around amino acid 37 of SEQ ID N0:16.
Clone "pt127 1"
A polynucleotide of the present invention has been identified as clone "pt127_1".
pt127_1 was isolated from a human adult blood (lymphoblastic leukemia MOLT-4) cDNA
fibrary using methods which are seiective for cDNAs encoding secreted proteins (see U.S.

Pat. No. 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein. pt127_1 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "pt127_1 protein').
The nucleotide sequence of pt127_1 as presently determined is reported in SEQ
ID
N0:17, and includes a poiy(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the pt127_I protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID
N0:18. Amino acids 8 to 20 of SEQ ID N0:18 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 21. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the pt127_1 protein.
The EcoRI/Notl restriction fragment obtainable from the deposit containing clone pt127_1 should be approximately 2600 bp.
The nucleotide sequence disclosed herein for pt127_1 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. pt127 1 demonstrated at least some similarity with sequences identified as AA081843 (zn19g10.r1 Stratagene neuroepithelium NT2RAMI 937234 Homo 2 0 sapiens cDNA clone 547938 5') and 839258 (yc91h08.s1 Homo sapiens cDNA
clone 23514 3'). Based upon sequence similarity, pt127_1 proteins and each similar protein or peptide may share at least some activity. The TopPredII computer program predicts five additional potential transmembrane domains within the pt127_1 protein sequence centered around amino acids 60,100,130,190, and 240 of SEQ ID N0:18.
Clo. ne "ao115 13"
A polynucleodde of the present invention has been identified as clone "qo115_13".
qo115_13 was isolated from a human adult brain (corpus callosum) cDNA library using methods which are selective for cDNAs encoding secreted proteins (see U.S.
Pat. No.
3 0 5,536,637), or was identified as encoding a secreted or transmembrane protein on the basis of computer analysis of the amino acid sequence of the encoded protein.
qo115_13 is a full-length clone, including the entire coding sequence of a secreted protein (also referred to herein as "qo115_13 protein').

The nucleotide sequence of qo115 13 as presently determined is reported in SEQ
ID N0:19, and includes a poly(A) tail. What applicants presently believe to be the proper reading frame and the predicted amino acid sequence of the qo115_13 protein corresponding to the foregoing nucleotide sequence is reported in SEQ ID
N0:20. Amino acids 29 to 41 of SEQ ID N0:20 are a predicted leader/signal sequence, with the predicted mature amino acid sequence beginning at amino acid 42. Due to the hydrophobic nature of the predicted leader/signal sequence, it is likely to act as a transmembrane domain should the predicted leader/signal sequence not be separated from the remainder of the qo115_13 protein.
The EcoRI/NotI restriction fragment obtainable from the deposit containing clone qo115_13 should be approximately 1200 bp.
The nucleotide sequence disclosed herein for qo115_l3 was searched against the GenBank and GeneSeq nucleotide sequence databases using BLASTN/BLASTX and FASTA search protocols. No significant hits were found in the database. The nucleotide sequence of qo115_13 indicates that it may contain repetitive elements.
Deposit of Clones Clones co821 31, dk329_1, fx317_11,1p547 4,1v310_7, nq34-12, pj154_l, pk147_l, pt127_l, and qo115_13 were deposited on February 18, 1998 with the American Type 2 0. Culture Collection (10801 University Boulevard, Manassas, Virginia 20110-2209 U.S.A.) as an original deposit under the Budapest Treaty and were given the accession number ATCC 98663, from which each clone comprising a particular polynucleotide is obtainable.
All restrictions on the availability to the public of the deposited material will be irrevocably removed upon the granting of the patent, except for the requirements 2 5 specified in 37 C.F.R. ~ 1.808(b), and the term of the deposit will comply with 37 C.F.R.
~ 1.806.
Each clone has been transfected into separate bacterial cells (E. coli) in this composite deposit. Each clone can be removed from the vector in which it was deposited by performing an EcoRI/NotI digestion (5' site, EcoRI; 3' site, NotI) to produce the 3 0 appropriate fragment for such clone. Each clone was deposited in either the pED6 or pNOTs vector depicted in Figures 1A and 1B, respectively. The pED6dpc2 vector ("pED6") was derived from pED6dpc1 by insertion of a new polylinker to facilitate cDNA cloning {Kaufman et al.,1991, Nucleic Acids Res.19: 4485-4490); the pNOTs vector was derived from pMT2 (Kaufman et nl.,1989, Mol. Cell. Biol. 9: 946-958) by deletion of the DHFR sequences, insertion of a new polylinker, and insertion of the M13 origin of replication in the CIaI site. In some instances, the deposited clone can become "flipped"
(i.e., in the reverse orientation) in the deposited isolate. In such instances, the cDNA insert can still be isolated by digestion with EcoRI and NotI. However, NotI will then produce the 5' site and EcoRI will produce the 3' site for placement of the cDNA in proper orientation for expression in a suitable vector. The cDNA may also be expressed from the vectors in which they were deposited.
Bacterial cells containing a particular clone can be obtained from the composite deposit as follows:
An oligonucleotide probe or probes should be designed to the sequence that is known for that particular clone. This sequence can be derived from the sequences provided herein, or from a combination of those sequences. The sequence of an oligonucleotide probe that was used to isolate or to sequence each full-length clone is identified below, and should be most reliable in isolating the clone of interest.
C~,one Probe Seduence co821 31 SEQ ID N0:21 dk329 1 SEQ ID N0:22 fx317_11 SEQ ID N0:23 2 0 1p547 4 SEQ ID N0:24 1v310_7 SEQ ID N0:25 nq34_12 SEQ ID N0:26 pj154_1 SEQ ID N0:27 pk147_1 SEQ ID NO:28 2 5 pt127_1 SEQ ID N0:29 qo115_13 SEQ ID N0:30 In the sequences listed above which include an N at position 2, that position is occupied in preferred probes/primers by a biotinylated phosphoaramidite residue rather than a 3 0 nucleotide (such as, for example, that produced by use of biotin phosphoramidite (1-dimethoxytrityloxy-2-(N-biotinyl-4-aminobutyl}-propyl-3-O-(2-cyanoethyl)-(N,N-diisopropyl)-phosphoramadite) (Glen Research, cat. no. 10-1953)}.
The design of the oligonucleotide probe should preferably follow these parameters:

{a) It should be designed to an area of the sequence which has the fewest ambiguous bases ("N's'"), if any;
(b) It should be designed to have a Tm of approx. 80 ° C {assuming 2° for each A or T and 4 degrees for each G or C).
The oligonucleotide should preferably be labeled with y 'ZP ATP (specific activity 6000 Ci/mmole) and T4 polynucleotide kinase using commonly employed techniques for labeling oligonucleotides. Other labeling techniques can also be used.
Unincorporated label should preferably be removed by gel filtration chromatography or other established methods. The amount of radioactivity incorporated into the probe should be quantitated by measurement in a scintillation counter. Preferably, specific activity of the resulting probe should be approximately 4e+6 dpm/pmole.
The bacterial culture containing the pool of full-length clones should preferably be thawed and 100 pl of the stock used to inoculate a sterile culture flask containing 25 ml of sterile L-broth containing ampicillin at 100 ug/ml. The culture should preferably be grown to saturation at 37°C, and the saturated culture should preferably be diluted in fresh L-broth. Aliquots of these dilutions should preferably be plated to determine the dilution and volume which will yield approximately 5000 distinct and well-separated colonies on solid bacteriological media containing L-broth containing ampicillin at 100 ug/ml and agar at 1.5% in a 150 mm petri dish when grown overnight at 37°C. Other 2 0 known methods of obtaining distinct, well-separated colonies can also be employed.
Standard colony hybridization procedures should then be used to transfer the colonies to nitrocellulose filters and lyse, denature and bake them.
The filter is then preferably incubated at 65°C for 1 hour with gentle agitation in 6X SSC (20X stock is 175.3 g NaCI/liter, 88.2 g Na citrate/liter, adjusted to pH 7.0 with 2 5 NaOH) containing 0.5% SDS,100 ug/ml of yeast RNA, and 10 mM EDTA
(approximately 10 mL per 150 mm filter). Preferably, the probe is then added to the hybridization mix at a concentration greater than or equal to le+6 dpm/mL. The filter is then preferably incubated at 65°C with gentle agitation overnight. The filter is then preferably washed in 500 mL of 2X SSC/0.5% SDS at room temperature without agitation, preferably followed 3 0 by 500 mL of 2X SSC/0.1% SDS at room temperature with gentle shaking for 15 minutes.
A third wash with 0.1X SSC/0.5% SDS at 65°C for 30 minutes to 1 hour is optional. The filter is then preferably dried and subjected to autoradiography for sufficient time to visualize the positives on the X-ray film. Other known hybridization methods can also be employed.

The positive colonies are picked, grown in culture, and plasmid DNA isolated using standard procedures. The clones can then be verified by restriction analysis, hybridization analysis, or DNA sequencing.
Fragments of the proteins of the present invention which are capable of exhibiting biological activity are also encompassed by the present invention. Fragments of the protein may be in linear form or they may be cyclized using known methods, for example, as described in H.U. Saragovi, et al., Bio/Technology 1J0 773-778 (1992) and in R.S.
McDowell, et al., ]. Amer. Chem. Soc.114. 9245-9253 (1992), both of which are incorporated herein by reference. Such fragments may be fused to carrier molecules such as immunoglobulins for many purposes, including increasing the valency of protein binding sites. For example, fragments of the protein may be fused through "linker' sequences to the Fc portion of an immunoglobulin. For a bivalent form of the protein, such a fusion could be to the Fc portion of an IgG molecule. Other immunoglobulin isotypes may also be used to generate such fusions. For example, a protein - IgM fusion would generate a decavalent form of the protein of the invention.
The present invention also provides both full-length and mature forms of the disclosed proteins. The full-length form of the such proteins is identified in the sequence listing by translation of the nucleotide sequence of each disclosed clone. The mature forms) of such protein may be obtained by expression of the disclosed full-length 2 0 polynucleotide {preferably those deposited with ATCC) in a suitable mammalian cell or other host cell. The sequences) of the mature forms) of the protein may also be determinable from the amino acid sequence of the full-length form.
The present invention also provides genes corresponding to the polynucleotide sequences disclosed herein. "Corresponding genes" are the regions of the genome that 2 5 are transcribed to produce the mRNAs from which cDNA polynucleotide sequences are derived and may include contiguous regions of the genome necessary for the regulated expression of such genes. Corresponding genes may therefore include but are not limited to coding sequences, 5' and 3' untranslated regions, alternatively spliced exons, introns, promoters, enhancers, and silencer or suppressor elements. The corresponding genes can 3 0 be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include the preparation of probes or primers from the disclosed sequence information for identification and/or amplification of genes in appropriate genomic libraries or other sources of genomic materials. An "isolated gene" is a gene that has been separated from the adjacent coding sequences, if any, present in the genome of the organism from which the gene was isolated.
The chromosomal location corresponding to the polynucleotide sequences disclosed herein may also be determined, for example by hybridizing appropriately labeled polynucleotides of the present invention to chromosomes in situ. It may also be possible to determine the corresponding chromosomal location for a disclosed polynucleotide by identifying significantly similar nucleotide sequences in public databases, such as expressed sequence tags (ESTs), that have already been mapped to particular chromosomal locations. For at least some of the polynucleotide sequences I0 disclosed herein, public database sequences having at least some similarity to the polynucleotide of the present invention have been listed by database accession number.
Searches using the GenBank accession numbers of these public database sequences can then be performed at an Internet site provided by the National Center for Biotechnology Information having the address http://www.ncbi.nlm.nih,gov/UniGene/, in order to identify "UruGene clusters" of overlapping sequences. Many of the "UruGene clusters"
so identified will already have been mapped to particular chromosomal sites.
Organisms that have enhanced, reduced, or modified expression of the genes) corresponding to the polynucleotide sequences disclosed herein are provided.
The desired change in gene expression can be achieved through the use of antisense polynucleotides or ribozymes that bind and/or cleave the mRNA transcribed from the gene (Albert and Morris,1994, Trends Pharmacol. Sci.15(7): 250-254; Lavarosky et al.,1997, Biochem. Mol. Med. 62(1): 11-22; and Hampel,1998, Prog. Nucleic Acid Res. Mol.
Biol. 58:1-39; all of which are incorporated by reference herein). Transgenic animals that have multiple copies of the genes) corresponding to the polynucleotide sequences disclosed 2 5 herein, preferably produced by transformation of cells with genetic constructs that are stably maintained within the transformed cells and their progeny, are provided.
Transgenic animals that have modified genetic control regions that increase or reduce gene expression levels, or that change temporal or spatial patterns of gene expression, are also provided (see European Patent No. 0 649 464 B1, incorporated by reference herein).
3 0 In addition, organisms are provided in which the genes) corresponding to the polynucleotide sequences disclosed herein have been partially or completely inactivated, through insertion of extraneous sequences into the corresponding genes) or through deletion of all or part of the corresponding gene{s). Partial or complete gene inactivation can be accomplished through insertion, preferably followed by imprecise excision, of transposable elements (Plasterk,1992, Bioessays 14(9): 629-633; Zwaal et al.,1993, Proc. Natl.
Acad. Sci. LISA 90(16): 7431-7435; Clark et al.,1994, Proc. Natl. Acad. Sci.
i,ISA 91(2): 719-722;
all of which are incorporated by reference herein), or through homologous recombination, preferably detected by positive/negative genetic selection strategies (Mansour et al.,1988, Nature 336: 34&352; U.S. Patent Nos. 5,464,764; 5,487,992; 5,627,059;
5,631,153; 5,614, 396;
5,616,491; and 5,679,523; all of which are incorporated by reference herein).
These organisms with altered gene expression are preferably eukaryotes and more preferably are mammals. Such organisms are useful for the development of non-human models for the study of disorders involving the corresponding gene(s), and for the development of assay systems for the identification of molecules that interact with the protein products) of the corresponding gene(s).
Where the protein of the present invention is membrane-bound (e.g., is a receptor), the present invention also provides for soluble forms of such protein. In such forms, part or all of the intracellular and transmembrane domains of the protein are deleted such that the protein is fully secreted from the cell in which it is expressed. The intracellular and transmembrane domains of proteins of the invention can be identified in accordance with known techniques for determination of such domains from sequence information.
For example, the TopPredII computer program can be used to predict the location of transmembrane domains in an amino acid sequence, domains which are described by the 2 0 location of the center of the transmsmbrane domain, with at least ten transmembrane amino acids on each side of the reported central residue(s).
Proteins and protein fragments of the present invention include proteins with amino acid sequence lengths that are at least 25%(more preferably at least 50%, and most preferably at least 75%) of the length of a disclosed protein and have at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90%
or 95%
identity) with that disclosed protein, where sequence identity is determined by comparing the amino acid sequences of the proteins when aligned so as to maximize overlap and identity while minimizing sequence gaps. Also included in the present invention are proteins and protein fragments that contain a segment preferably comprising 8 or more 3 0 (more preferably 20 or more, most preferably 30 or more) contiguous amino acids that shares at least 75% sequence identity (more preferably, at least 85% identity;
most preferably at least 95% identity) with any such segment of any of the disclosed proteins.
In particular, sequence identity may be determined using WU-BLAST
(Washington University BLAST) version 2.0 software, which builds upon WU-BLAST

version 1.4, which in turn is based on the public domain NCBI-BLAST version 1.4 (Altschui and Gish, 1996, Local alignment statistics, Doolittle ed., Methods in Enzymology 266: 460-480; Altschul et al., 1990, Basic local alignment search tool, Journal of Molecular Biology 215: 403-410; Gish and States, 1993, Identification of protein coding regions by database similarity search, Nature Genetics 3: 266-272; Karlin and Altschul, 1993, Applications and statistics for multiple high-scoring segments in molecular sequences, Proc. Natl. Acad. Sci. USA 90: 5873-5877; all of which are incorporated by reference herein). WU-BLAST version 2.0 executable programs for several UNIX
platforms can be downloaded from ftp:l/blast.wustl.edu/blast/executables. The complete suite of search programs (BLASTP, BLASTN, BLASTX, TBLASTN, and TBLASTX) is provided at that site, in addition to several support programs. WU-BLAST 2.0 is copyrighted and may not be sold or redistributed in any form or manner without the express written consent of the author; but the posted executables may otherwise be freely used for commercial, nonprofit, or academic purposes. In all search programs in the suite -- BLASTP, BLASTN, BLASTX, TBLASTN and TBLASTX -- the gapped alignment routines are integral to the database search itself, and thus yield much better sensitivity and selectivity while producing the more easily interpreted output. Gapping can optionally be turned off in all of these programs, if desired. The default penalty (Q) for a gap of length one is Q=9 for proteins and BLASTP, and Q=10 for BLASTN,.but may be changed to any 2 0 integer value including zero, one through eight, nine, ten, eleven, twelve through twenty, twenty-one through fifty, fifty-one through one hundred, etc. The default per-residue penalty for extending a gap (R) is R=2 for proteins and BLASTP, and R=10 for BLASTN, but may be changed to any integer value including zero, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve through twenty, twenty-one through fifty, fifty-one 2 5 through one hundred, etc. Any combination of values for Q and R can be used in order to align sequences so as to maximize overlap and identity while minimizing sequence gaps.
The default amino acid comparison matrix is BLOSUM62, but other amino acid comparison matrices such as PAM can be utilized.
Species homologues of the disclosed polynucleorides and proteins are also 3 0 provided by the present invention. As used herein, a "species homologue"
is a protein or polynucleotide with a different species of origin from that of a given protein or polynucleotide, but with significant sequence similarity to the given protein or WO 99!42470 PCTIUS99/03458 polynucleotide. Preferably, polynucleotide species homologues have at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90%
identity) with the given polynucleotide, and protein species homologues have at Ieast 30%
sequence identity (more preferably, at least 45% identity; most preferably at least 60%
identity) with the given protein, where sequence identity is determined by comparing the nucleotide sequences of the polynucleotides or the amino acid sequences of the proteins when aligned so as to maximize overlap and identity while minimizing sequence gaps.
Species homologues may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from the desired species. Preferably, species homologues are those isolated from mammalian species. Most preferably, species homologues are those isolated from certain mammalian species such as, for example, Pan troglodytes, Gorilla gorilla, Pongo pygmaeus, Hylobates concolor, Macaca mulatta, Papio papio, Papio hamadryas, Cercopithecus aethiops, Cebus capucinus, Aotus trivirgatus, Sanguinus Oedipus, Microcebus murintcs, Mus musculus, Rattus norvegicus, Cricetulus griseus, Fells catus, Mustela vison, Canis famiIiuris, Oryctolagics cuniculus, Bos taurus, Ovis cries, Sus scrofa, and Ecluus caballus, for which genetic maps have been created allowing the identification of syntenic relationships between the genomic organization of genes in one species and the genomic organization of the related genes in another species (O'Brien and Seu~nez, 1988, Ann. Rev. Genet. 22: 323-351; O'Brien et al., 1993, Nature 2 0 Genetics 3:103-112; Johansson et al.,1995, Genomics 25: 682-690; Lyons et aL,1997, Nature Genetics 15: 47-56; O'Brien et al.,1997, Trends in Genetics 13(10): 393-399;
Carver and Stubbs, 1997, Genome Research 7:1123-1137; all of which are incorporated by reference herein).
The invention also encompasses allelic variants of the disclosed polynucleotides or proteins; that is, naturally-occurring alternative forms of the isolated polynucleotides 2 5 which also encode proteins which are identical or have significantly similar sequences to those encoded by the disclosed polynucleotides. Preferably, allelic variants have at least 60% sequence identity (more preferably, at least 75% identity; most preferably at least 90%
identity) with the given polynucleotide, where sequence identity is determined by comparing the nucleotide sequences of the polynucleotides when aligned so as to maximize 3 0 overlap and identity while minimizing sequence gaps. Allelic variants may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source from individuals of the appropriate species.

