US20030087384A1

US20030087384A1 - Fibroblast growth factor receptor-like molecules and uses thereof

Info

Publication number: US20030087384A1
Application number: US10/229,584
Authority: US
Inventors: Christiaan Saris; Sharon Mu; Min Xia; Thomas Boone; Todd Covey
Original assignee: Amgen Inc
Current assignee: Amgen Inc
Priority date: 2000-03-22
Filing date: 2002-08-28
Publication date: 2003-05-08
Also published as: WO2001070977A2; US20020009776A1; JP2006340720A; AU2001252940A1; US20080044859A1; US7348162B2; WO2001070977A3; JP2003527858A; EP1268793A2; CA2403572A1; MXPA02009224A; JP2009278975A

Abstract

The present invention provides Fibroblast Growth Factor Receptor-Like (FGFR-L) polypeptides and nucleic acid molecules encoding the same. The invention also provides selective binding agents, vectors, host cells, and methods for producing FGFR-L polypeptides. The invention further provides pharmaceutical compositions and methods for the diagnosis, treatment, amelioration, and/or prevention of diseases, disorders, and conditions associated with FGFR-L polypeptides.

Description

This application is a continuation of U.S. Provisional Patent Application No. 60/191,379, filed on Mar. 22, 2000, the disclosure of which is explicitly incorporated by reference herein.[0001]

FIELD OF THE INVENTION

The present invention relates to Fibroblast Growth Factor Receptor-Like (FGFR-L) polypeptides and nucleic acid molecules encoding the same. The invention also relates to selective binding agents, vectors, host cells, and methods for producing FGFR-L polypeptides. The invention further relates to pharmaceutical compositions and methods for the diagnosis, treatment, amelioration, and/or prevention of diseases, disorders, and conditions associated with FGFR-L polypeptides.

BACKGROUND OF THE INVENTION

Technical advances in the identification, cloning, expression, and manipulation of nucleic acid molecules and the deciphering of the human genome have greatly accelerated the discovery of novel therapeutics. Rapid nucleic acid sequencing. techniques can now generate sequence information at unprecedented rates and, coupled with computational analyses, allow the assembly of overlapping sequences into partial and entire genomes and the identification of polypeptide-encoding regions. A comparison of a predicted amino acid sequence against a database compilation of known amino acid sequences allows one to determine the extent of homology to previously identified sequences and/or structural landmarks. The cloning and expression of a polypeptide-encoding region of a nucleic acid molecule provides a polypeptide product for structural and functional analyses. The manipulation of nucleic acid molecules and encoded polypeptides may confer advantageous properties on a product for use as a therapeutic.

In spite of the significant technical advances in genome research over the past decade, the potential for the development of novel therapeutics based on the human genome is still largely unrealized. Many genes encoding potentially beneficial polypeptide therapeutics or those encoding polypeptides, which may act as “targets” for therapeutic molecules, have still not been identified. Accordingly, it is an object of the invention to identify novel polypeptides, and nucleic acid molecules encoding the same, which have diagnostic or therapeutic benefit.

SUMMARY OF THE INVENTION

The present invention relates to novel FGFR-L nucleic acid molecules and encoded polypeptides.

The invention provides for an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of:

(a) the nucleotide sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4;

(b) the nucleotide sequence of the DNA insert in ATCC Deposit No. ______;

(c) a nucleotide sequence encoding the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(d) a nucleotide sequence which hybridizes under moderately or highly stringent conditions to the complement of any of (a)-(c); and

(e) a nucleotide sequence complementary to any of (a)-(c).

The invention also provides for an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of:

(a) a nucleotide sequence encoding a polypeptide which is at least about 70 percent identical to the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(b) a nucleotide sequence encoding an allelic variant or splice variant of the nucleotide sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4, the nucleotide sequence of the DNA insert in ATCC Deposit No. ______, or (a);

(c) a region of the nucleotide sequence of either SEQ ID NO: 1 or SEQ ID NO: 4, the DNA insert in ATCC Deposit No. ______, (a), or (b) encoding a polypeptide fragment of at least about 25 amino acid residues, wherein the polypeptide fragment has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, or is antigenic;

(d) a region of the nucleotide sequence of either SEQ ID NO: 1 or SEQ ID NO: 4, the DNA insert in ATCC Deposit No. ______, or any of (a)-(c) comprising a fragment of at least about 16 nucleotides;

(e) a nucleotide sequence which hybridizes under moderately or highly stringent conditions to the complement of any of (a)-(d); and

(f) a nucleotide sequence complementary to any of (a)-(d).