The invention also includes polynucleotides with sequences complementary to those of the polynucleotides disclosed herein.
The present invention also includes polynucleotides that hybridize under reduced stringency conditions, more preferably stringent conditions, and most preferably highly stringent conditions, to ~ polynucleotides described herein. Examples of stringency conditions are shown in the table below: highly stringent conditions are those that are at least as stringent as, for example, conditions A-F; stringent conditions are at least as stringent as, for example, conditions G-L; and reduced stringency conditions are at least as stringent as, for example, conditions M-R.

StringencyPolynucleotideHybridHybridization TemperatureWash ConditionHybrid Lengthand Temperature (bp)s Buffers and Buffer' A DNA:DNA z 50 65C; ixSSC -or- 65C; 0.3xSSC
42C; lxSSC, 50% formamide B DNA:DNA <50 TB*; lxSSC TB*; lxSSC

C DNA:RNA x SO 67C; lxSSC -or- 67C; 0.3xSSC
45C; lxSSC, SO% formamide D DNA:RNA <50 Tp"; lxSSC Tp*; lxSSC

E RNA:RNA 2 50 70C; lxSSC -or- 70C; 0.3xSSC
50C; lxSSC, 50% formamide F RNA:RNA <50 TF*; lxSSC TF*; lxSSC

G DNA:DNA z 50 65C; 4xSSC -or- 65C; lxSSC
42C; 4xSSC, 50% formamide H DNA:DNA <50 TH*; 4xSSC TH*; 4xSSC

I DNA:RNA z 50 67C; 4xSSC -or- 67C; lxSSC
45C; 4xSSC, 50% forrnamide J DNA:RNA <50 T~*; 4xSSC T~*; 4xSSC

K RNA:RNA z 50 70C; 4xSSC -or- 67C; ixSSC
50C; 4xSSC, 50% formamide L RNA:RNA <50 T~*; 2xSSC T~*; 2xSSC

M DNA:DNA z 50 50C; 4xSSC -or- 50C; 2xSSC
40C; 6xSSC, 50% formamide N DNA:DNA <50 T~*; 6xSSC Ty*; 6xSSC

O DNA:RNA x SO 55C; 4xSSC -or- 55C; 2xSSC
42C; 6xSSC, 50% formamide P DNA:RNA <50 TP*; 6xSSC T,,*; 6xSSC

Q RNA:RNA 2 50 60C; 4xSSC -or- 60C; 2xSSC
45C; 6xSSC, 50% formamide 2 R RNA:RNA <50 TR*; 4xSSC TR*; 4xSSC

~: The hybrid length is that anticipated for the hybridized regions) of the hybridizing polynucleotides. When hybridizing a polynudeotide to a target polynucleotide of unknown sequence, the hybrid length is assumed to be that of the hybridizing polynucleotide. When polynucieotides of known sequence are hybridized, the 2 5 hybrid length can be determined by aligning the sequences of the polynucleotides and identifying the region or regions of optimal sequence complementarity.
': SSPE (lxSSPE is 0.15M NaCi, lOmM NaH:PO~, and 1.25m-VI EDTA, pH 7.4) can be substituted for SSC
(lxSSC is 0.15V1 NaCI and lSmM sodium citrate) in the hybridization and wash buffers; washes are performed for 15 minutes after hybridization is complete.
3 0 *TB - TR: The hybridization temperature for hybrids anticipated to be less than 50 base pairs in length should be ~-10°C less than the melting temperature (Tm) of the hybrid, where Tm is determined according to the following equations. For hybrids less than 18 base pairs in length, Tm(°C) = 2(# of A + T bases) + 4(# of G +
C bases). For hybrids between 18 and 49 base pairs in length, Tm('C) = 81.5 +
16.6(log,°[\a']) + 0.41(%G+C) (600/N), where ~i is the number of bases in the hybrid, and [\a'] is the concentration of sodium ions in the 3 5 hybridization buffer ([Na'J for lxSSC = 0.165 M).

Additional examples of stringency conditions for polynucleotide hybridization are provided in Sambrook, J., E.F. Fritsch, and T. Maniatis, 1989, Molecular Cloning: A
Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, chapters 9 and 11, and Current Protocols in Molecular Biology,1995, F.M.
Ausubel et al., eds., John Wiley & Sons, Inc., sections 2.10 and 6.3-6.4, incorporated herein by reference.
Preferably, each such hybridizing polynucleotide has a length that is at least 25%(more preferably at least 50%, and most preferably at least 75%) of the length of the polynucleotide of the present invention to which it hybridizes, and has at least 60%
sequence identity (more preferably, at least 75% identity; most preferably at least 90% or 95% identity) with the polynucleotide of the present invention to which it hybridizes, where sequence identity is determined by comparing the sequences of the hybridizing polynucleotides when aligned so as to maximize overlap and identity while minimizing sequence gaps.
The isolated polynucleotide of the invention may be operably linked to an expression control sequence such as the pMT2 or pED expression vectors disclosed in Kaufman et al., Nucleic Acids Res. 9 4485-4490 (1991), in order to produce the protein recombinantly. Many suitable expression control sequences are known in the art. General methods of expressing recombinant proteins are also known and are exemplified in R.
Kaufman, Methods in Enzymology ~ 537-566 (1990). As defined herein "operably 2 0 linked" means that the isolated polynucleotide of the invention and an expression control sequence are situated within a vector or cell in such a way that the protein is expressed by a host cell which has been transformed (transfected) with the ligated polynucleotide/expression control sequence.
A number of types of cells may act as suitable host cells for expression of the 2 5 protein. Mammalian host cells include, for example, monkey COS cells, Chinese Hamster Ovary (CHO) cells, human kidney 293 cells, human epidermal A431 cells, human Co1o205 cells, 3T3 cells, CV-1 cells, other transformed primate cell lines, normal diploid cells, cell strains derived from in vitro culture of primary tissue, primary explants, HeLa cells, mouse L cells, BHK, HL-60, U937, HaK or Jurkat cells.
3 0 Alternatively, it may be possible to produce the protein in lower eukaryotes such as yeast or in prokaryotes such as bacteria. Potentially suitable yeast strains include Saccharomyces cerevisiae, Schizosaccharomyces pombe, Kluyveromyces strains, Candida, or any yeast strain capable of expressing heterologous proteins. Potentially suitable bacterial strains include Escherichia coli, Bacillus subtilis, Salmonella typhimurium, or any bacterial ~5 strain capable of expressing heterologous proteins. If the protein is made in yeast or bacteria, it may be necessary to modify the protein produced therein, for example by phosphorylation or glycosylation of the appropriate sites, in order to obtain the functional protein. Such covalent attachments may be accomplished using known chemical or enzymatic methods.
The protein may also be produced by operably linking the isolated polynucteotide of the invention to suitable control sequences in one or more insect expression vectors, and employing an insect expression system. Materials and methods for baculovirus/insect cell expression systems are commercially available in kit form from, e.g., Invitrogen, San Diego, California, U.S.A. (the MaxBac~ kit), and such methods are well known in the art, as described in Summers and Smith, Texas A~~ricultural E~eriment Station Bulletin No. 1~5,~, y1987), incorporated herein by reference. As used herein, an insect cell capable of expressing a polynucleotide of the present invention is "transformed."
The protein of the invention may be prepared by culturing transformed host cells under culture conditions suitable to express the recombinant protein. The resulting expressed protein may then be purified from such culture (i.e., from culture medium or cell extracts) using known purification processes, such as gel filtration and ion exchange chromatography. The purification of the protein may also include an affinity column 2 0 containing agents which will bind to the protein; one or more column steps over such affinity resins as concanavalin A-agarose, heparin-toyopearl~ or Cibacrom blue Sepharose0; one or more steps involving hydrophobic interaction chromatography using such resins as phenyl ether, butyl ether, or propyl ether; or immunoaffinity chromatography.
2 5 Alternatively, the protein of the invention may also be expressed in a form which will facilitate purification. For example, it may be expressed as a fusion protein, such as those of maltose binding protein (MBP), glutathione-S-transferase (GST) or thioredoxin (TRX). Kits for expression and purification of such fusion proteins are commercially available from New England BioLabs (Beverly, MA), Pharmacia (Piscataway, NJ) and 3 0 Invitrogen Corporation (Carlsbad, CA), respectively. The protein can also be tagged with an epitope and subsequently purified by using a specific antibody directed to such epitope. One such epitope ("Flag") is commercially available from the Eastman Kodak Company (New Haven, CT).

Finally, one or more reverse-phase high performance liquid chromatography (RP-HPLC) steps employing hydrophobic RP-HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, can be employed to further purify the protein. Some or all of the foregoing purification steps, in various combinations, can also be employed to provide a substantially homogeneous isolated recombinant protein. The protein thus purified is substantially free of other mammalian proteins and is defined in accordance with the present invention as an "isolated protein."
The protein of the invention may also be expressed as a product of transgenic animals, e.g., as a component of the milk of transgenic cows, goats, pigs, or sheep which are characterized by somatic or germ cells containing a nucleotide sequence encoding the protein.
The protein may also be produced by known conventional chemical synthesis.
Methods for constructing the proteins of the present invention by synthetic means are known to those skilled in the art. The synthetically-constructed protein sequences, by virtue of sharing primary, secondary or tertiary structural and/or conformational characteristics with proteins may possess biological properties in common therewith, including protein activity. Thus, they may be employed as biologically active or immunological substitutes for natural, purified proteins in screening of therapeutic compounds and in immunological processes for the development of antibodies.
2 0 The proteins provided herein also include proteins characterized by amino acid sequences similar to those of purified proteins but into which modification are naturally provided or deliberately engineered. For example, modifications in the peptide or DNA
sequences can be made by those skilled in the art using known techniques.
Modifications of interest in the protein sequences may include the alteration, substitution, replacement, 2 5 insertion or deletion of a selected amino acid residue in the coding sequence. For example, one or more of the cysteine residues may be deleted or replaced with another amino acid to alter the conformation of the molecule. Techniques for such alteration, substitution, replacement, insertion or deletion are well known to those skilled in the art (see, e.g., U.S. Patent No. 4,518,584}. Preferably, such alteration, substitution, replacement, 3 0 insertion or deletion retains the desired activity of the protein.
Other fragments and derivatives of the sequences of proteins which would be expected to retain protein activity in whole or in part and may thus be useful for screening or other immunological methodologies may also be easily made by those skilled in the art given the disclosures herein. Such modifications are believed to be encompassed by the presentinvention.
USES AND BIOLOGICAL ACTIVITY
5 The polynucleotides and proteins of the present invention are expected to exhibit one or more of the uses or biological activities (including those associated with assays cited herein) identified below. Uses or activities described for proteins of the present invention may be provided by administration or use of such proteins or by administration or use of polynucleotides encoding such proteins (such as, for example, in gene therapies or vectors suitable for introduction of DNA).
Research Uses and Utilities The polynucleotides provided by the present invention can be used by the research community for various purposes. The polynucleotides can be used to express I S recombinant protein for analysis, characterization or therapeutic use; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in disease states); as molecular weight markers on Southern gels; as chromosome markers or tags (when labeled) to identify chromosomes or to map related gene positions; to compare 2 0 with endogenous DNA sequences in patients to identify potential genetic disorders; as probes to hybridize and thus discover novel, related DNA sequences; as a source of information to derive PCR primers for genetic fingerprinting; as a probe to "subtract-out"
known sequences in the process of discovering other novel polynucleotides; for selecting and making oligomers far attachment to a "gene chip" or other support, including for 2 5 examination of expression patterns; to raise anti-protein antibodies using DNA
immunization techniques; and as an antigen to raise anti-DNA antibodies or elicit another immune response. Where the polynucleotide encodes a protein which binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the polynucleotide can also be used in interaction trap assays (such as, for example, those 3 0 described in Gyuris et al.,1993, Cell 7S: 791-803 and in Rossi et al.,1997, Proc. Natl. Acad.
Sci. LISA 94: 8405-8410, all of which are incorporated by reference herein) to identify polynucleotides encoding the other protein with which binding occurs or to identify inhibitors of the binding interaction.
S$

The proteins provided by the present invention can similarly be used in assay to determine biological activity, including in a panel of multiple proteins for high-throughput screening; to raise antibodies or to elicit another immune response; as a reagent (including the labeled reagent) in assays designed to quantitatively determine levels of the protein (or its receptor) in biological fluids; as markers for tissues in which the corresponding protein is preferentially expressed (either constitutively or at a particular stage of tissue differentiation or development or in a disease state); and, of course, to isolate correlative receptors or ligands. Where the protein binds or potentially binds to another protein (such as, for example, in a receptor-ligand interaction), the protein can be used to identify the other protein with which binding occurs or to identify inhibitors of the binding interaction. Proteins involved in these binding interactions can also be used to screen for peptide or small molecule inhibitors or agonists of the binding interaction.
Any or all of these research utilities are capable of being developed into reagent grade or kit format for commercialization as research products.
Methods for performing the uses listed above are well known to those skilled in the art. References disclosing such methods include without limitation "Molecular Cloning: A Laboratory Manual", 2d ed., Cold Spring Harbor Laboratory Press, Sambrook, J., E.F. Fritsch and T. Maniatis eds., 1989, and "Methods in Enzymology: Guide to 2 0 Molecular Cloning Techniques", Academic Press, Berger, S.L. and A.R.
ICimmel eds.,1987.
Nutritional Uses Polynucleotides and proteins of the present invention can also be used as nutritional sources or supplements. Such uses include without limitation use as a protein 2 5 or amino acid supplement, use as a carbon source, use as a nitrogen source and use as a source of carbohydrate. In such cases the protein or polynucleotide of the invention can be added to the feed of a particular organism or can be administered as a separate solid or liquid preparation, such as in the form of powder, pills, solutions, suspensions or capsules. In the case of microorganisms, the protein or polynucleotide of the invention 3 0 can be added to the medium in or on which the microorganism is cultured.
Cytokine and Cell Proliferation/Differentiation Activity A protein of the present invention may exhibit cytokine, cell proliferation (either inducing or inhibiting) or cell differentiation (either inducing or inhibiting} activity or may induce production of other cytokines in certain cell populations. Many protein factors discovered to date, including all known cytokines, have exhibited activity in one or more factor-dependent cell proliferation assays, and hence the assays serve as a convenient confirmation of cytokine activity. The activity of a protein of the present invention is evidenced by any one of a number of routine factor dependent cell proliferation assays for cell lines including, without limitation, 32D, DA2, DA1G, T10, B9, B9/11, BaF3, MC9/G, M+ (preB M+), 2E8, RBS, DA1,123, T1165, HT2, CTLL2, TF-1, Mo7e and CMK.
The activity of a protein of the invention may, among other means, be measured by the following methods:
Assays for T-cell or thymocyte proliferation include without limitation those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M.
Kruisbeek, D.H.
Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., j. Immunal. 137:3494-3500, 1986;
Bertagnolli et al., J. Immunol.145:1706-1712, 1990; Bertagnolli et al., Cellular Immunology 133:327-341, 1991; Bertagnolli, et al., J. Immunol. 149:3778-3783, 1992;
Bowman et al., J.
Immunol. 152:1756-1761,1994.
Assays for cytokine production and/or proliferation of spleen cells, lymph node cells or thymocytes include, without limitation, those described in:
Polyclonal T cell 2 0 stimulation, Kruisbeek, A.M. and Shevach, E.M. In Current Protocols in Immunology. J.E.e.a.
Coligan eds. Vol 1 pp. 3.12.1-3.12.14, John Wiley and Sons, Toronto. 1994; and Measurement of mouse and human Interferon y, Schreiber, R.D. In Current Protocols in Immunology. j.E.e.a. Coligan eds. Vol 1 pp. 6.8.1-6.8.8, John Wiley and Sons, Toronto.1994.
Assays for proliferation and differentiation of hematopoietic and lymphopoietic 2 5 cells include, without limitation, those described in: Measurement of Human and Murine Interleukin 2 and Interleukin 4, Bottomly, K., Davis, L.S. and Lipsky, P.E. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.3.1-6.3.12, John Wiley and Sons, Toronto. 1991; deVries et al., J. Exp. Med. 173:1205-1211, 1991; Moreau et al., Nature 336:690-692, 1988; Greenberger et al., Proc. Natl. Acad. Sci. U.S.A. 80:2931-2938, 1983;
3 0 Measurement of mouse and human interleukin 6 - Nordan, R. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.6.1-6.6.5, John Wiley and Sons, Toronta.1991;
Smith et al., Proc. Natl. Acad. Sci. U.S.A. 83:1857-1861, 1986; Measurement of human Interleukin 11- Bennett, F., Giannotti, J., Clark, S.C. and Turner, K. J. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.15.1 John Wiley and Sons, Toronto.1991;

Measurement of mouse and human Interleukin 9 - Ciarletta, A., Giannotti, J., Clark, S.C.
and Turner, K.J. In Current Protocols in Immunology. J.E.e.a. Coligan eds. Vol 1 pp. 6.13.1, John Wiley and Sons, Toronto.1991.
Assays for T-cell clone responses to antigens (which will identify, among others, proteins that affect APC-T cell interactions as well as direct T-cell effects by measuring proliferation and cytokine production) include, without limitation, those described in:
Current Protocols in Immunology, Ed by J. E. Coligan, A,M. Kruisbeek, D.H.
Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function; Chapter 6, Cytokines and their cellular receptors; Chapter 7, Immunologic studies in Humans);
Weinberger et al., Proc. Natl. Acad. Sci. USA 77:6091-6095, 1980; Weinberger et aL, Eur. J.
Immun.

11:405-411, 1981; Takai et al., J. Immunol. 137:3494-3500, 1986; Takai et al., j. Immunol.
140:508-512, 1988.
Immune Stimula~~ or Sup~ressin Activ h~
A protein of the present invention may also exhibit immune stimulating or immune suppressing activity, including without limitation the activities for which assays are described herein. A protein may be useful in the treatment of various immune deficiencies and disorders (including severe combined immunodeficiency (SCID)), e.g., 2 0 in regulating (up or down) growth and proliferation of T and/or B
lymphocytes, as well as effecting the cytolytic activity of NK cells and other cell populations.
These immune deficiencies may be genetic or be caused by viral (e.g., HIV) as well as bacterial or fungal infections, or may result from autoimmune disorders. More specifically, infectious diseases causes by viral, bacterial, fungal or other infection may be treatable using a 2 5 protein of the present invention, including infections by HIV, hepatitis viruses, herpesviruses, mycobacteria, Leishmania spp., malaria spp. and various fungal infections such as candidiasis. Of course, in this regard, a protein of the present invention may also be useful where a boost to the immune system generally may be desirable, i.e., in the treatment of cancer.
3 0 Autoimmune disorders which may be treated using a protein of the present invention include, for example, connective tissue disease, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, autoimmune pulmonary inflammation, Guillain-Barre syndrome, autoimmune thyroiditis, insulin dependent diabetes mellitis, myasthenia gravis, graft-versus-host disease and autoimmune inflammatory eye disease.

Such a protein of the present invention may also to be useful in the treatment of allergic reactions and conditions, such as asthma (particularly allergic asthma) or other respiratory problems. Other conditions, in which immune suppression is desired (including, for example, organ transplantation}, may also be treatable using a protein of the present invention.
Using the proteins of the invention it may also be possible to regulate immune responses in a number of ways. Down regulation may be in the form of inhibiting or blocking an immune response already in progress or may involve preventing the induction of an immune response. The functions of activated T cells may be inhibited by suppressing T cell responses or by inducing specific tolerance in T cells, or both.
Immunosuppression of T cell responses is generally an active, non-antigen-specific, process which requires continuous exposure of the T cells to the suppressive agent.
Tolerance, which involves inducing non-responsiveness or anergy in T cells, is distinguishable from immunosuppression in that it is generally antigen-specific and persists after exposure to the tolerizing agent has ceased. Operationally, tolerance can be demonstrated by the lack of a T cell response upon reexposure to specific antigen in the absence of the tolerizing agent.
Down regulating or preventing one or more antigen functions (including without limitation B lymphocyte antigen functions (such as , for example, B7)), e.g., preventing 2 0 high level lymphokine synthesis by activated T cells, will be useful in situations of tissue, skin and organ transplantation and in graft-versus-host disease (GVHD). For example, blockage of T cell function should result in reduced tissue destruction in tissue transplantation. Typically, in tissue transplants, rejection of the transplant is initiated through its recognition as foreign by T cells, followed by an immune reaction that destroys 2 5 the transplant. The administration of a molecule which inhibits or blocks interaction of a B7 lymphocyte antigen with its natural ligand(s) on immune cells (such as a soluble, monomeric form of a peptide having B7-2 activity alone or in conjunction with a monomeric form of a peptide having an activity of another B lymphocyte antigen (e.g., B7-1, B7-3) or blocking antibody), prior to transplantation can lead to the binding of the 3 0 molecule to the natural ligand(s} on the immune cells without transmitting the corresponding costimulatory signal. Blocking B lymphocyte antigen function in this matter prevents cytokine synthesis by immune cells, such as T cells, and thus acts as an immunosuppressant. Moreover, the lack of costimulation may also be sufficient to anergize the T cells, thereby inducing tolerance in a subject. Induction of long-term WO 99/42470 PCT/US99/0345$
tolerance by B lymphocyte antigen-blocking reagents may avoid the necessity of repeated administration of these blocking reagents. To achieve sufficient immunosuppression or tolerance in a subject, it may also be necessary to block the function of a combination of B lymphocyte antigens.
The efficacy of particular blocking reagents in preventing organ transplant rejection or GVHD can be assessed using animal models that are predictive of efficacy in humans. Examples of appropriate systems which can be used include allogeneic cardiac grafts in rats and xenogeneic pancreatic islet cell grafts in mice, both of which have been used to examine the immunosuppressive effects of CTLA4Ig fusion proteins in vivo as described in Lenschow et al., Science 257:789-792 (1992) and Turka et al., Proc. Natl. Acad.
Sci USA, 89:11102-11105 (1992). In addition, murine models of GVHD (see Paul ed., Fundamental Immunology, Raven Press, New York, 1989, pp. 846-847) can be used to determine the effect of blocking B lymphocyte antigen function in vivo on the development of that disease.
Blocking antigen function may also be therapeutically useful for treating autoimmune diseases. Many autoimmune disorders are the result of inappropriate activation of T cells that are reactive against self tissue and which promote the production of cytokines and autoantibodies involved in the pathology of the diseases.
Preventing the activation of autoreactive T cells may reduce or eliminate disease symptoms.
2 0 Administration of reagents which block costimulation of T cells by disrupting receptor:ligand interactions of B lymphocyte antigens can be used to inhibit T
cell activation and prevent production of autoantibodies or T cell-derived cytokines which may be involved in the disease process. Additionally, blocking reagents may induce antigen-specific tolerance of autoreactive T cells which could lead to long-term relief from 2 5 the disease. The efficacy of blocking reagents in preventing or alleviating autoimmune disorders can be determined using a number of well-characterized animal models of human autoimmune diseases. Examples include murine experimental autoimmune encephalitis, systemic lupus erythmatosis in MRL/lpr/Ipr mice or NZB hybrid mice, murine autoimmune collagen arthritis, diabetes mellitus in NOD mice and BB
rats, and 3 0 murine experimental myasthenia gravis (see Paul ed., Fundamental Immunology, Raven Press, New York,1989, pp. 840-856).
Upregulation of an antigen function (preferably a B lymphocyte antigen function), as a means of up regulating immune responses, may also be useful in therapy.
Upregulation of immune responses may be in the form of enhancing an existing immune response or eliciting an initial immune response. For example, enhancing an immune response through stimulating B lymphocyte antigen function may be useful in cases of viral infection. In addition, systemic viral diseases such as influenza, the common cold, and encephalitis might be alleviated by the administration of stimulatory forms of B
lymphocyte antigens systemically.
Alternatively, anti-viral immune responses may be enhanced in an infected patient by removing T cells from the patient, costimulating the T cells in vitro with viral antigen-pulsed APCs either expressing a peptide of the present invention or together with a stimulatory form of a soluble peptide of the present invention and reintroducing the in 10 vitro activated T cells into the patient. Another method of enhancing anti-viral immune responses would be to isolate infected cells from a patient, transfect them with a nucleic acid encoding a protein of the present invention as described herein such that the cells express all or a portion of the protein on their surface, and reintroduce the transfected cells into the patient. The infected cells would now be capable of delivering a costimulatory signal to, and thereby activate, T cells in vivo.
In another application, up regulation or enhancement of antigen function (preferably B lymphocyte antigen function) may be useful in the induction of tumor immunity. Tumor cells (e.g., sarcoma, melanoma, lymphoma, leukemia, neuroblastoma, carcinoma) transfected with a nucleic acid encoding at least one peptide of the present 2 0 invention can be administered to a subject to overcome tumor-specific tolerance in the subject. If desired, the tumor cell can be transfected to express a combination of peptides.
For example, tumor cells obtained from a patient can be transfected ex vivo with an expression vector directing the expression of a peptide having B7-2-like activity alone, or in conjunction with a peptide having B7-1-like activity and/or B7-3-like activity. The 2 5 transfected tumor cells are returned to the patient to result in expression of the peptides on the surface of the transfected cell. Alternatively, gene therapy techniques can be used to target a tumor cell for transfection in vivo.
The presence of the peptide of the present invention having the activity of a B
lymphocyte antigens) on the surface of the tumor cell provides the necessary 3 0 costimulation signal to T cells to induce a T cell mediated immune response against the transfected tumor cells. In addition, tumor cells which lack MHC class I or MHC class II
molecules, or which fail to reexpress sufficient amounts of MHC class I or MHC
class II
molecules, can be transfected with nucleic acid encoding all or a portion of (e.g., a cytoplasmic-domain truncated portion) of an MHC class I a chain protein and (3z microglobulin protein or an MHC class II a chain protein and an MHC class II p chain protein to thereby express MHC class I or MHC class II proteins on the cell surface.
Expression of the appropriate class I or class II MHC in conjunction with a peptide having the activity of a B lymphocyte antigen (e.g., B7-1, B7-2, B7-3) induces a T
cell mediated 5 immune response against the transfected tumor cell. Optionally, a gene encoding an antisense construct which blocks expression of an MHC class II associated protein, such as the invariant chain, can also be cotransfected with a DNA encoding a peptide having the activity of a B lymphocyte antigen to promote presentation of tumor associated antigens and induce tumor specific immunity. Thus, the induction of a T cell mediated immune response in a human subject may be sufficient to overcome tumor-specific tolerance in the subject.
The activity of a protein of the invention may, among other means, be measured by the following methods:
Suitable assays for thymocyte or splenocyte cytotoxicity include, without 15 limitation, those described in: Current Protocols in Immunology, Ed by J.
E. Coligan, A.M.
Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-lnterscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Herrmann et al., Proc. Natl.
Acad. Sci.
USA 78:2488-2492,1981; Herrmann et al., J. immunol.128:1968-1974,1982; Handa et al., 2 0 J. Immunol. 135:1564-1572,1985; Takai et al., J. Immunol.137:3494-3500,1986; Takai et al., J. Immunol.140:508-512, 1988; Herrmann et al., Proc. Natl. Acad. Sci. USA
78:2488-2492, 1981; Herrmann et al., J. Immunol. 128:1968-1974, 1982; Handa et al., J.
Immunol.
135:1564-1572, 1985; Takai et al., J. Immunol. 137:3494-3500, 1986; Bowmanet al., J
Virology 61:1992-1998; Takai et al., J. Immunol. 140:508-512, 1988;
Bertagnolli et al., 2 5 Cellular Immunology 133:327-341,1991; Brown et al., j. immunol. 153:3079-3092, 1994.
Assays for T-cell-dependent immunogiobulin responses and isotype switching (which will identify, among others, proteins that modulate T-cell dependent antibody responses and that affect Thl /Th2 profiles) include, without limitation, those described in: Maliszewski, J. Immunol. 144:3028-3033,1990; and Assays for B cell function: In vitro 3 0 antibody production, Mond, J.J. and Brunswick, M. In Current Protocols in Immunology.
J.E.e.a. Coligan eds. Vol 1 pp. 3.8.1-3.8.16, John Wiley and Sons, Toronto.
1994.
Mixed lymphocyte reaction (MLR) assays (which will identify, among others, proteins that generate predominantly Th1 and CTL responses) include, without limitation, those described in: Current Protocols in Immunology, Ed by J. E. Coligan, A.M.
Kruisbeek, D.H. Margulies, E.M. Shevach, W Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 3, In Vitro assays for Mouse Lymphocyte Function 3.1-3.19; Chapter 7, Immunologic studies in Humans); Takai et al., J. Immunol. 137:3494-3500,1986; Takai et al., J. Immunol.140:508-512, 1988; Bertagnolli et al., J. Immunol. 149:3778-3783,1992.
5 Dendritic cell-dependent assays (which will identify, among others, proteins expressed by dendritic cells that activate naive T-cells) include, without limitation, those described in: Guery et al., J. Irnrnunol. 134:536-544, 1995; Inaba et al., Journal of Experimental Medicine 173:549-559, 1991; Macatonia et al., Journal of Immunology 154:5071-5079,1995; Porgador et al., Journal of Experimental Medicine 182:255-260,1995;
10 Nair et al., Journal of Virology 67:4062-4069, 1993; Huang et al., Science 264:961-965, 1994; Macatonia et al., Journal of Experimental Medicine 169:1255-1264,1989;
Bhardwaj et al., Journal of Clinical Investigation 94:797-807, 1994; and Inaba et al., Journal of Experimental Medicine 172:631-640,1990.
Assays for lymphocyte survival/apoptosis (which will identify, among others, 15 proteins that prevent apoptosis after superantigen induction and proteins that regulate lymphocyte homeostasis} include, without limitation, those described in:
Darzynkiewicz et al., Cytometry 13:795-808,1992; Gorczyca et al., Leukemia 7:659-670,1993;
Gorczyca et al., Cancer Research 53:1945-1951, 1993; Itoh et al., Cell 66:233-243, 1991;
Zacharchuk, Journal of Immunology 145:4037-4045, 1990; Zamai et al., Cytometry 14:891-897, 1993;
2 0 Gorczyca et al., International Journal of Oncology 1:639-648,1992.
Assays for proteins that influence early steps of T-cell commitment and development include, without limitation, those described in: Antica et al., Blood 84:111-117, 1994; Fine et al., Cellular Immunology 155:111-122, 1994; Galy et al., Blood 85:2770-2778,1995; Toki et al., Proc. Nat. Acad Sci. USA 88:7548-7551,1991.
Hemato~cZiesis Regulating Ac_tivitv A protein of the present invention may be useful in regulation of hematopoiesis and, consequently, in the treatment of myeloid or lymphoid cell deficiencies.
Even marginal biological activity in support of colony forming cells or of factor-dependent cell 3 0 lines indicates involvement in regulating hematopoiesis, e.g. in supporting the growth and proliferation of erythroid progenitor cells alone or in combination with other cytokines, thereby indicating utility, for example, in treating various anemias or for use in conjunction with irradiation/chemotherapy to stimulate the production of erythroid precursors and/or erythroid cells; in supporting the growth and proliferation of myeloid WO 99!42470 PCT/US99/03458 cells such as granulocytes and monocytes/macrophages (i.e., traditional CSF
activity) useful, for example, in conjunction with chemotherapy to prevent or treat consequent myelo-suppression; in supporting the growth and proliferation of megakaryocytes and consequently of platelets thereby allowing prevention or treatment of various platelet 5 disorders such as thrombocytopenia, and generally for use in place of or complimentary to platelet transfusions; and/or in supporting the growth and proliferation of hematopoietic stem cells which are capable of maturing to any and all of the above-mentioned hematopoietic cells and therefore find therapeutic utility in various stem cell disorders (such as those usually treated with transplantation, including, without 10 limitation, aplastic anemia and paroxysmal nocturnal hemoglobinuria), as well as in repopulating the stem cell compartment post irradiation/chemotherapy, either in-vivo or ex-vivo (i.e., in conjunction with bone marrow transplantation or with peripheral progenitor cell transplantation (homologous or heterologous)) as normal cells or genetically manipulated for gene therapy.
15 The activity of a protein of the invention may, among other means, be measured by the following methods:
Suitable assays for proliferation and differentiation of various hematopoietic lines are cited above.
Assays for embryonic stem cell differentiation (which will identify, among others, 2 0 proteins that influence embryonic differentiation hematopoiesis) include, without limitation, those described in: Johansson et al. Cellular Biology 15:141-151,1995; Keller et al., Molecular and Cellular Biology 13:473-486, 1993; McClanahan et al., Blood 81:2903-2915, 1993.
Assays for stem cell survival and differentiation (which will identify, among 2 5 others, proteins that regulate lympho-hematopoiesis) include, without limitation, those described in: Methylcellulose colony forming assays, Freshney, M.G. In Culture of Hematopoietic Cells. R.I. Freshney, et aI. eds. Vol pp. 265-268, Wiley-Liss, Inc., New York, NY. 1994; Hirayama et al., Proc. Natl. Acad. Sci. USA 89:5907-5911, 1992;
Primitive hematopoietic colony forming cells with high proliferative potential, McNiece, LK. and 3 0 Briddell, R.A. In Culture of Hernatopoietic Cells. R.I. Freshney, et al.
eds. Vol pp. 23-39, Wiley-Liss, Inc., New York, NY.1994; Neben et al., Experimental Hematology 22:353-359, 1994; Cobblestone area forming cell assay, Ploemacher, R.E. In C~~Itt~re of Hematopoietic Cells. R.I. Freshney, et aI. eds. Vol pp. 1-21, Wiley-Liss, Inc.., New York, NY.1994; Long term bone marrow cultures in the presence of stromal cells, Spooncer, E., Dexter, M. and Allen, T. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp. 163-179, Wiley-Liss, Inc., New York, NY.1994; Long term culture initiating cell assay, Sutherland, H.J. In Culture of Hematopoietic Cells. R.I. Freshney, et al. eds. Vol pp.139-162, Wiley-Liss, Inc., New York, NY. 1994.

Tissue Growth Activity A protein of the present invention also may have utility in compositions used for bone, cartilage, tendon, ligament and/or nerve tissue growth or regeneration, as well as for wound healing and tissue repair and replacement, and in the treatment of burns, 10 incisions and ulcers.
A protein of the present invention, which induces cartilage and/or bone growth in circumstances where bone is not normally formed, has application in the healing of bone fractures and cartilage damage or defects in humans and other animals.
Such a preparation employing a protein of the invention may have prophylactic use in closed as 15 well as open fracture reduction and also in the improved fixation of artificial joints. De novo bone formation induced by an osteogenic agent contributes to the repair of congenital, trauma induced, or oncologic resection induced craniofacial defects, and also is useful in cosmetic plastic surgery.
A protein of this invention may also be used in the treatment of periodontal 2 0 disease, and in other tooth repair processes. Such agents may provide an environment to attract bone-forming cells, stimulate growth of bone-forming cells or induce differentiation of progenitors of bone-forming cells. A protein of the invention may also be useful in the treatment of osteoporosis or osteoarthritis, such as through stimulation of bone and/or cartilage repair or by blocking inflammation or processes of tissue 2 5 destruction (collagenase activity, osteoclast activity, etc.) mediated by inflammatory processes.
Another category of tissue regeneration activity that may be attributable to the protein of the present invention is tendon/ligament formation. A protein of the present invention, which induces tendon/ligament-like tissue or other tissue formation in 3 0 circumstances where such tissue is not normally formed, has application in the healing of tendon or ligament tears, deformities and other tendon or ligament defects in humans and other animals. Such a preparation employing a tendon/ligament-like tissue inducing protein may have prophylactic use in preventing damage to tendon or ligament tissue, as well as use in the improved fixation of tendon or ligament to bone or other tissues, and in repairing defects to tendon or ligament tissue. De novo tendon/ligament-like tissue formation induced by a composition of the present invention contributes to the repair of congenital, trauma induced, or other tendon or ligament defects of other origin, and is also useful in cosmetic plastic surgery for attachment or repair of tendons or ligaments. The 5 compositions of the present invention may provide an environrnent to attract tendon- or ligament-forming cells, stimulate growth of tendon- or ligament-forming cells, induce differentiation of progenitors of tendon- or ligament-forming cells, or induce growth of tendon/ligament cells or progenitors ex vivo for return in vivo to effect tissue repair. The compositions of the invention may also be useful in the treatment of tendinitis, carpal 10 tunnel syndrome and other tendon or ligament defects. The compositions may also include an appropriate matrix and/or sequestering agent as a carrier as is well known in the art.
The protein of the present invention may also be useful for proliferation of neural cells and for regeneration of nerve and brain tissue, i.e. for the treatment of central and 15 peripheral nervous system diseases and neuropathies, as well as mechanical and traumatic disorders, which involve degeneration, death or trauma to neural cells or nerve tissue. More specifically, a protein may be used in the treatment of diseases of the peripheral nervous system, such as peripheral nerve injuries, peripheral neuropathy and localized neuropathies, and central nervous system diseases, such as Alzheimer's, 2 0 Parkinson s disease, Huntingtori s disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome. Further conditions which may be treated in accordance with the present invention include mechanical and traumatic disorders, such as spinal cord disorders, head trauma and cerebrovascular diseases such as stroke. Peripheral neuropathies resulting from chemotherapy or other medical therapies may also be treatable using a protein of the 2 5 invention.
Proteins of the invention may also be useful to promote better or faster closure of non-healing wounds, including without limitation pressure ulcers, ulcers associated with vascular insufficiency, surgical and traumatic wounds, and the like.
It is expected that a protein of the present invention may also exhibit activity for 3 0 generation or regeneration of other tissues, such as organs (including, for example, pancreas, liver, intestine, kidney, skin, endothelium), muscle (smooth, skeletal or cardiac) and vascular (including vascular endothelium) tissue, or for promoting the growth of cells comprising such tissues. Part of the desired effects may be by inhibition or modulation of fibrotic scarring to allow normal tissue to regenerate. A protein of the invention may also exhibit angiogenic activity.
A protein of the present invention may also be useful for gut protection or regeneration and treatment of lung or liver fibrosis, reperfusion injury in various tissues, 5 and conditions resulting from systemic cytokine damage.
A protein of the present invention may also be useful for promoting or inhibiting differentiation of tissues described above from precursor tissues or cells; or for inhibiting the growth of tissues described above.
The activity of a protein of the invention may, among other means, be measured 10 by the following methods:
Assays for tissue generation activity include, without limitation, those described in: International Patent Publication No. W095/16035 (bone, cartilage, tendon);
International Patent Publication No. W095/05846 (nerve, neuronal);
International Patent Publication No. W091 /07491 (skin, endothelium ).
15 Assays for wound healing activity include, without limitation, those described in:
Winter, Epidermal Wound Healing,, pps. 71-112 (Maibach, HI and Rovee, DT, eds.), Year Book Medical Publishers, Inc., Chicago, as modified by Eaglstein and Mertz, J.
Invest.
Dermatol 71:382-84 (1978).
20 Activin/Inhibin Activity A protein of the present invention may also exhibit activin- or inhibin-related activities. Inhibins are characterized by their ability to inhibit the release of follicle stimulating hormone (FSH), while activins and are characterized by their ability to stimulate the release of follicle stimulating hormone (FSH). Thus, a protein of the present 2 5 invention, alone or in heterodimers with a member of the inhibin a family, may be useful as a contraceptive based on the ability of inhibins to decrease fertility in female mammals and decrease spermatogenesis in male mammals. Administration of sufficient amounts of other inhibins can induce infertility in these mammals. Alternatively, the protein of the invention, as a homodimer or as a heterodimer with other protein subunits of the inhibin-3 0 ~i group, may be useful as a fertility inducing therapeutic, based upon the ability of activin molecules in stimulating FSH release from cells of the anterior pituitary.
See, for example, United States Patent 4,798,885. A protein of the invention may also be useful for advancement of the onset of fertility in sexually immature mammals, so as to increase the lifetime reproductive performance of domestic animals such as cows, sheep and pigs.