The invention further provides for an isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of:

(a) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one conservative amino acid substitution, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(b) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid insertion, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(c) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid deletion, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(d) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 which has a C- and/or N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(e) a nucleotide sequence encoding a polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one modification selected from the group consisting of amino acid substitutions, amino acid insertions, amino acid deletions, C-terminal truncation, and N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(f) a nucleotide sequence of any of (a)-(e) comprising a fragment of at least about 16 nucleotides;

(g) a nucleotide sequence which hybridizes under moderately or highly stringent conditions to the complement of any of (a)-(f); and

(h) a nucleotide sequence complementary to any of (a)-(e).

The present invention provides for an isolated polypeptide comprising an amino acid sequence selected from the group consisting of:

(a) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5; and

(b) the amino acid sequence encoded by the DNA insert in ATCC Deposit No. ______.

The invention also provides for an isolated polypeptide comprising the amino acid sequence selected from the group consisting of

(a) the amino acid sequence as set forth in SEQ ID NO: 3 or SEQ ID NO: 6, optionally further comprising an amino-terminal methionine;

(b) an amino acid sequence for an ortholog of either SEQ ID NO: 2 or SEQ ID NO: 5;

(c) an amino acid sequence which is at least about 70 percent identical to the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(d) a fragment of the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 comprising at least about 25 amino acid residues, wherein the fragment has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, or is antigenic; and

(e) an amino acid sequence for an allelic variant or splice variant of the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, the amino acid sequence encoded by the DNA insert in ATCC Deposit No. ______, or any of (a)-(c).

The invention further provides for an isolated polypeptide comprising the amino acid sequence selected from the group consisting of:

(a) the amino acid sequence as se t forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one conservative amino acid substitution, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(1) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid insertion, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(c) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one amino acid deletion, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5;

(d) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 which has a C- and/or N-terminal truncation, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5; and

(e) the amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 with at least one modification selected from the group consisting of amino acid substitutions, amino acid insertions, amino acid deletions, C-terminal truncation, and N-terminal truncation, wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5.

Also provided are fusion polypeptides comprising FGFR-L amino acid sequences.

The present invention also provides for an expression vector comprising the isolated nucleic acid molecules as set forth herein, recombinant host cells comprising the recombinant nucleic acid molecules as set forth herein, and a method of producing an FGFR-L polypeptide comprising culturing the host cells and optionally isolating the polypeptide so produced.

A transgenic non-human animal comprising a nucleic acid molecule encoding an FGFR-L polypeptide is also encompassed by the invention. The FGFR-L nucleic acid molecules are introduced into the animal in a manner that allows expression and increased levels of an FGFR-L polypeptide, which may include increased circulating levels. Alternatively, the FGFR-L nucleic acid molecules are introduced into the animal in a manner that prevents expression of endogenous FGFR-L polypeptide (i.e., generates a transgenic animal possessing an FGFR-L polypeptide gene knockout). The transgenic non-human animal is preferably a mammal, and more preferably a rodent, such as a rat or a mouse.

Also provided are derivatives of the FGPR-L polypeptides of the present invention.

Additionally provided are selective binding agents such as antibodies and peptides capable of specifically binding the FGFR-L polypeptides of the invention. Such antibodies and peptides may be agonistic or antagonistic.

Pharmaceutical compositions comprising the nucleotides, polypeptides, or selective binding agents of the invention and one or more pharmaceutically acceptable formulation agents are also encompassed by the invention. The pharmaceutical compositions are used to provide therapeutically effective amounts of the nucleotides or polypeptides of the present invention. The invention is also directed to methods of using the polypeptides, nucleic acid molecules, and selective binding agents.

The FGFR-L polypeptides and nucleic acid molecules of the present invention may be used to treat, prevent, ameliorate, and/or detect diseases and disorders, including those recited herein.

The present invention also provides a method of assaying test molecules to identify a test molecule that binds to an FGFR-L polypeptide. The method comprises contacting an FGFR-L polypeptide with a test molecule to determine the extent of binding of the test molecule to the polypeptide. The method further comprises determining whether such test molecules are agonists or antagonists of an FGFR-L polypeptide. The present invention further provides a method of testing the impact of molecules on the expression of FGFR-L polypeptide or on the activity of FGFR-L polypeptide.

Methods of regulating expression and modulating (i.e., increasing or decreasing) levels of an FGFR-L polypeptide are also encompassed by the invention. One method comprises administering to an animal a nucleic acid molecule encoding an FGFR-L polypeptide. In another method, a nucleic acid molecule comprising elements that regulate or modulate the expression of an FGFR-L polypeptide may be administered. Examples of these methods include gene therapy, cell therapy, and anti-sense therapy as further described herein.