The activity of a protein of the invention may, among other means, be measured by the following methods:
Assays for activin/inhibin activity include, without limitation, those described in:
Vale et al., Endocrinology 91:562-572,1972; Ling et al., Nature 321:779-782,1986; Vale et al., Nature 321:776-779,1986; Mason et al., Nature 318:659-663, 1985; Forage et al., Proc.
Natl. Acad. Sci. USA 83:3091-3095,1986.
Chemotactic/Chemokinetic Activity A protein of the present invention may have chemotactic or chemokinetic activity (e.g., act as a chemokine) for mammalian cells, including, for example, monocytes, fibroblasts, neutrophils, T-cells, mast cells, eosinophils, epithelial and/or endothelial cells.
Chemotactic and chemokinetic proteins can be used to mobilize or attract a desired cell population to a desired site of action. Chemotactic or chemokinetic proteins provide particular advantages in treatment of wounds and other trauma to tissues, as well as in treatment of localized infections. For example, attraction of lymphocytes, monocytes or neutrophils to tumors or sites of infection may result in improved immune responses against the tumor or infecting agent.
A protein or peptide has chemotactic activity for a particular cell population if it can stimulate, directly or indirectly, the directed orientation or movement of such cell 2 0 population. Preferably, the protein or peptide has the ability to directly stimulate directed movement of cells. Whether a particular protein has chemotactic activity for a population of cells can be readily determined by employing such protein or peptide in any known assay for cell chemotaxis.
The activity of a protein of the invention may, among other means, be measured 2 5 by the following methods:
Assays for chemotactic activity (which will identify proteins that induce or prevent chemotaxis) consist of assays that measure the ability of a protein to induce the migration of cells across a membrane as well as the ability of a protein to induce the adhesion of one cell population to another cell population. Suitable assays for movement and adhesion 3 0 include, without limitation, those described in: Current Protocols in Immunology, Ed by J.E. Coligan, A.M. Kruisbeek, D.H. Margulies, E.M. Shevach, W.Strober, Pub.
Greene Publishing Associates and Wiley-Interscience (Chapter 6.12, Measurement of alpha and beta Chemokines 6.12.1-6.12.28; Taub et al. ]. Clin. Invest. 95:1370-1376, 1995; Lind et al.

WO 99/42470 PCT/US99/0345$
APMIS 103:140-146,1995; Muller et al Eur. J. Immunol. 25: 1744-1748; Gruber et al. J. of Immunol. 152:5860-5867,1994; Johnston et al. J. of Immunol. 153:1762-1768, 1994.
Hemostatic and Thrombolxtic Activit3r 5 A protein of the invention may also exhibit hemostatic or thrombolytic activity.
As a result, such a protein is expected to be useful in treatment of various coagulation disorders (including hereditary disorders, such as hemophilias) or to enhance coagulation and other hemostatic events in treating wounds resulting from trauma, surgery or other causes. A protein of the invention may also be useful for dissolving or inhibiting 10 formation of thromboses and for treatment and prevention of conditions resulting therefrom (such as, for example, infarction of cardiac and central nervous system vessels (e.g., stroke).
The activity of a protein of the invention may, among other means, be measured by the following methods:
15 Assay for hemostatic and thrombolytic activity include, without limitation, those described in: Linet et al., J. Clin. Pharmacol. 26:131-140, 1986; Burdick et al., Thrombosis Res. 45:413-419,1987; Humphrey et al., Fibrinolysis 5:71-79 (1991); Schaub, Prostaglandins 35:467-474, 1988.
20 Receptor/Ligand Activity A protein of the present invention may also demonstrate activity as receptors, receptor ligands or inhibitors or agonists of receptor/ligand interactions.
Examples of such receptors and Iigands include, without limitation, cytokine receptors and their ligands, receptor kinases and their ligands, receptor phosphatases and their ligands, 2 5 receptors involved in cell-cell interactions and their ligands (including without limitation, cellular adhesion molecules (such as selectins, integrins and their ligands) and receptor/ligand pairs involved in antigen presentation, antigen recognition and development of cellular and humoral immune responses). Receptors and ligands are also useful for screening of potential peptide or small molecule inhibitors of the relevant 3 0 receptor/ligand interaction. A protein of the present invention {including, without limitation, fragments of receptors and ligands) may themselves be useful as inhibitors of receptor/ligand interactions.
The activity of a protein of the invention may, among other means, be measured by the following methods:

WO 99/42470 PC'T/US99/03458 Suitable assays for receptor-ligand activity include without limitation those described in:Current Protocols in Immunology, Ed by ).E. Coligan, A.M.
ICruisbeek, D.H.
Margulies, E.M. Shevach, W.Strober, Pub. Greene Publishing Associates and Wiley-Interscience (Chapter 7.28, Measurement of Cellular Adhesion under static conditions 7.28.1-7.28.22), Takai et al., Proc. Natl. Acad. Sci. USA 84:6864-6868, 1987;
Bierer et al., j. Exp. Med.168:1145-1156, 1988; Rosenstein et al., J. Exp.
Med.169:149-160 1989; Stoltenborg et al., J. Immunol. Methods 175:59-68,1994; Stitt et al., Cell 80:661-670, 1995.
Anti-Inflammatory Activi Proteins of the present invention may also exhibit anti-inflammatory activity.
The anti-inflammatory activity may be achieved by providing a stimulus to cells involved in the inflammatory response, by inhibiting or promoting cell-cell interactions (such as, for example, cell adhesion), by inhibiting or promoting chemotaxis of cells involved in the inflammatory process, inhibiting or promoting cell extravasation, or by stimulating or suppressing production of other factors which more directly inhibit or promote an inflammatory response. Proteins exhibiting such activities can be used to treat inflammatory conditions including chronic or acute conditions), including without limitation inflammation associated with infection (such as septic shock, sepsis or systemic 2 0 inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, arthritis, complement-mediated hyperacute rejection, nephritis, cytokine or chemokine-induced lung injury, inflammatory bowel disease, Crohn's disease or resulting from over production of cytokines such as TNF or IL-1. Proteins of the invention may also be useful to treat anaphylaxis and hypersensitivity to an antigenic substance or material.
Cadherin/Tumor Invasion SuppressgQr Activit~r Cadherins are calcium-dependent adhesion molecules that appear to play major roles during development, particularly in defining specific cell types. Loss or alteration of normal cadherin expression can lead to changes in cell adhesion properties linked to 3 0 tumor growth and metastasis. Cadherin malfunction is also implicated in other human diseases, such as pemphigus vulgaris and pemphigus foliaceus (auto-immune blistering skin diseases), Crohn's disease, and some developmental abnormalities.
The cadherin superfamily includes well over forty members, each with a distinct pattern of expression. All members of the superfamily have in common conserved extracellular repeats (cadherin domains), but structural differences are found in other parts of the molecule. The cadherin domains bind calcium to form their tertiary structure and thus calcium is required to mediate their adhesion. Only a few amino acids in the first cadherin domain provide the basis for homophilic adhesion; modification of this recognition site can change the specificity of a cadherin so that instead of recognizing only itself, the mutant molecule can now also bind to a different cadherin. In addition, some cadherins engage in heterophilic adhesion with other cadherins.
E-cadherin, one member of the cadherin superfamily, is expressed in epithelial cell types. Pathologically, if E-cadherin expression is lost in a tumor, the malignant cells become invasive and the cancer metastasizes. Transfection of cancer cell lines with polynucleotides expressing E-cadherin has reversed cancer-associated changes by returning altered cell shapes to normal, restoring cells' adhesiveness to each other and to their substrate, decreasing the cell growth rate, and drastically reducing anchorage-independent cell growth. Thus, reintroducing E-cadherin expression reverts carcinomas to a less advanced stage. It is likely that other cadherins have the same invasion suppressor role in carcinomas derived from other tissue types. Therefore, proteins of the present invention with cadherin activity, and polynucleotides of the present invention encoding such proteins, can be used to treat cancer. Introducing such proteins or polynucleotides into cancer cells can reduce or eliminate the cancerous changes observed 2 0 in these cells by providing normal cadherin expression.
Cancer cells have also been shown to express cadherins of a different tissue type than their origin, thus allowing these cells to invade and metastasize in a different tissue in the body. Proteins of the present invention with cadherin activity, and polynucleotides of the present invention encoding such proteins, can be substituted in these cells for the 2 ~ .inappropriately expressed cadherins, restoring normal cell adhesive properties and reducing or eliminating the tendency of the cells to metastasize.
Additionally, proteins of the present invention with cadherin activity, and polynucleotides of the present invention encoding such proteins, can used to generate antibodies recognizing and binding to cadherins. Such antibodies can be used to block 3 0 the adhesion of inappropriately expressed tumor-cell cadherins, preventing the cells from forming a tumor elsewhere. Such an anti-cadherin antibody can also be used as a marker for the grade, pathological type, and prognosis of a cancer, i.e. the more progressed the cancer, the less cadherin expression there will be, and this decrease in cadherin expression can be detected by the use of a cadherin-binding antibody.

Fragments of proteins of the present invention with cadherin activity, preferably a polypeptide comprising a decapeptide of the cadherin recognition site, and poly-nucleotides of the present invention encoding such protein fragments, can also be used to block cadherin function by binding to cadherins and preventing them from binding in ways that produce undesirable effects. Additionally, fragments of proteins of the present invention with cadherin activity, preferably truncated soluble cadherin fragments which have been found to be stable in the circulation of cancer patients, and polynucleotides encoding such protein fragments, can be used to disturb proper cell-cell adhesion.
Assays for cadherin adhesive and invasive suppressor activity include, without limitation, those described in: Hortsch et al. J Biol Chem 270 (32): 18809-18817, 1995;
Miyaki et al. Oncogene 11: 2547-2552,1995; Ozawa et al. Cell 63: 1033-1038,1990.
Tumor Inhibition ActivitX
In addition to the activities described above for immunological treatment or prevention of tumors, a protein of the invention may exhibit other anti-tumor activities.
A protein may inhibit tumor growth directly or indirectly (such as, for example, via antibody-dependent cell-mediated cytotoxicity (ADCC)}. A protein may exhibit its tumor inhibitory activity by acting on tumor tissue or tumor precursor tissue, by inhibiting formation of tissues necessary to support tumor growth (such as, for example, by 2 0 inhibiting angiogenesis), by causing production of other factors, agents or cell types which inhibit tumor growth, or by suppressing, eliminating or inhibiting factors, agents or cell types which promote tumor growth.
Other Activities 2 5 . A protein of the invention may also exhibit.one or more of the.following additional activities or effects: inhibiting the growth, infection or function of, or killing, infectious agents, including, without limitation, bacteria, viruses, fungi and other parasites; effecting (suppressing or enhancing) bodily characteristics, including, without limitation, height, weight, hair color, eye color, skin, fat to lean ratio or other tissue pigmentation, or organ 3 0 or body part size or shape (such as, for example, breast augmentation or diminution, change in bone form or shape); effecting biorhythms or caricadic cycles or rhythms;
effecting the fertility of male or female subjects; effecting the metabolism, catabolism, anabolism, processing, utilization, storage or elimination of dietary fat, lipid, protein, carbohydrate, vitamins, minerals, cofactors or other nutritional factors or component(s);

effecting behavioral characteristics, including, without limitation, appetite, libido, stress, cognition (including cognitive disorders), depression (including depressive disorders) and violent behaviors; providing analgesic effects or other pain reducing effects;
promoting differentiation and growth of embryonic stem cells in lineages other than hematopoietic lineages; hormonal or endocrine activity; in the case of enzymes, correcting deficiencies of the enzyme and treating deficiency-related diseases; treatment of hyperproliferative disorders (such as, for example, psoriasis); immunoglobulin-like activity (such as, for example, the ability to bind antigens or complement); and the ability to act as an antigen in a vaccine composition to raise an immune response against such protein or another material or entity which is cross-reactive with such protein.
ADMINISTRATION AND DOSING
A protein of the present invention (from whatever source derived, including without limitation from recombinant and non-recombinant sources) may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
Such a composition may also contain (in addition to protein and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the 2 0 carrier will depend on the route of administration. The pharmaceutical composition of the invention may also contain cytokines, lymphokines, or other hematopoietic factors such as M-CSF, GM-CSF, TNF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IFN, TNFO, T\1F1, TNF2, G-CSF, Meg-CSF, thrombopoietin, stem cell factor, and erythropoietin. The pharmaceutical composition may further contain other 25. , agents which either enhance the activity of the protein or compliment its activity or use in treatment. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with protein of the invention, or to minimize side effects. Conversely, protein of the present invention may be included in formulations of the particular cytokine, lymphokine, other hematopoietic factor, 3 0 thrombolytic or anti-thrombotic factor, or anti-inflammatory agent to minimize side effects of the cytokine, lymphokine, other hematopoietic factor, thromboiytic or anti-thrombotic factor, or anti-inflammatory agent.
A protein of the present invention may be active in multimers (e.g., heterodimers or homodimers) or complexes with itself or other proteins. As a result, pharmaceutical compositions of the invention may comprise a protein of the invention in such multimeric or complexed form.
The pharmaceutical composition of the invention may be in the form of a complex of the proteins) of present invention along with protein or peptide antigens.
The protein and/or peptide antigen will deliver a stimulatory signal to both B and T
lymphocytes. B
lymphocytes will respond to antigen through their surface immunoglobulin receptor. T
lymphocytes will respond to antigen through the T cell receptor (TCR) following presentation of the antigen by MHC proteins. MHC and structurally related proteins including those encoded by class I and class II MHC genes on host cells will serve to present the peptide antigens) to T lymphocytes. The antigen components could also be supplied as purified MHC-peptide complexes alone or with co-stimulatory molecules that can directly signal T cells. Alternatively antibodies able to bind surface immunolgobulin and other molecules on B cells as well as antibodies able to bind the TCR and other molecules on T cells can be combined with the pharmaceutical composition of the invention.
The pharmaceutical composition of the invention may be in the form of a liposome in which protein of the present invention is combined, in addition to other pharmaceutically acceptable Garners, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers 2 0 in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent No. 4,235,871; U.S. Patent No.
4,501,728; U.S.
Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are incorporated herein 2 5 by reference.
As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, 3 0 prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

In practicing the method of treatment or use of the present invention, a therapeutically effective amount of protein of the present invention is administered to a mammal having a condition to be treated. Protein of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more cytokines, lymphokines or other hematopoietic factors, protein of the present invention may be administered either simultaneously with the cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering protein of the present invention in combination with cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
Administration of protein of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, topical application or cutaneous, subcutaneous, intraperitoneal, parenteral or intravenous injection.
Intravenous administration to the patient is preferred.
When a therapeutically effective amount of protein of the present invention is 2 0 administered orally, protein of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95%
protein of the present invention, and preferably from about 25 to 90% protein of the present invention.
2 5 . When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid 3 0 form, the pharmaceutical composition contains from about 0.5 to 90% by weight of protein of the present invention, and preferably from about I to 50% protein of the present invention.
When a therapeutically effective amount of protein of the present invention is administered by intravenous, cutaneous or subcutaneous injection, protein of the present invention will be in the form of a pyrogen-tree, parenterally acceptable aqueous solution.
The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A
preferred pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to protein of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringei s Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringei s Injection, or other vehicle as known in the art.
The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.
The amount of protein of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone.
Ultimately, the attending physician will decide the amount of protein of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of protein of the present invention and observe the patient's response. Larger doses of protein of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.01 lzg to about 100 2 0 mg (preferably about O.lng to about 10 mg, more preferably about 0.1 pg to about 1 mg}
of protein of the present invention per kg body weight.
The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient.
It is 2 5 .contemplated that the duration of each application of the pz~otein of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration.
Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.
Protein of the invention may also be used to immunize animals to obtain 3 0 polyclonal and monoclonal antibodies which specifically react with the protein. Such antibodies may be obtained using either the entire protein or fragments thereof as an immunogen. The peptide immunogens additionally may contain a cysteine residue at the carboxyl terminus, and are conjugated to a hapten such as keyhole limpet hemocyanin (KLH). Methods for synthesizing such peptides are known in the art, for example, as in R.P. Merrifield, J. Amer.Chem.Soc. $~, 2149-2154 (1963); J.L. Krstenansky, et al., FEBS Lett.
2~1 20 (1987). Monoclonal antibodies binding to the protein of the invention may be useful diagnostic agents for the immunodetection of the protein. Neutralizing monoclonal antibodies binding to the protein may also be useful therapeutics for both conditions associated with the protein and also in the treatment of some forms of cancer where abnormal expression of the protein is involved. In the case of cancerous cells or leukemic cells, neutralizing monoclonal antibodies against the protein may be useful in detecting and preventing the metastatic spread of the cancerous cells, which may be mediated by the protein.
For compositions of the present invention which are useful for bone, cartilage, tendon or ligament regeneration, the therapeutic method includes administering the composition topically, systematically, or locally as an implant or device.
When administered, the therapeutic composition for use in this invention is, of course, in a pyrogen-free,,physiologically acceptable form. Further, the composition may desirably be encapsulated or injected in a viscous form for delivery to the site of bone, cartilage or tissue damage. Topical administration may be suitable for wound healing and tissue repair. Therapeutically useful agents other than a protein of the invention which may also optionally be included in the composition as described above, may alternatively or additionally, be administered simultaneously or sequentially with the composition in the methods of the invention. Preferably for bone and/or cartilage formation, the composition would include a matrix capable of delivering the protein-containing composition to the site of bone and/or cartilage damage, providing a structure for the developing bone and cartilage and optimally capable of being resorbed into the body.
Such matrices may be formed of materials presently in use for other implanted medical 2 5 applications. , .
The choice of matrix material is based on biocompatibility, biodegradability, mechanical properties, cosmetic appearance and interface properties. The particular application of the compositions will define the appropriate formulation.
Potential matrices for the compositions may be biodegradable and chemically defined calcium 3 0 sulfate, tricalciumphosphate, hydroxyapatite, polylactic acid, polyglycolic acid and polyanhydrides. Other potential materials are biodegradable and biologically well-defined, such as bone or dermal collagen. Further matrices are comprised of pure proteins or extracellular matrix components. Other potential matrices are nonbiodegradable and chemically defined, such as sintered hydroxapatite, bioglass, aluminates, or other ceramics. Matrices may be comprised of combinations of any of the above mentioned types of material, such as polylactic acid and hydroxyapatite or collagen and tricalciumphosphate. The bioceramics may be altered in composition, such as in calcium aiuminate-phosphate and processing to alter pore size, particle size, particle shape, and biodegradability.
Presently preferred is a 50:50 (mole weight) copolymer of lactic acid and glycolic acid in the form of porous particles having diameters ranging from 150 to 800 microns.
In some applications, it will be useful to utilize a sequestering agent, such as carboxymethyl cellulose or autologous blood clot, to prevent the protein compositions from disassociating from the matrix.
A preferred family of sequestering agents is cellulosic materials such as alkylcelluloses (including hydroxyalkylceliuloses), including methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl-methylcellulose, and carboxymethylcellulose, the most preferred being cationic salts of carboxymethylcellulose (CMC). Other preferred sequestering agents include hyaluronic acid, sodium alginate, polyethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer and polyvinyl alcohol). The amount of sequestering agent useful herein is 0.5-20 wt%, preferably 1-10 wt% based on total formulation weight, which represents the amount necessary to prevent desorbtion of the protein from the polymer matrix and to 2 0 provide appropriate handling of the composition, yet not so much that the progenitor cells are prevented from infiltrating the matrix, thereby providing the protein the opportunity to assist the osteogenic activity of the progenitor cells.
In further compositions, proteins of the invention may be combined with other agents beneficial to the treatment of the bone and/or cartilage defect, wound, or tissue in 2 5 question. These agents include various growth factors such as epidermal growth factor (EGF), platelet derived growth factor (PDGF), transforming growth factors (TGF-a and TGF-(3), and insulin-like growth factor (IGF).
The therapeutic compositions are also presently valuable for veterinary applications. Particularly domestic animals and thoroughbred horses, in addition to 3 0 humans, are desired patients for such treatment with proteins of the present invention.
The dosage regimen of a protein-containing pharmaceutical composition to be used in tissue regeneration will be determined by the attending physician considering various factors which modify the action of the proteins, e.g., amount of tissue weight desired to be formed, the site of damage, the condition of the damaged tissue, the size of a wound, type of damaged tissue (e.g., bone), the patient's age, sex, and diet, the severity of any infection, time of administration and other clinical factors. The dosage may vary with the type of matrix used in the reconstitution and with inclusion of other proteins in the pharmaceutical composition. For example, the addition of other known growth 5 factors, such as IGF I (insulin like growth factor I), to the final composition, may also effect the dosage. Progress can be monitored by periodic assessment of tissue/bone growth and/or repair, for example, X-rays, histomorphometric determinations arid tetracycline labeling.
Polynucleotides of the present invention can also be used for gene therapy.
Such 10 polynucleotides can be introduced either in vivo or ex vivo into cells for expression in a mammalian subject. Polynucleotides of the invention may also be administered by other known methods for introduction of nucleic acid into a cell or organism (including, without limitation, in the form of viral vectors or naked DNA).
Cells may also be cultured ex vivo in the presence of proteins of the present 1 S invention in order to proliferate or to produce a desired effect on or activity in such cells.
Treated cells can then be introduced in vivo for therapeutic purposes.
Patent and literature references cited herein are incorporated by reference as if fully set forth.

SEQUENCE LISTING
<110> Jacobs, Xenneth McCoy, John M.
LaVallie, Edward R.
Coffins-Racie, Lisa A.
Merberg, David Treacy, Maurice Agostino, Michael J.
Steininger II, Robert J.
Genetics Institute, Inc.
<120> SECRETED PROTEINS AND POLYNUCLEOTIDES ENCODING THEM
<130> GI 6064A
E~ s5~o Zso ~Sy us <140> "ExpressMafl"maiGn labelnumber.~

< 141> Date of Deposit l R' I~lLF3~~~~ v !~ >0,9 I hereby certify that this paper or fee is being <160> 31 depos'tted with the United States Postal Service "Express Mail Post Office to Addressee" service <170> Patentln Ver. 2.0 under 37 GFR 1 10 ort the date indicated above and is addressed to the Assistant Commissioner <210> 1 For Patejjls, Washington,1~. ~p231 <211> 2401 <212> DNA
<213> Homo sapiens <400> I
cgcatcctca gccaccgtcg cagctgcctc cgccaccacc gccgcctcct cttccttggc 60 caccccagaa ctgggcagca gcctcaagaa gaagaagcgg ctctcccagt cagatgagga 120 tgtcattagg ctaataggac agcacttgaa tggcttaggg ctcaaccaga ctgttgatct 180 cctcatgcaa gagtcaggat gtcgtttaga acatccttct gctaccaaat tccgaaatca 240 tgtcatggaa ggagactggg ataaggcaga aaatgacctg aatgaactaa agcctttagt 300 gcattctcct catgctattg tgaggatgaa gtttttgctg ctgcagcaga agtacctaga 360 atacctggag gatggcaagg tcctggaggc acttcaagtt ctacgctgtg aattgacgcc 420 gctgaaatac aatacagagc gcattcatgt tcttagtggg tatctgatgt gtagccatgc 480 agaagaccta cgtgcaaaag cagaatggga aggcaaaggg acagcttccc gatctaaact 540 attggataaa cttcagacct atttaccacc atcagtgatg cttcccccac ggcgtttaca 600 gactctcctg cggcaggcgg tggaactaca aagggatcgg tgcctatatc acaataccaa 660 acttgataat aatctagatt ctgtgtctct gcttatagac catgtttgta gtaggaggca 720 gttcccatgt tatacgcagc agatacttac ggagcattgt aatgaagtgt ggttctgtaa 780 attctctaat gatggcacta aactagcaac aggatcaaaa gatacaacag ttatcatatg 840 gcaagttgat ccggatacac acctgctaaa actgcttaaa acattagaag gacatgctta 900 tggcgtttct tatattgcat ggagtccaga tgacaactat cttgttgctt gtggcccaga 960 tgactgctct gagctttggc tttggaatgt acaaacagga gaactaagga caaaaatgag 1020 ccagtctcat gaagacagtt tgacaagtgt ggcttggaat ccagatggga agcgctttgt 1080 gactggaggt cagcgtgggc agttctatca gtgtgactta gatggtaatc tccttgactc 1140 ctgggaaggg gtaagagtgc aatgcctttg gtgcttgagt gatggaaaga ctgttctggc 1200 atcagataca caccagcgaa ttcggggcta taacttcgag gaccttacag ataggaacat 1260 agtacaagaa gatcatccta ttatgtcttt tactatttca aaaaatggcc gattagcttt 1320 gttaaatgta gcaactcagg gagttcattt atgggacttg caagacagag ttttagtaag 1380 aaagtatcaa ggtgttacac aagggtttta tacaattcat tcatgttttg gaggccataa 1440 tgaagacttc atcgctagtg gcagtgaaga tcacaaggtt tacatctggc acaaacgtag 1500 tgaactgcca attgcggagc tgacagggca cacacgtaca gtaaactgtg tgagctggaa 1560 cccacagatt ccatccatga tggccagcgc ctcagatgat ggcactgtta gaatatgggg 1620 accagcacct tttatagacc accagaatat tgaagaggaa tgcagtagca tggatagttg 1680 atggtgaatt tggagcagac gacttctgtt taacttaaaa ttagtcgtat tttaatggct 1740 tgggatttgg tgcaaacaaa catgattgat agctggacag acatgctcgt catgaaaaaa 1800 gaaccatttc tgaagcccga ttggggccaa acatttacac cttgcttcat agtaaccagt 1860 tgagatgaag cacgtcgtta gaacgttgtt ggacaccatg ttgaattatt cccccatcgg 1920 ttgtgaagaa ctgtgctaca ttcaggctta cccattgaac tcagtatata tatttttttc 1980 cttcctgtct tttgtctggc aggataccat tcttgttgct cttctgtgta atgaagttta 2040 aatgcttgtt tggaaaactt tatttaacag tttagaaggc ttgatagaaa gagtgcatta 2100 gtctgaagag tatacattgg ataggaaaga atttccttct tttgtttctc caaatctttc 2160 cgccttattt agcttgagat ctttgcagct tggttcatgg attctagcct tgcccgttgc 2220 gcagtatata ctgatccaga tgataaacca gtgaactatg tcaaaagcac tctcaatatt 2280 acatttgaca aaaagttttg tacttttcac atagcttgtt gccccgtaaa agggttaaca 2340 gcacaatttt ttaaasataa attaagaagt atttatagga ttaaaaaaaa aaaaaaaaaa 2400 a <210> 2 <211> 498 <212> PRT
<213> Homo sapiens <400> 2 Met Gln Glu Ser Gly Cys Arg Leu Glu His Pro Ser Ala Thr Lys Phe Arg Asn His Val Met Glu Gly Asp Trp Asp Lys Ala Glu Asn Asp Leu Asn Glu Leu Lys Pro Leu Val His Ser Pro His Ala Ile Val Arg Met Lys Phe Leu Leu Leu Gln Gln Lys Tyr Leu Glu Tyr Leu Glu Asp Gly Lys Val Leu Glu Ala Leu Gln Val Leu Arg Cys Glu Leu Thr Pro Leu Lys Tyr Asn Thr Glu Arg Ile His Val Leu Ser Gly Tyr Leu Met Cys Ser His Ala Glu Asp Leu Arg Ala Lys Ala Glu Trp Glu Gly Lys Gly Thr Ala Ser Arg Ser Lys Leu Leu Asp Lys Leu Gln Thr Tyr Leu Pro Pro Ser Val Met Leu Pro Pro Arg Arg Leu Gln Thr Leu Leu Arg Gln Ala Val Glu Leu Gln Arg Asp Arg Cys Leu Tyr His Asn Thr Lys Leu Asp Asn Asn Leu Asp Ser Val Ser Leu Leu Ile Asp His Val Cys Ser Arg Arg Gln Phe Pro Cys Tyr Thr Gln Gln Ile Leu Thr Glu His Cys Asn Glu Val Trp Phe Cys Lys Phe Ser Asn Asp Gly Thr Lys Leu Ala Thr Gly Ser Lys Asp Thr Thr Val Ile Ile Trp Gln Val Asp Pro Asp Thr His Leu Leu Lys Leu Leu Lys Thr Leu Glu Gly His Ala Tyr Gly Val Ser Tyr Ile Ala Trp Ser Pro Asp Asp Asn Tyr Leu Val Ala Cys Gly Pro Asp Asp Cys Ser Glu Leu Trp Leu Trp Asn Val Gln Thr Gly Glu Leu Arg Thr Lys Met Ser Gln Ser His Glu Asp Ser Leu Thr Ser Val Ala Trp Asn Pro Asp Gly Lys Arg Phe Val Thr Gly Gly Gln Arg Gly Gln Phe Tyr Gln Cys Asp Leu Asp Gly Asn Leu Leu Asp Ser Trp Glu Gly Val Arg Val Gln Cys Leu Trp Cys Leu Ser Asp Gly Lys Thr Val Leu Ala Ser Asp Thr His Gln Arg Ile Arg Gly Tyr Asn Phe Glu Asp Leu Thr Asp Arg Asn Ile Val Gln Glu Asp His Pro Ile Met Ser Phe Thr Ile Ser Lys Asn Gly Arg Leu Ala Leu Leu Asn Val Ala Thr Gln Gly Val His Leu Trp Asp Leu Gln Asp Arg Val Leu Val Arg Lys Tyr G1n Gly Val Thr Gln Gly Phe Tyr Thr Ile His Ser Cys Phe Gly Gly His Asn Glu Asp Phe Ile Ala Ser Gly Ser Glu Asp His Lys Val Tyr Ile Trp His Lys Arg Ser Glu Leu Pro Ile Ala Glu Leu Thr Gly His Thr Arg Thr Val Asn Cys Val Ser Trp Asn Pro Gln Ile Pro Ser Met Met Ala Ser Ala Ser Asp Asp Gly Thr Val Arg Ile Trp Gly Pro Ala Pro Phe Ile Asp His Gln Asn Ile Glu Glu Glu Cys Ser Ser Met Asp Ser <210> 3 <211> 1110 <212> D13A
<213> Homo sapiens <400> 3 J

ggtgcgggag ccgctctccg ccggtcggtc cccgcgcggc tgagcccagg ccgccagcgc 60 cgcggccccg tgcggtgtcc ctgagctcct gctccccgcc gggctgctcc gagcaacggt 120 gcttcggagc tccaaactcg ggctgccggg gcaagtgtct tcatgaaccc agaggatgtc 180 cgggaagcac tacaagggtc ctgaagtcag ttgttgcatc aaatacttca tatttggctt 240 caatgtcata ttttggtttt tgggaataac atttcttgga attggactgt gggcatggaa 300 tgaaaaagga gttctgtcca acatctcttc catcaccgat ctcggcggct ttgacccagt 360 ttggctcttc cttgtggtgg gaggagtgat gttcattttg ggatttgcag ggtgcattgg 420 agcgctacgg gaaaacactt tccttctcaa gtttttttct gtgttcctgg gaattatttt 480 cttcctggag ctcactgccg gagttctagc atttgttttc aaagactgga tcaaagacca 540 gctgtatttc tttataaaca acaacatcag agcatatcgg gatgacattg atttgcaaaa 600 cctcatagac ttcacccagg aatatattcc aatgcaagtc gagagcgatg tggcgttcca 660 ttctcctgct gcactaaaga tcccgcagaa gatgtcatca acactcagtg tggctatgat 720 gccaggcaaa aaccagaagt tgaccagcag attgtaatct acacgaaagg ctgtgtgccc 780 cagtttgaga agtggttgca ggacaattta accwtcgttg ctggtatttt cataggcatt 840 gcattgctgc agatatttgg gatmtgcctg gcccagaatt tggttagcga tatcgawgct 900 gtcagggcga gctggtagac cccctgcaac cgctgctgca agacactgga cagacccagc 960 tttcgggacc ctcccgcgtg ccgaactgat cttcgagctg catggaccta atcacagatg 1020 cagcctgcag tctcgcctaa tggagctgcc attaggggag tgtaaaactg ggaaatgctg 1080 ctcactgaca gaattaaaaa aaaaaaaaaa 1110 <210> 4 <211> 193 <212> PRT
<213> Homo sapiens <400> 4 Met Ser Gly Lys His Tyr Lys Gly Pro Glu Val Ser Cys Cys Ile Lys Tyr Phe Ile Phe Gly Phe Asn Val Ile Phe Trp Phe Leu Gly Ile Thr Phe Leu Gly Ile Gly Leu Trp Ala Trp Asn Glu Lys Gly Val Leu Ser Asn Ile Ser Ser Ile Thr Asp Leu Gly Gly Phe Asp Pro Val Trp Leu Phe Leu Val Val Gly Gly Val Met Phe Ile Leu Gly Phe Ala Gly Cys Ile Gly Ala Leu Arg Glu Asn Thr Phe Leu Leu Lys Phe Phe Ser Val Phe Leu Gly Ile Ile Phe Phe Leu Glu Leu Thr Ala Gly Val Leu Ala Phe Val Phe Lys Asp Trp Ile Lys Asp Gln Leu Tyr Phe Phe Ile Asn Asn Asn Ile Arg Ala Tyr Arg Asp Asp Ile Asp Leu Gln Asn Leu Ile Asp Phe Thr Gln Glu Tyr Ile Pro Met Gln Val Glu Ser Asp Val Ala Phe His Ser Pro Ala Ala Leu Lys Ile Pro Gln Lys Met Ser Ser T.hr Leu Ser Val Ala Met Met Pro Gly Lys Asn Gln Lys Leu Thr Ser Arg Q

lao 185 l90 Leu <210> 5 <211> 1621 <212> DNA
<213> Homo Sapiens <400> 5 ctttaaaatg tggctaatgc ctgccttagg gaaccgttgt gaggattaag tgagacatgg 60 tatataaaac gacctccttc tggcataaac ttgaggtgga agataccttg aggatgcttg 120 aaggtctgct aggcagcttc acagcctttt ctttcctctt ctctatcaga ggtctctttg 180 gaagcaataa tgatgactat aacaagaact tatcttgctt tgcaagattc ttccgccgtc 240 agagtttctg atttattttc tggggttcca tgtatgccag ggagaaagag agagcgcgaa 300 agagagagga tgtctctctc agactggcac ctggcggtga agctggctga ccagccactt 360 actccaaagt ctattcttcg gttgccagag acagaactgg gagaatactc gctagggggc 420 tatagtattt catttctgaa gcagcttatt gctggcaaac tccaggagtc tgttccagac 480 cctgagctga ttgatctgat ctactgtggt cggaagctaa aagatgacca gacacttgac 540 ttctatggca ttcaacctgg gtccactgtc catgttctgc gaaagtcctg gcctgaacct 600 gatcagaaac cggaacctgt ggacaaagtg gctgccatga gagagttccg ggtgttgcac 660 actgccctgc acagcagctc ctcttacagg gaggcggtct ttaagatgct cagcaataag 720 gagtctctgg atcagatcat tgtggccacc ccaggcctca gcagtgaccc tattgctctt 780 ggggttctcc aggacaagga cctcttctct gtcttcgctg atcccaatat gcttgatacg 840 ttggtgcctg ctcacccagc cctcgtcaat gccattgtcc tggttctgca ctccgtagca 900 ggcagtgccc caatgcctgg gactgactcc tcttcccgga gcatgccctc cagctcatac 960 cgggatatgc caggtggctt cctgtttgaa gggctctcag atgatgagga tgactttcac 1020 ccaaacacca ggtccacacc ctctagcagt actcccagct cccgcccagc ctccctgggg 1080 tacagtggag ctgctgggcc ccggcccatc acccagagtg agctggccac cgccttggcc 1140 ctggccagca ctccggagag cagctctcac acaccgactc ctggcaccca gggtcattcc 1200 tcagggacct caccaatgtc ctctggtgtc cagtcaggga cgcccatcac caatgatctc 1260 ttcagccaag ccctacagca tgcccttcag gcctctgggc agcccagcct tcagagccag 1320 tggcagcccc agctgcagca gctacgtgac atgggcatcc aggacgatga gctgagcctg 1380 cgggccctgc aggccaccgg tggggacatc caagcagccc tggagctcat ctttgctgga 1440 ggagccccat gaactccctg cttcccctga acccccagca agttgcagag gctactgccc 1500 ttgggaggca ctcatgaagg tgcctccatc tctcccttcc ccaatatacc tgatggtcaa 1560 ctctaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1620 a <210> 6 <211> 420 <212> PRT
<213> Homo Sapiens <400> 6 Met Met Thr IIe Thr Arg Thr Tyr Leu Ala Leu Gln Asp Ser Ser Ala 1 5 10 i5 VaI Arg Val Ser Asp Leu Phe Ser Gly Val Pro Cys Met Pro Gly Arg Lys Arg Glu Arg Glu Arg Glu Arg Met Ser Leu Ser Asp Trp His Leu Ala Val Lys Leu Ala Asp Gln Pro Leu Thr Pro Lys Ser Ile Leu Arg Leu Pro Glu Thr Glu Leu Gly Glu Tyr Ser Leu Gly Gly Tyr Ser Ile J

Ser Phe Leu Lys Gln Leu Ile Ala Gly Lys Leu Gln Glu Ser Val Pro Asp Pro Glu Leu Ile Asp Leu Ile Tyr Cys Gly Arg Lys Leu Lys Asp Asp Gln Thr Leu Asp Phe Tyr Gly Ile Gln Pro Gly Ser Thr Val His Val Leu Arg Lys Ser Trp Pro Glu Pro Asp Gln Lys Pro Glu Pro Val Asp Lys Val Ala Ala Met Arg Glu Phe Arg Val Leu His Thr Ala Leu His Ser Ser Ser Ser Tyr Arg Glu Ala Val Phe Lys Met Leu Ser Asn Lys Glu Ser Leu Asp Gln Ile Ile Val Ala Thr Pro Gly Leu Ser Ser Asp Pro Ile Rla Leu Gly Val Leu Gln Asp Lys Asp Leu Phe Ser Val Phe Ala Asp Pro Asn Met Leu Asp Thr Leu Val Pro Ala His Pro Ala Leu Val Asn Ala Ile Val Leu Val Leu His Ser Val Ala Gly Ser Ala Pro Met Pro Gly Thr Asp Ser Ser Ser Arg Ser Met Pro Ser Ser Ser Tyr Arg Asp Met Pro Gly Gly Phe Leu Phe Glu Gly Leu Ser Asp Asp Glu Asp Asp Phe His Pro Asn Thr Arg Ser Thr Pro Ser Ser Ser Thr Pro Ser Ser Arg Pro Ala Ser Leu Gly Tyr Ser Gly Ala Ala Gly Pro Arg Pro Ile Thr Gln Ser Glu Leu Ala Thr Ala Leu Ala Leu Ala Ser Thr Pro Glu Ser Ser Ser His Thr Pro Thr Pro Gly Thr Gln Gly His Ser Ser Gly Thr Ser Pro Met Ser Ser Gly Val Gln Ser Gly Thr Pro Ile Thr Asn Asp Leu Phe Ser Gln Ala Leu Gln His A~a Leu Gln Ala Ser Gly Gln Pro Ser Leu Gln Ser Gln Trp Gln Pro Gin Leu Gln Gln Leu Arg Asp Met Gly Ile Gln Asp Asp Glu Leu Ser Leu Arg Ala Leu Gln Ala Thr Gly Gly Asp Ile Gln Ala Ala Leu Glu Leu Ile Phe Ala Gly Gly Ala Pro <210> 7 <211> 1534 <212> DNA
<213> Homo sapiens <400> 7 aaaccctggt gctccagaca aagatcttag tcgggactag ccggccaagg atgaagcctc 60 acttcagaaa cacagtggag cgaatgtatc gagacacatt ctcctacaac ttttataata 120 gacccatcct ttctcgtcgg aataccgtct ggctgtgcta cgaagtgaaa acaaagggtc 180 cctcaaggcc ccctttggac gcaaagatct ttcgaggcca ggtgtattcc gaacttaagt 240 accacccaga gatgagattc ttccactggt tcagcaagtg gaggaagctg catcgtgacc 300 aggagtatga ggtcacctgg tacatatcct ggagcccctg cacaaagtgt acaagggata 360 tggccacgtt cctggccgag gacccgaagg ttaccctgac catcttcgtt gcccgcctct 420 actacttctg ggacccagat taccaggagg cgcttcgcag cctgtgtcag aaaagagacg 480 gtccgcgtgc caccatgaag atcatgaatt atgacgaatt tcagcactgt tggagcaagt 540 tcgtgtacag ccaaagagag ctatttgagc cttggaataa tctgcctaaa tattatatat 600 tactgcacat catgctgggg gagattctca gacactcgat ggatccaccc acattcactt 660 tcaactttaa caatgaacct tgggtcagag gacggcatga gacttacctg tgttatgagg 720 tggagcgcat gcacaatgac acctgggtcc tgctgaacca gcgcaggggc tttctatgca 780 accaggctcc acataaacac ggtttccttg aaggccgcca tgcagagctg tgcttcctgg 840 acgtgattcc cttttggaag ctggacctgg accaggacta cagggttacc tgcttcacct 900 cctggagccc ctgcttcagc tgtgcccagg aaatggctaa attcatttca aaaaacaaac 960 acgtgagcct gtgcatcttc actgcccgca tctatgatga tcaaggaaga tgtcaggagg 1020 ggctgcgcac cctggccgag gctggggcca aaatttcaat aatgacatac agtgaattta 1080 agcactgctg ggacaccttt gtggaccacc agggatgtcc cttccagccc tgggatggac 1140 tagatgagca cagccaagac ctgagtggga ggctgcgggc cattctccag aatcaggaaa 1200 actgaaggat gggcctcagt ctctaaggaa ggcagagacc tgggttgagc ctcagaataa 1260 aagatcttct tccaagaaat gcaaacaggc tgttcaccac catctccagc tgatcacaga 1320 caccagcaaa gcaatgcact cctgaccaag tagattcttt taaaaattag agtgcattac 1380 tttgaatcaa aaatttattt atatttcaag aataaagtac taagattgtg ctcaaaaaaa 1440 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1500 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaa 1534 <210> 8 <211> 384 <212> PRT
<213> Homo sapiens <400> 8 Met Lys Pro His Phe Arg Asn Thr Val Glu Arg Met Tyr Arg Asp Thr Phe Ser Tyr Asn Phe Tyr Asn Arg Pro Ile Leu Ser Arg Arg Asn Thr Val Trp Leu Cys Tyr Glu Val Lys Thr Lys Gly Pro Ser Arg Pro Pro Leu Asp Ala Lys ile Phe Arg Gly Gln Val Tyr Ser Glu Leu Lys Tyr His Pro Glu Met Arg Phe Phe His Trp Phe Ser Lys Trp Arg Lys Leu His Arg Asp Gln Glu Tyr Glu Val Thr Trp Tyr Ile Ser Trp Ser Pro g5 90 95 Cys Thr Lys Cys Thr Arg Asp Met Ala Thr Phe Leu Ala Glu Asp Pro Lys Val Thr Leu Thr Ile Phe Val Ala Arg Leu Tyr Tyr Phe Trp Asp Pro Asp Tyr Gln Glu Ala Leu Arg Ser Leu Cys Gln Lys Arg Asp Gly Pro Arg Ala Thr Met Lys Ile Met Asn Tyr Asp Glu Phe Gln His Cys Trp Ser Lys Phe Val Tyr Ser Gln Arg Glu Leu Phe Glu Pro Trp Asn Asn Leu Pro Lys Tyr Tyr Ile Leu Leu His Ile Met Leu Gly Glu Ile Leu Arg His Ser Met Asp Pro Pro Thr Phe Thr Phe Asn Phe Asn Asn Glu Pro Trp Val Arg Gly Arg His Glu Thr Tyr Leu Cys Tyr Glu Val Glu Arg Met His Asn Asp Thr Trp Val Leu Leu Asn Gln Arg Arg Gly Phe Leu Cys Asn Gln Ala Pro His Lys His Gly Phe Leu Glu Gly Arg His Ala Glu Leu Cys Phe Leu Asp Val Ile Pro Phe Trp Lys Leu Asp Leu Asp Gln Asp Tyr Arg Val Thr Cys Phe Thr Ser Trp Ser Pro Cys Phe Ser Cys Ala Gln Glu Met Ala Lys Phe Ile Ser Lys Asn Lys His Val Ser Leu Cys Ile Phe Thr Ala Arg Ile Tyr Asp Asp Gln Gly Arg Cys Gln Glu Gly Leu Arg Thr Leu Ala Glu Ala Gly Ala Lys Ile Ser Ile Met Thr Tyr Ser Glu Phe Lys His Cys Trp Asp Thr Phe Val Asp His Gln Gly Cys Pro Phe Gln Pro Trp Asp Gly Leu Asp Glu His Ser Gln Asp Leu Ser Gly Arg Leu Arg Ala Ile Leu Gln Asn Gln Glu Asn <210> 9 <211> 3005 <212> DNA
<213> Homo sapiens <220>
<221> unsure <222> (/407) <400> 9 aaagaagttg tacgaaggtc aaagaaattg tctgttccag cctcagtggt gtcgaggata 60 atgggaagag gaggatgcaa catcactgca atacrkgatg ttactggtgc ccatattgat 120 gtggataaac asaaagataa gaatggcgag agaatgatca caataagggg tggcacagaa 180 tcaacaagat atgcagttca actaatcaat gcactcattc aagatcctgc taaggaactg 240 gaagacttga ttcctaaaaa tcatatcaga acacctgcca gcaccaaatc aattcatgct 300 aacttctcat ctggagtagg taccacagca gcttccagta aaaatgcatt tcctttgggt 360 gctccaactc ttgtaacttc acaggcaaca acgttatcta cgttccagcc cgctaataaa 420 cttaataaga atgttccaac aaatgtacgt tcttctttcc cagtttctct acccttagct 480 tatcctcacc ctcattttgc cctgctggct gctcaaacta tgcaacagat tcggcatcct 540 cgcttaccca tggcccagtt tggaggaacc ttctcacctt ctcctaacac atggggacca 600 ttcccagtga gacctgtgaa tcctggcaac acaaatagct ctccaaagca taataacaca 660 agccgtctac ctaaccagaa cgggactgtt ttaccctcag agtctgctgg actagctact 720 gccagttgcc ctatcactgt ctcttctgta gttgctgcca gtcagcaact gtgtgtcact 780 aatacccgga ctccttcatc agtcagaaag cagttgtttg cctgtgtgcc taagacaagt 840 cctccagcaa cagtgatttc ttctgtgaca agcacttgta gttccctgcc ttctgtctcc 900 tctgcaccta tcactagcgg gcaagctccc accacatttc tacctgcaag tacttctcaa 960 gcacagcttt cttcacaaaa gatggagtct ttctctgctg tgccacccac caaagagaaa 1020 gtgtccacac aggaccagcc catggcaaac ctatgtaccc catcttcaac tgcaaacagt 1080 tgcagtagct ctgccagcaa caccccggga gctccagaaa ctcacccatc cagtagtccc 1140 actcctactt ccagtaacac acaagaggag gcacagccat ccagtgtgtc tgatttaagt 1200 cctatgtcaa tgccttttgc atctaactca gaacctgctc cattgacttt gacatcaccc 1260 agaatggttg ctgctgataa tcaggacacc agtaatttac ctcagttagc tgtaccagca 1320 cctcgagttt ctcatcgaat gcagcccaga ggttcttttt actccatggt accaaatgca 1380 actattcacc aggatcccca gtctatnttt gttacgaatc cagttacttt aacaccacct 1440 caaggcccac cagctgcagt gcagctttct tcagctgtga acattatgaa tggttctcag 1500 atgcacataa acccagcaaa taagtctttg ccacctacat ttggcCCagc cacacttttc 1560 aatcacttca gcagtctttt tgatagtagt caggtgccag ctaaccaggg ctggggagat 1620 ggtccactgt cctcacgagt tgctacagat gcctctttca ctgttcagtc agcgttcctg 1680 ggtaactcag tgcttggaca cttggaaaac atgcaccctg ataactcaaa ggcacctggc 1740 ttcagaccac cttcccagcg agtttctact agtccagttg ggttaccatc cattgaccca 1800 tcaggcagct ccccatcttc ctcttctgct cctctggcaa gtttttccgg cataccagga 1860 acaagggttt tcctgcaagg gccagctcct gttgggactc ctagtttcaa cagacaacat 1920 ttttctcccc atccttggac aagcgcctca aactcatcca cttctgcccc accaacgttg 1980 ggccaaccaa aaggagtcag tgccagtcaa gatcgaaaga tacctccccc aattggaaca 2040 gagagactgg cccgaattcg gcaaggaggg tctgttgcac aagccccggc ggggaccagt 2100 tttgtcgctc ccgttggaca cagtggaatc tggtcatttg gtgtcaatgc tgtgtcagaa 2160 ggcttatcag gttggtcgca atctgtgatg gggaaccatc caatgcatca acaattatca 2220 gacccaagca cattctccca acatcagcca atggagagag atgattctgg aatggtagcc 2280 ccctctaaca tttttcatca gcctatggca agtggttttg tggatttttc taaaggtctg 2340 ccaatttcca tgtatggagg caccataata ccctctcatc ctcagcttgc tgatgttcca 2400 ggaggccctc tgtttaatgg acttcacaat ccagatcctg cttggaaccc tatgataaaa 2460 gttatccaaa attcaactga atgcactgat gcccagcaga tttggcctgg cacgtgggca 2520 cctcatattg gaaacatgca tctcaaatat gtcaactaag ttagaaggtc tttactcttt 2580 agccttgttt aagaaaccta tgaccttgga agaaccatgg ggattttttt ttaatgtgcc 2640 taagaaattt tctctgaggc tttagcaatg gaaatttgat tgcccattgt ataagaacaa 2700 attgatttcc tatccacctg attatgttct ctggttagtt tagccatttt gaacttaaga 2760 tcatatgacc ttagtgcttt tggctaaaca tacagaatac tacttgtatg cagaagagaa 2820 ttagttgatt acatgtttca accttttagg gtgataaata catgtataat tgtttacata 2880 cttaaaagga aaaagttgag taaatttct~ gtcatatagt ggctctacgt aatgtagcct 2940 gtattaatgt gaaatattta ccagaatatt caataaaaag atgaacagtc aaaaaaaaaa 3000 aaaaa 3005 <210> 10 <211> 832 <212> PRT
<213> Homo Sapiens <220>
<221> UNSURE
<222> (12) <220>
<221> UNSURE
<222> (449) <400> 10 Met Gly Arg Gly Gly Cys Asn Ile Thr Ala Ile Xaa Asp Val Thr Gly Ala His Ile Asp Val Asp Lys Gln Lys Asp Lys Asn Gly Glu Arg Met Ile Thr Ile Arg Gly Gly Thr Glu Ser Thr Arg Tyr Ala Val Gln Leu Ile Asn Ala Leu Ile Gln Asp Pro Ala Lys Glu Leu Glu Asp Leu Ile Pro Lys Asn His Ile Arg Thr Pro Ala Ser Thr Lys Ser Ile His Ala Asn Phe Ser Ser Gly Val Gly Thr Thr Ala Ala Ser Ser Lys Asn Ala Phe Pro Leu Gly Ala Pro Thr Leu Val Thr Ser Gln Ala Thr Thr Leu Ser Thr Phe Gln~Pro Ala Asn Lys Leu Asn Lys Asn Val Pro Thr Asn Val Arg Ser Ser Phe Pro Val Ser Leu Pro Leu Ala Tyr Pro His Pro His Phe Ala Leu Leu Ala Ala Gln Thr Met Gln Gln Ile Arg His Pro Arg Leu Pro Met Ala Gln Phe Gly Gly Thr Phe Ser Pro Ser Pro Asn Thr Trp Gly Pro Phe Pro Val Arg Pro Val Asn Pro Gly Asn Thr Asn lg0 185 190 Ser Ser Pro Lys His Asn Asn Thr Ser Arg Leu Pro Asn Gln Asn Gly Thr Val Leu Pro Ser Glu Ser Ala Gly Leu Ala Thr Ala Ser Cys Pro Ile Thr Val Ser Ser Val Val Ala Ala Ser Gln Gln Leu Cys Val Thr 1~

Asn Thr Arg Thr Pro Ser Ser Val Arg Lys Gln Leu Phe Ala Cys Val Pro Lys Thr Ser Pro Pro Ala Thr Val Ile Ser Ser Val Thr Ser Thr Cys Ser Ser Leu Pro Ser Val Ser Ser Ala Pro Ile Thr Ser Gly Gln Ala Pro Thr Thr Phe Leu Pro Ala Ser Thr Ser Gln Ala Gln Leu Ser Ser Gln Lys Met Glu Ser Phe Ser Ala Val Pro Pro Thr Lys Glu Lys Val Ser Thr Gln Asp Gln Pro Met Ala Asn Leu Cys Thr Pro Ser Ser Thr Ala Asn Ser Cys Ser Ser Ser Ala Ser Asn Thr Pro Gly Ala Pro Glu Thr His Pro Ser Ser Ser Pro Thr Pro Thr Ser Ser Asn Thr Gln Glu Glu Ala Gln Pro Ser Ser Val Ser Asp Leu Ser Pro Met Ser Met Pro Phe Ala Ser Asn Ser Glu Pro Ala Pro Leu Thr Leu Thr Ser Pro Arg Met Val Ala Ala Asp Asn Gln Asp Thr Ser Asn Leu Pro Gln Leu Ala Val Pro Ala Pro Arg Val Ser His Arg Met Gln Pro Arg Gly Ser Phe Tyr Ser Met Val Pro Asn Ala Thr Ile His Gln Asp Pro Gln Ser Xaa Phe Val Thr Asn Pro Val Thr Leu Thr Pro Pro Gln Gly Pro Pro Ala Ala Val Gln Leu Ser Ser Ala Val Asn Ile Met Asn Gly Ser Gln Met His Ile Asn Pro Ala Asn Lys Ser Leu Pro Pro Thr Phe Gly Pro Ala Thr Leu Phe Asn His Phe Ser Ser Leu Phe Asp Ser Ser Gln Val Pro Ala Asn Gln Gly Trp Gly Asp Gly Pro Leu Ser Ser Arg Val Ala Thr Asp Ala Ser Phe Thr Val Gln Ser Ala Phe Leu Gly Asn Ser Val Leu Gly His Leu Glu Asn Met His Pro Asp Asn Ser Lys Ala Pro Gly Phe Arg Pro Pro Ser Gln Arg Val Ser Thr Ser Pro Val Gly Leu Pro Ser Ile Asp Pro Ser Gly Ser Ser Pro Ser Ser Ser Ser Ala Pro Leu Ala Ser Phe Ser Gly Ile Pro Gly Thr Arg Val Phe Leu Gln Gly Pro Ala Pro Val Gly Thr Pro Ser Phe Asn Arg Gln His Phe Ser Pro His Pro Trp Thr Ser Ala Ser Asn Ser Ser Thr Ser Ala Pro Pro Thr Leu Gly Gln Pro Lys Gly Val Ser Ala Ser Gln Asp Arg Lys Ile Pro Pro Pro Ile Gly Thr Glu Arg Leu Ala Arg Ile Arg Gln Gly Gly Ser Val Ala Gln Ala Pro Ala Gly Thr Ser Phe Val Ala Pro Val Gly His Ser Gly Ile Trp Ser Phe Gly Val Asn Ala Val Ser Glu Gly Leu Ser Gly Trp Ser Gln Ser Val Met G1y Asn His Pro Met His Gln Gln Leu Ser Asp Pro Ser Thr Phe Ser Gln His Gln Pro Met Glu Arg Asp Asp Ser Gly Met Val Ala Pro Ser Asn Ile Phe His Gln Pro Met Ala Ser Gly Phe Val Asp Phe Ser Lys Gly Leu Pro Ile Ser Met Tyr Gly Gly Thr Ile Ile Pro Ser His Pro Gln Leu Ala Asp Val Pro Gly Gly Pro Leu Phe Asn Gly Leu His Asn Pro Asp Pro Ala Trp Asn Pro Met Ile Lys Val Ile Gln Asn Ser Thr Glu Cys Thr Asp Ala Gln Gln Ile Trp Pro Gly Thr Trp Ala Pro His Ile Gly Asn Met His Leu Lys Tyr Val Asn <210> 11 <21>> 1561 <2~2> DNA
<213> Ho::o Sapiens <220>

<221> unsure <222> (1150) <400> 11 gagaaggaag ggaagccgga aggggcgcga gtgaagcaaa gcgaggacag acagctccca 60 gagggcgagg ggtgcgtgtg cgtccgcttc tcacctcagg tctcccttcg gccccgctgc 120 cctccctcgc ggctgggtga cagctgggtc cggtccgtcg cgggctgcct ggggtgcgag 180 gatcgcgcac cccgtcttcg cgcgctgtgc ctgccgcccc gccccctcgt cccgcccgtc 240 ccgtcgcgtc gcgtcccgtc ccctcgggtg ctgccagccg ggtgctgatg cgagtcggtg 300 gcagcgagga cattttctga ctccctggcc cctgacacgg ctgcactttc catcccgtcg 360 cggggccggc cgctactccg gccccaggat gcagaatgtg attaatactg tgaagggaaa 420 ggcactggaa gtggctgagt acctgacccc ggtcctcaag gaatcaaagt ttaaggaaac 480 aggtgtaatt accccagaag agtttgtggc agctggagat cacctagtcc accactgtcc 540 aacatggcaa tgggctacag gggaagaatt gaaagtgaag gcatacctac caacaggcaa 600 acaatttttg gtaaccaaaa atgtgccgtg ctataagcgg tgcaaacaga tggaatattc 660 agatgaattg gaagctatca gtgaagaaga tgatggtgat ggcggatggg tagatacata 720 tcacaacaca ggtattacag gaataacgga agccgttaaa gagatcacac tggaaaataa 780 ggacaatata aggcttcaag attgctcagc actatgtgaa gaggaagaag atgaagatga 840 aggagaagct gcagatatgg aagaatatga agagagtgga ttgttggaaa cagatgaggc 900 taccctagat acaaggaaaa tagtagaagc ttgtsaagcc aaaactgatg ctggcggtga 960 agatgctatt ttgcaaacca gaacttatga cctttacatc acttatgata aatattacca 1020 gactccacga ttatggttgt ttggctatga tgagcaacgg cagcctttaa cagttgagca 1080 catgtatgaa gacatcagtc aggatcatgt gaagaaaaca gtgaccattg aaaatcaccc 1140 tcatctgccn ccacctccca tgtgttcagt tcacccatgc aggcatgctg aggtgatgaa 1200 gaaaatcatt gagactgttg cagaaggagg gggagaactt ggagttcata tgtatcttct 1260 tattttcttg aaatttgtac aagctgtcat tccaacaata gaatatgact acacaagaca 1320 cttcacaatg taatgaagag agcataaaat ctatcctaat tattggttct gatttttaaa 1380 gaattaaccc atagatgtga ccattgacca tattcatcaa tatatacagt ttctctaata 1440 agggacttat atgtttatgc attaaataaa aatatgttcc actaccagcc ttatttgttt 1500 aataaaaatc agtgcaaaga gaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa 1560 a 1561 <210> I2 <211> 314 <212> PRT
<213> Homo Sapiens <400> 12 Met Gln Asn Val Ile Asn Thr Val Lys Gly Lys Ala Leu Glu Val Ala Glu Tyr Leu Thr Pro Val Leu Lys Glu Ser Lys Phe Lys Glu Thr Gly Val Ile Thr Pro Glu Glu Phe Val Ala Ala Gly Asp His Leu Val His His Cys Pro Thr mrp Gln Trp Ala Thr Gly Glu Glu Leu Lys Val Lys Ala Tyr Leu Pro =hr Gly Lys Gln Phe Leu Val Thr Lys Asn Val Pro Cys Tyr Lys Arg Cys Lys Gln Met Glu Tyr Ser Asp Glu Leu Glu Ala Ile Ser Glu Glu asp Asp Gly Asp Gly Gly Trp Val Asp Thr Tyr His Asn Thr Gly Ile ~hr Gly Ile Thr Glu Ala Val Lys Glu Ile Thr Leu Glu Asn Lys Asp Asn Ile Arg Leu Gln Asp Cys Ser Ala Leu Cys Glu Glu Glu Glu Asp Glu Asp Glu Gly Glu Ala Ala Asp Met Glu Glu Tyr Glu Glu Ser Gly Leu Leu Glu Thr Asp Glu Ala Thr Leu Asp Thr Arg Lys Ile Val Glu Ala Cys Lys Ala Lys Thr Asp Ala Gly Gly Glu Asp Ala Ile Leu Gln Thr Arg Thr Tyr Asp Leu Tyr Ile Thr Tyr Asp Lys Tyr Tyr Gln Thr Pro Arg Leu Trp Leu Phe Gly Tyr Asp Glu Gln Arg Gln Pro Leu Thr Val Glu His Met Tyr Glu Asp Ile Ser Gln Asp His Val Lys Lys Thr Val Thr Ile Glu Asn His Pro His Leu Pro Pro Pro Pro Met Cys Ser Val His Pro Cys Arg His Ala Glu Val Met Lys Lys Ile Ile Glu Thr Val Ala Glu Gly Gly Gly Glu Leu Gly Val His Met Tyr Leu Leu Ile Phe Leu Lys Phe Val Gln Ala Val Ile Pro Thr Ile Glu Tyr Asp Tyr Thr Arg His Phe Thr Met <210> 13 <211> 2379 <212> DNA
<213> Homo Sapiens <400> 13 atttagttac acatagacat aactcttcaa ccttaactat ggcaatacat ttgtgcttta 60 actgttacat agcagtatca ccacttacca ggatccaaat cgaaataata aaagccgtct 120 ccatagttta aaatcgaata gtgccatcat cacagtatat Cagtcaaata gaagcttcat 180 cagaaatgta tcccacatag agttttaaga cttggattct cttctgccct tgttaatctc 240 caactaatta ctacagattg acacgtttct aactagctgt cctttgtaag aagtcaggaa 300 atctgatgct gtgtccaaaa ttatgcactg tttgttgaag tagaaccaga aatcctgacc 360 tcccgttaaa tgacatcagt ttccccctct gagcaacaga ctgcttgtct tgctaggaga 420 ggaggatggg gggctgagca ctcaggctgt ccattgaaac cccttgtcca tgaacagggt 480 cataccccta agactgatgg ggtgttgatc ttctaggaca tcacttgttt attcagtgcc 540 ccaaacacag atttctcttc tagcacttta gaattgatcc ttgaagtctc tcctggtcca 600 ttcaaataca agctgtgtga gtctggtggt tttctgtgat tggtctaatg tgagctcttt 660 gaacagacag atctgacagt ggaatgactc tcccctgctt ctggcataac tgctttgcct 720 ctgtccagtg tccaagcatc ttagctgttc aagaggagag ggcagcataa cttcctgacc 780 actggtgtca gatatcagag cattctggac tcctgagagg cagtggcctc ttgagcgaac 840 aggggaggcc agtagatgcc ccagatccag agccgtggct gcaaatccag caggaataag 900 gagggacaac cacagcctcc tcatccatgt gtcatttcca agggtttgcc ttgtgtctca 960 gctcattctg ggcagcacgt ttgtcttctg tccctagaga tttgaaggat tttggactct 1020 tgtgaatggg tgactggact tggctttaca gagttgggtg cttttttctc tctgcaatta 1080 cctgtcatag cattttgtgc tcaccacgaa ggatggtctc tgccttctct tgtcggtgta 1140 tgccatctga acctaggaac acaaagtata ttggcctcaa acgggagacc cagggttgcc 1200 agttttccgt gggccttccc ctcccttgaa atgtctttaa ttacctcccc ttcatcgtca 1260 ggccacgtgt gacttctgtt cttagcactg ccagggtcat tgacttccat ctaagcttgc 1320 atcaggaaga tgttccttct gtgatcattg gtactgaagc cagaaaagct ctcattcagg 1380 aactctgaag agcaaaaagg gacaaacact aactgctgag ctgggccatt tgatctcctt 1440 tcaccttgca ttgctgtcac agcaccttgt atgatggcag gacaggctcc agcagagaga 1500 actgcacagt gaccactgta tttttcacgc tcttccaggg atccctgtcc cccgacattg 1560 aagagatctc attcaggcca gagacacaga gaccacatag cccagtgatt aaaccccggt 1620 ttcactctgg ccccaggagt ggagcctggc cactcctgtt tggttctcac tgggaggccc 1680 actggccttg gatcatctcc tcatgcacac ccggagtttt acctgcttgc ttgctttcct 1740 ggactgctgt ttgcaagaaa gtaactaaaa catgaaaagt aaacctccag cttccacagt 1800 atattacctg ccgttgcatg catttgaaag ttagcctcct cccttgccac cgtcttggtg 1860 gcagtagcga tgcaagaatg atgggagctt tccgagagcg ttcagtgttt cactgaagac 1920 aggacccata gccttcattt ctggctctgt gtctcctctg gcatatggac acatttcctg 1980 gcatttgcct gagtctacac cactttttga gaacctgaaa tagaagggaa tcttctgtgg 2040 cccacagtct ccatattggc cctagaagac tggcctggcg gaggaatttg cgttggcttg 2100 ctttcagggg ttagctacaa gattcagctt tatatctctg ttgcttcttg gccagtgtag 2160 tcaataaggg tcttctttaa catctaagat agaggtttgg ttggccgggc gtggtcgctw 2220 actcctgtaa tcccagcact ttgggaggcc cagtgaggtg ggagaattgc ttgaacccag 2280 gaggcagagg ttgcagtgag ctgagattgc accattgcat tccagcctgg gtaacagagt 2340 gagactcttg tctcaaaaaa aaaaaaaaaa aaaaaaaaa 2379 <210> 14 <211> 67 <212> PRT
<213> Homo Sapiens <400> 14 Met Gly Asp Trp Thr Trp Leu Tyr Arg Val Gly Cys Phe Phe Leu Ser Ala Ile Thr Cys His Ser Ile Leu Cys Ser Pro Arg Arg Met Val Ser Ala Phe Ser Cys Arg Cys Met Pro Ser Glu Pro Arg Asn Thr Lys Tyr Ile Gly Leu Lys Arg Glu Thr Gln Gly Cys Gln Phe Ser Val Gly Leu Pro Leu Pro <210> 15 <211> 1607 <212> DNA
<213> Homo Sapiens <400> 15 atacaagtca agatgctacc catgtagaca cactgtattt ttaaggtggg caagtgcgat 60 taacgatgaa ccattttaaa ggggaggtta tttgaaacct ctaatttgat tattgggagg 120 attttcatgc tttctttagt atttattacc atcataccga ttcaaactat tttattgtct 180 aatacattag cattttgtat tttgatggaa attgttacag aatttaaaga tttgatgaaa 240 taagatgtag cagatttttt gtagcaagtt tctggtaaaa gggttttttg caagtctcag 300 gttcttgctg cactattttt ttttaaatat ttattccagt tattctaatt cagaagcatt 360 cttttcaagt aacagcagca cttgtgaaag gaaaaaaaaa tgcacatgtt tcttagtagg 420 ttactaaatt tgtacaatta attaagattt tagccatcag tgagtttgaa aagggaaatg 480 tatttatttt cagcattaaa atgcttccaa aagatcaagt tgcttttgtt tgtttgtttt 540 tttaaccgta atgtagatgg agaaattgga ggcaacctca gtataggaac tgccactttg 600 agcagtttag gtcttaaaga gaaagtcaat ctaatgccaa ggggagaaca atgagctgaa 660 attgtaccaa ctcctctggc cctccttccc tcaattaaaa aaacacactt accagttttg 720 cttattttac agatatctgg tggttctata gtttaaagca gcttgtgaaa ttaaaaaagt 780 ggactcaatt ttgtttacct ttctgtaagt ttttcatttt tgctgtatag cattggcaaa B40 aatatgtaca aattgacctc tgttcttatt tcctattgtg agcattataa agataagctc 900 ctatgtaaaa ccttgctctc agatgagtaa aatatgtatc acagcatagc tcagcaataa 960 ttcatgctca gctgtgggga ccctgggggc tttttgaaga tgatggaacc gcactagggt 1020 tgaaactgat ggctgtggag ttaattgtgt tttcgagctt gaatctcacc tgtgattttt 1080 tttttttaat gttgtttcat gacttgattt ttctcatasg ccaatgtatt tgtaggttta 1140 ctggatttta tttttaggga gtgggtaatt tcttcccttt tttgattaag ttggttcagc 1200 tatggtgcta ttcagtaggt atcttcagtg tcaggtcccg tagctgaatg ccattgttat 1260 tataattatt atttgtaatc acattgtaag cttgaatttg ggcttgwacc tgcatctttt 1320 gtattctgta catctggtta cttagacttt gggagtccaa tttggtttca gtcatgtatg 1380 tctactttgt agtttaagta gacttcatca actatggtct attttgggtt tgtagtttta 1440 atttagaatt gtgttaaatt gatgttttgc atttgacttc atttgacatt agttgaagta 1500 aattatttaa tttttgaatt ctggaatttg aacatttact gtaatttgta atataactgc 1560 tgtgaaatac ttgaataaag atgacaagaa saaaaaaaaa aaaaaaa 1607 <210> 16 <211> 58 <212> PRT
<213> Homo sapiens <400> 16 Met Tyr Leu Phe Ser Ala Leu Lys Cys Phe Gln Lys Ile Lys Leu Leu Leu Phe Val Cys Phe Phe Asn Arg Asn Val Asp Gly Glu Ile Gly Gly Asn Leu Ser Ile Gly Thr Ala Thr Leu Ser Ser Leu Gly Leu Lys Glu Lys Val Asn Leu Met Pro Arg Gly Glu Gln <210> 17 <211> 2695 <212> DNA
<213> Ho:io sapiens <400> 17 gaacagagta gtagccaggc aatgttctca taataaacag aaaaggaaaa gaaactccaa 60 tgtggaaacc atctcaaacc tctgtgtgaa gtctaccaat tttctgttaa tcaaagcaag 120 ctatgtgagt gtactcagag tccaggggca aggtagtcac cctgtgtgtg gtgggaaaat 180 actgcaagat tatatgtcaa ataatgggat actcaggaat atttacaaaa atgttgaata 240 ttttaatgaa ataacaaata tttagacatt caatagactt gagagtaact ttaccaaggg 300 tctaagta~g agagatatgt ttaatatatt tttatgggct gaaaaccctg agtgggaaaa 360 taggactaat ttcaccagga tgacctcctg gaaatgcatt ttccattttg gaaattattt 420 taaaagttca ttttttctgg atgggtatgt gtatgtgtgt gtgtctgtcy aygtgtgtat 480 gttttatgag cttgttaaca ctaatgtcat acaaaagtac tggttagcag gaataagatt 540 ttaaggtgta ttggcattcc catggttccc aagaaaattt tagatgactt tgattaaaaa 600 gtttggat4t tgtctattta aatctagcat aaaaattggt catggtgatg atcctagtta 660 tgactaatct ccctttaaga tttaggcatt tactgtgtga aatatgtggc acattttcca 720 taacaaacag ctaaagttac tgaacacaaa ttatggaaag gtgaaatgag gaaaacattg 780 WO 99142470 PG"T/US99/03458 caaaacactg aaagagaata tgtctttatt tgcatgctgg caaatgaaaa ttccggtttc 840 acttctactt cagtatctaa caagtctcta acaagaacag acattgaatg aatgaattaa 900 gttgagctgt ttgaaaatta gaatgttttc cataaataca ttattgaact atcaattagc 960 ataaactgct actttcttgt ttgacactgg tcacagtatt tgaaagtaaa aagaatgtta 1020 ctgcacattc agaaatcagg tccacataaa atttaaggtc aggatattaa aggatcacag 1080 ccagtgctgt taggccttca tttattctat ctttttgtct gttcagacat gataactttt 1140 ctacccatca ttttttccat tctagtagtg gttacatttg ttcttgggaa ttttgctaat 1200 ggcttcatag tgttggtaaa ttccattgag tgggtcaaga gacaaaagat ctcctttgct 1260 gaccaaattc tcactgctct ggcagtctcc agagttggtt tgctctgggt aatattatwa 1320 cattggtatg caactgtttt gaatccaggt tcatatagtt taggagtaag aattactact 1380 attaatgcct gggctgtaac caaccatttc agcatctggg ttgctactag cctcagcata 1440 ttttatttgc tcaagattgc caatttctcc aactttattt ttcttcactt aaaaaggaga 1500 attaagagtg tcattccagt gatactattg gggtctttgt tatttttggt ttgtcatctt 1560 gttgtggtaa acatggatga gagtatgtgg acaaaagaat atgaaggaaa cgtgagttgg 1620 gagatcaaat tgagtgatcc gacgcacctt tcagatatga ctgtaaccac gcttgcaaac 1680 ttaataccct ttactctgtc cctgttatct tttctgctct taatctgttc tttgtgtaaa 1740 catctcaaga agatgcagtt ccatggcaaa ggatctccag attccaacac caaggtccac 1800 ataaaagctt tgcaaacggt gacctccttc ctcttgttat ttgctgttta ctttctgtcc 1860 ctaatcacat cgatttggaa ttttagqagg aggctgtaga acgaacctgt cctcatgctc 1920 agccaaacta ctgcaattat atacccttca tttcattcat tcatcctaat ttggggaagc 1980 aagaagctga aacagacctt tcttttgatt ttgtgtcaga ttaagtgctg agtaaaagac 2040 ctgaaactct caaatttcta gattcacaag tgggacatcg tgtgtctcca agagaaaaca 2100 aactgatgtt gtctggaaca ttttatactt tccactggtt tttctgtatt gtatgttttt 2160 gagtaatttc caaaagtata tctagaaaag tcttttaccc taaagttagt ctaaaaaggt 2220 atctatatak gcatgtgtat ggtgtatatg aaacacttaa gagagagtgg caataacata 2280 atcatttttw acaaactgcc aaattataga aaatattgta agaaattttt cagaatcatg 2340 aagccatgtg tattcacaat acagttcata ttatcatgtt tcatttgaaa aatttatgat 2400 ctatatttat aattgttaag aacttacagc ttatttcaca aaatcattgc tcttttccac 2460 tgttatttgt accatacgta tgtaccatag tgtgcttaaa cgtgattatt tgaacgtcta 2520 gttttttgga tggtatgcgc attctaatct aaatcaataa tgaagtttta tctttggggt 2580 agtttttgtt gcataatgaa ttctaatttt atgtttaatt taaagcaaac aattattgtt 2640 agaaaactat gcacaaaata aaattcaagg atgaaaaata aaaaaaaaaa aaaaa 2695 <210> 18 <211> 256 <212> PRT
<213> Homo sapiens <220>
<221> UNSURE
<222> (64) <400> 18 Met Ile Thr Phe Leu Pro Ile Ile Phe Ser Ile Leu Val Val Val Thr Phe Val Leu Gly Asn Phe Ala Asn Gly Phe Ile Val Leu Val Asn Ser Ile Glu Trp Val Lys Arg Gln Lys Ile Ser Phe Ala Asp Gln Ile Leu Thr Ala Leu Ala Val Ser Arg Val Gly Leu Leu Trp Val Ile Leu Xaa His Trp Tyr Ala Thr Val Leu Asn Pro Gly Ser Tyr Ser Leu Gly Val Arg Ile Thr Thr Ile Asn Ala Trp Ala Val Thr Asn His Phe Ser Ile Trp Val Ala Thr Ser Leu Ser Ile Phe Tyr Leu Leu Lys Ile Ala Asn Phe Ser Asn Phe Ile Phe Leu His Leu Lys Arg Arg Ile Lys Ser Val Ile Pro Val Ile Leu Leu Gly Ser Leu Leu Phe Leu Val Cys His Leu Val Val Val Asn Met Asp Glu Ser Met Trp Thr Lys Glu Tyr Glu Gly Asn Val Ser Trp Glu Ile Lys Leu Ser Asp Pro Thr His Leu Ser Asp Met Thr Val Thr Thr Leu Ala Asn Leu Ile Pro Phe Thr Leu Ser Leu Leu Ser Phe Leu Leu Leu Ile Cys Ser Leu Cys Lys His Leu Lys Lys Met Gln Phe His Gly Lys Gly Ser Pro Asp Ser Asn Thr Lys Val His Ile Lys Ala Leu Gln Thr Val Thr Ser Phe Leu Leu Leu Phe Ala Val Tyr Phe Leu Ser Leu Ile Thr Ser Ile Trp Asn Phe Arg Arg Arg Leu <210> 19 <211> 1111 <212> DNA
<213> Homo Sapiens <400> 19 gccgagcgcc gccgccgaag cttccgtctc gctcgctcgc gcagcggcgg cagcagaggt 60 cgcgcacaga tgcgggttag actggcgggg ggaggaggcg gaggagggaa ggaagctgca 120 tgcatgagac ccacagactc ttgcaagccg gatgccctct gtggatgaaa gatgtatcat 180 ggaatgaacc cgagcaatgg agatggattt ctagagcagc agcagcagca gcagcaacct 240 cagtcccccc agagactctt ggccgtgatc ctgtggtttc agctggcgct gtgcttCggc 300 cctgcacagc tcacgggcgg gttcgatgac cttcaagtgt gtgctgaccc cggcattccc 360 gagaatggct tcaggacccc cagcggaggg gttttctttg aaggctctgt agcccgattt 420 cactgccaag acggattcaa gctgaagggc gctacaaaga gactgtgttt gaagcatttt 480 aatggasccc taggctggat cccaagtgat aattccatct gtgtgcaaga agattgccgt 540 atccctcaaa tcgaagatgc tgagattcat aacaagacat atagacatgg agagaagcta 600 atcatcactt gtcatgaagg attcaagatc cggtaccccg acctacacaa tatggtttca 660 ttatgtcgcg acgatggaac gtggaataat ctgcccatct gtcaaggctg cctgagacct 720 ctagcctctt ctaatggcta tgtaaacatc tctgagctcc agacctcctt cccggtgggg 780 actgtgatct cctatcgctg ctttcccgga tttaaacttg atgggcctgc gtatcttgag 840 tgcttacaaa accttatctg gtcgtccagc ccaccccggt gccttgctct ggaaggagga 900 agacctgaac atcttttccc tgtcctttat ttcccacaca tcaggttggc agctgctgtg 960 ctttattttt gccctgtgtt aaagtcctct cccaccccag cacctacctg ttcctcaact 1020 agcaccacca catctctgtt ctaaatgttg ttctcctgca ataaaggacg tttgaattta 1080 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa a 1111 <210> 20 <211> 290 <212> PRT
<213> Homo sapiens <400> 20 Met Tyr His Gly Met Asn Pro Ser Asn Gly Asp Gly Phe Leu Glu Gln Gln Gln Gln Gln Gln Gln Pro Gln Ser Pro Gln Arg Leu Leu Ala Val Ile Leu Trp Phe Gln Leu Ala Leu Cys Phe Gly Pro Ala Gln Leu Thr Gly Gly Phe Asp Asp Leu Gln Val Cys Ala Asp Pro Gly Ile Pro Glu Asn Gly Phe Arg Thr Pro Ser Gly Gly Val Phe Phe Glu Gly Ser Val Ala Arg Phe His Cys Gln Asp Gly Phe Lys Leu Lys Gly Ala Thr Lys Arg Leu Cys Leu Lys His Phe Asn Gly Thr Leu Gly Trp Ile Pro Ser Asp Asn Ser Ile Cys Val Gln Glu Asp Cys Arg Ile Pro Gln Ile Glu Asp Ala Glu Ile His Asn Lys Thr Tyr Arg His Gly Glu Lys Leu Ile Ile Thr Cys His Glu Gly Phe Lys Ile Arg Tyr Pro Asp Leu His Asn Met Val Ser Leu Cys Arg Asp Asp Gly Thr Trp Asn Asn Leu Pro Ile Cys Gln Gly Cys Leu Arg Pro Leu Ala Ser Ser Asn Gly Tyr Val Asn Ile Ser Glu Leu Gln Thr Ser Phe Pro Val Gly Thr Val Ile Ser Tyr Arg Cys Phe Pro Gly Phe Lys Leu Asp Gly Ser Ala Tyr Leu Glu Cys Leu Gln Asn Leu Ile Trp Ser Ser Ser Pro Pro Arg Cys Leu Ala Leu Glu Gly Gly Arg pro Glu His Leu Phe Pro Val Leu Tyr Phe Pro His Ile Arg Leu Ala Ala Ala Val Leu Tyr Phe Cys Pro Val Leu Lys Ser Ser Pro Thr Pro Ala Pro Thr Cys Ser Ser Thr Ser Thr Thr Thr Ser Leu Phe <210> 21 <211> 29 <212> DNA
<213> Artificial Sequence <220>
<223> oligonucleotide <220>
<221> misc_feature <222> (2) <223> biotinylated phosphoaramidite residue <400> 21 gncatggaag gagactggga taaggcaga 29 <210> 22 <211> 29 <212> DNA
<213> Artificial Sequence <220>
<223> oiigonucleotide <220>
<221> misc_feature <222> (2) <223> biotinylated phosphoaramidite residue <400> 22 ' tnccaggaac acagaaaaaa acttgagaa 29 <210> 23 <211> 29 <212> DNA
<213> Artificial Sequence <220>
<223> oiigonucleotide <220>
<221> misc_feature <222> (2) <223> biotinylated phosphoaramidite residue <400> 23 gngctgggag tactgctaga gggtgtgga 29 <210> 24 <211> 29 <212> DVA
<213> Artificial Sequence <220>
<223> o~igonucleotide <220>
<221> misc_feature <222> (z) <223> biotinylated phosphoaramiditeresidue <400> 29 cnctctttgg ctgtacacga acttgctcc 29 <210> 25 <211> 29 <212> DNA

<213> Artificial Sequence <220>

<223> oligonucleotide <220>

<221> misc_feature <222> (2) <223> biotinylated phosphoaramiditeresidue <400> 25 gngggtggca cagcagagaa agactccat 29 <210> 26 <211> 29 <212> DNA

<213> Artificial Sequence <220>

<223> oligonucleotide <220>

<221> misc_feature <222> (2) <223> biotinylated phosphoaramiditeresidue <400> 26 tngcatcttc accgccagca tcagttttg 29 <210> 27 <211> 29 <212> DNA

<213> Artificial Sequence <220>

<223> oligonucleotide <220>

<221> misc_feature <222> (2) <223> biotinylated phosphoaramiditeresidue <400> 27 cnaactctgt aaagccaagt ccagtcacc 29 <210> 28 <211> 29 <212> DNA

<213> Artificial Sequence <220>

<223> oligonucleotide <220>
<221> misc_feature <222> (2) <223> biotinylated phosphoaramidite residue <400> 28 tnctgaggtt gcctccaatt tctccatct 29 <210> 29 <211> 29 <212> DNA
<213> Artificial Sequence <220>
<223> oligonucleotide <220>
<221> misc_feature <222> (2) <223> biotinylated phosphoaramidite residue <400> 29 gntgacaaac caaaaataac aaagacccc 29 <210> 30 <211> 29 <212> DNA
<213> Artificial Sequence <220>
<223> oligonucleotide <220>
<221> misc_feature <222> (2) <223> biotinylated phosphoaramidite residue <400> 30 gntacatctt tcatccacag agggcatcc <210> 31 <211> 189 <212> PRT
<213> Homo Sapiens <400> 31 Met Val His Cys Pro His Glu Leu Leu Gln Met Pro Leu Ser Leu Phe Ser Gln Arg Ser Trp Val Thr Gln Cys Leu Asp Thr Trp Lys Thr Cys Thr Leu Ile Thr Gln Arg His Leu Ala Ser Asp His Leu Pro Ser Glu Phe Leu Leu Val Gln Leu Gly Tyr His Pro Leu Thr His Gln Ala Ala Pro His Leu Pro Leu Leu Leu Leu Trp Gln Val Phe Pro Ala Tyr Gln Glu Gln GIy Phe Ser Cys Lys Gly Gln Leu Leu Leu Gly Leu Leu Val Ser Thr Asp Asn Ile Phe Leu Pro Ile Leu Gly Gln Ala Pro Gln Thr His Pro Leu Leu Pro His Gln Arg Trp Ala Asn Gln Lys Glu Ser Val Pro Val Lys Ile Glu Arg Tyr Leu Pro Gln Leu Glu Gln Arg Asp Trp Pro Glu Phe Gly Lys Glu Gly Leu Leu His Lys Pro Arg Arg Gly Pro Val Leu Ser Leu Pro Leu Asp Thr Val Glu Ser Gly His Leu Val Ser Met Leu Cys Gln Lys Ala Tyr Gln Val Gly Arg Asn Leu

Claims

What is claimed is:

1. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:1;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:1 from nucleotide 185 to nucleotide 1678;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:1 from nucleotide 482 to nucleotide 1678;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone co821_31 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone co821_31 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone co821_31 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone co821_31 deposited under accession number ATCC 98663;
{h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:2;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:2, the fragment comprising eight contiguous amino acids of SEQ ID NO:2;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i}; and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-{i), and that has a length that is at least 25% of the length of SEQ ID NO:1.

2. The polynucleotide of claim 1 wherein said polynucleotide is operably linked to at least one expression control sequence.

3. A host cell transformed with the polynucleotide of claim 2.

4. The host cell of claim 3, wherein said cell is a mammalian cell.

5. A process for producing a protein encoded by the polynucleotide of claim 2, which process comprises:
(a) growing a culture of the host cell of claim 3 in a suitable culture medium; and (b) purifying said protein from the culture.

6. A protein produced according to the process of claim 5.

7. An isolated polynucleotide encoding the protein of claim 6.

8. The polynucleotide of claim 7, wherein the polynucleotide comprises the cDNA insert of clone co821_31 deposited under accession number ATCC 98663.

9. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:2;
(b) a fragment of the amino acid sequence of SEQ ID NO:2, the fragment comprising eight contiguous amino acids of SEQ ID NO:2; and (c) the amino acid sequence encoded by the cDNA insert of clone co821_31 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

10. The protein of claim 9, wherein said protein comprises the amino acid sequence of SEQ ID NO:2.

11. A composition comprising the protein of claim 9 and a pharmaceutically acceptable carrier.

12. An isolated polynucleotide selected from the group consisting of:

(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:3;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:3 from nucleotide 176 to nucleotide 754;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:3 from nucleotide 425 to nucleotide 754;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone dk329_1 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone dk329_1 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone dk329_1 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone dk329_1 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:4;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:4, the fragment comprising eight contiguous amino acids of SEQ ID NO:4;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-{i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:3.

13. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:4;
(b) a fragment of the amino acid sequence of SEQ ID NO:4, the fragment comprising eight contiguous amino acids of SEQ ID NO:4; and (c) the amino acid sequence encoded by the cDNA insert of clone dk329_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

14. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:5;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:5 from nucleotide 190 to nucleotide 1449;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:5 from nucleotide 913 to nucleotide 1449;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone fx317-11 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone fx317_11 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone fx317_11 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone fx317_11 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:6;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:6, the fragment comprising eight contiguous amino acids of SEQ ID NO:6;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:5.

15. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:6;
(b) a fragment of the amino acid sequence of SEQ ID NO:6, the fragment comprising eight contiguous amino acids of SEQ ID NO:6; and (c) the amino acid sequence encoded by the cDNA insert of clone fx317_11 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

16. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:7;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:7 from nucleotide 51 to nucleotide 1202;
(c) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone lp547_4 deposited under accession number ATCC 98663;
(d) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone lp547_4 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:8;
(f) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:8, the fragment comprising eight contiguous amino acids of SEQ ID NO:8;
(g) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(f); and (h) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(f), and that has a length that is at least 25% of the length of SEQ ID NO:7.

17. A protein comprising an amino acid sequence selected from the group consisting of:

(a) the amino acid sequence of SEQ ID NO:8;
(b) a fragment of the amino acid sequence of SEQ ID NO:8, the fragment comprising eight contiguous amino acids of SEQ ID NO:8; and (c) the amino acid sequence encoded by the cDNA insert of clone lp547_ 4 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

18. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:9;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:9 from nucleotide 61 to nucleotide 2559;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:9 from nucleotide 904 to nucleotide 2559;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone lv310_7 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone lv310_7 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone lv310_7 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone lv310_7 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:10;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:10, the fragment comprising eight contiguous amino acids of SEQ ID NO:10;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%

formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:9.

19. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:10;
(b) a fragment of the amino acid sequence of SEQ ID NO:10, the fragment comprising eight contiguous amino acids of SEQ ID NO:10; and (c) the amino acid sequence encoded by the cDNA insert of clone lv310_7 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

20. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:11;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:11 from nucleotide 389 to nucleotide 1330;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:11 from nucleotide 1286 to nucleotide 1330;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone nq34_12 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone nq34_12 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone nq34_12 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone nq34_l2 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:12;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:12, the fragment comprising eight contiguous amino acids of SEQ ID NO:12;

(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:11.

21. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:12;
(b) a fragment of the amino acid sequence of SEQ ID NO:12, the fragment comprising eight contiguous amino acids of SEQ ID NO:12; and (c) the amino acid sequence encoded by the cDNA insert of clone nq34_12 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

22. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:13;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:13 from nucleotide 1026 to nucleotide 1226;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:13 from nucleotide 1101 to nucleotide 1226;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone pj154_1 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone pj154_1 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone pj154_1 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone pj154_1 deposited under accession number ATCC 98663;

(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:14;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:14, the fragment comprising eight contiguous amino acids of SEQ ID NO:14;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:13.

23. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:14;
(b) a fragment of the amino acid sequence of SEQ ID NO:14, the fragment comprising eight contiguous amino acids of SEQ ID NO:14; and (c) the amino acid sequence encoded by the cDNA insert of clone pj154_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

24. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:15;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:15 from nucleotide 478 to nucleotide 651;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:15 from nucleotide 562 to nucleotide 651;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone pk147_1 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone pk147_1 deposited under accession number ATCC 98663;

(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone pk147_1 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone pk147_1 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:16;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:16, the fragment comprising eight contiguous amino acids of SEQ ID NO:16;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:15.

25. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:16;
(b) a fragment of the amino acid sequence of SEQ ID NO:16, the fragment comprising eight contiguous amino acids of SEQ ID NO:16; and (c) the amino acid sequence encoded by the cDNA insert of clone pk147_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

26. An isolated polynucleotide selected from the group consisting of:
(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:17;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:17 from nucleotide 1129 to nucleotide 1896;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:17 from nucleotide 1189 to nucleotide 1896;

(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone pt127_1 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone pt127_1 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone pt127_1 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone pt127_1 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:18;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:18, the fragment comprising eight contiguous amino acids of SEQ ID NO:18;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:17.

27. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:18;
(b) a fragment of the amino acid sequence of SEQ ID NO:18, the fragment comprising eight contiguous amino acids of SEQ ID NO:18; and (c) the amino acid sequence encoded by the cDNA insert of clone pt127_1 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.

28. An isolated polynucleotide selected from the group consisting of:

(a) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:19;
(b) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:19 from nucleotide 172 to nucleotide 1041;
(c) a polynucleotide comprising the nucleotide sequence of SEQ ID
NO:19 from nucleotide 295 to nucleotide 1041;
(d) a polynucleotide comprising the nucleotide sequence of the full-length protein coding sequence of clone qo115_13 deposited under accession number ATCC 98663;
(e) a polynucleotide encoding the full-length protein encoded by the cDNA insert of clone qo115_13 deposited under accession number ATCC 98663;
(f) a polynucleotide comprising the nucleotide sequence of the mature protein coding sequence of clone qo115_13 deposited under accession number ATCC 98663;
(g) a polynucleotide encoding the mature protein encoded by the cDNA insert of clone qo115_13 deposited under accession number ATCC 98663;
(h) a polynucleotide encoding a protein comprising the amino acid sequence of SEQ ID NO:20;
(i) a polynucleotide encoding a protein comprising a fragment of the amino acid sequence of SEQ ID NO:20, the fragment comprising eight contiguous amino acids of SEQ ID NO:20;
(j) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 65 degrees C, or 4X SSC at 42 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i); and (k) a polynucleotide that hybridizes under conditions at least as stringent as 4X SSC at 50 degrees C, or 6X SSC at 40 degrees C with 50%
formamide, to any one of the polynucleotides specified in (a)-(i), and that has a length that is at least 25% of the length of SEQ ID NO:19.

29. A protein comprising an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO:20;
(b) a fragment of the amino acid sequence of SEQ ID NO:20, the fragment comprising eight contiguous amino acids of SEQ ID NO:20; and (c) the amino acid sequence encoded by the cDNA insert of clone qo115_13 deposited under accession number ATCC 98663;
the protein being substantially free from other mammalian proteins.