The FGFR-L polypeptide can be used for identifying ligands thereof. Various forms of “expression cloning” have been used for cloning ligands for receptors (e.g., Davis et al., 1996 , Cell, 87:1161-69). These and other FGFR-L polypeptide ligand cloning experiments are described in greater detail herein. Isolation of an FGFR-L polypeptide ligand allows for the identification or development of novel agonists or antagonists of the FGFR-L polypeptide signaling pathway. Such agonists and antagonists include FGFR-L polypeptide ligands, anti-FGFR-L polypeptide ligand is antibodies and derivatives thereof, small molecules, or antisense oligonucleotides, any of which can be used for potentially treating one or more diseases or disorders, including those recited herein.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. [0053] 1A-1C illustrate the nucleotide sequence of the murine FGFR-L gene (SEQ ID NO: 1) and the deduced amino acid sequence of murine FGFR-L polypeptide (SEQ ID NO: 2). The predicted signal peptide (underline) and transmembrane domain (double-underline) are indicated;
FIGS. [0054] 2A-2B illustrate the amino acid sequence alignment of murine FGFR-L polypeptide (Smaf2-00017-f4; SEQ ID NO: 2) and Iberian ribbed newt (Pleurodeles waltlii) Fibroblast Growth Factor Receptor-4 (PIR:B49151; SEQ ID NO: 7);
FIGS. [0055] 3A-3B illustrate the nucleotide sequence of a cDNA clone encoding the N-terminal portion of the human FGFR-L gene (SEQ ID NO: 4) and the deduced amino acid sequence of the N-terminal portion of the human FGFR-L polypeptide (SEQ ID NO: 5). The predicted signal peptide (underline) and transmembrane domain (double-underline) are indicated;
FIG. 4 illustrates the amino acid sequence alignment of murine FGFR-L polypeptide (SEQ ID NO: 2) and a virtual human FGFR-L polypeptide sequence (SEQ ID NO: 8) constructed from residues 1-472 of SEQ ID NO: 5 and residues 473-504 of GenBank Accession No. AJ277437. The predicted signal peptide (underline), transmembrane domain (double-underline), and N-linked glycosylation sites (bold) are indicated; [0056]
FIG. 5 illustrates the expression of FGFR-L MRNA as detected by Northern blot analysis in [0057] day 7, 11, 15, and 17 mouse embryos;
FIG. 6 illustrates the expression of FGFR-L mrRNA as detected by Northern blot analysis in murine heart, brain, spleen, lung, liver, skeletal muscle, kidney, and testis; [0058]
FIG. 7 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in NIH 3T3 cells and F10, F4, and D3 mouse bone marrow-derived stromal cell lines; [0059]
FIG. 8 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in human brain, heart, skeletal muscle, colon, thymus, spleen, kidney, liver, small intestine, placenta, lung, and peripheral blood leukocytes; [0060]
FIG. 9 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in promyelocytic leukemia HL-60 cells, HeLa S3 cells, chronic myelogenous leukemia L-562 cells, lymphoblastic leukemia MOLT-4 cells, Burkitt's lymphoma Raji cells, colorectal adenocarcinoma SW480 cells, lung carcinoma A549 cells, and melanoma G361 cells; [0061]
FIG. 10 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in human heart, brain, placenta, lung, liver, skeletal muscle, kidney, and pancreas; [0062]
FIG. 11 illustrates the expression of FGFR-L mRNA as detected by Northern blot analysis in 266-6 cells, AR42J cells, CaPan I cells, HIG-82 cells, OHS4 cells, [0063] SW 1353 cells, SW 872 cells, K562 (old, i.e., later passage) cells, K562 (new, i.e., earlier passage) cells, Jurkat cells, and F4 cells;
FIGS. [0064] 12A-12B illustrate the expression of FGFR-L mRNA as detected by Northern blot analysis in human adipose tissue (using a human FGFR-L-derived probe) and murine adipose tissue (using a murine FGFR-L-derived probe);
FIG. 13 illustrates the expression of FGFR-L mRNA in a number of murine tissues as detected in an RNAse protection assay. The absence of the cyclophilin band in the pancreas RNA sample suggests that thi sample was degraded; [0065]
FIG. 14 illustrates the expression of FGFR-L mRNA as detected by in situ hybridization in the peri-renal, white, and brown adipose tissue of a normal adult mouse (H&E=hematoxylin and eosin counterstaining; ISH=in situ hybridization); [0066]
FIG. 15 illustrates the. expression of FGFR-L mRNA as detected by in situ hybridization in the duodenum, ileum, colon, and pancreas of a normal adult mouse (H&E=hematoxylin and eosin counterstaining; ISH=in situ hybridization); [0067]
FIG. 16 illustrates the expression of FGFR-L mRNA as detected by in situ hybridization in the trachea, articular cartilage of the knee joint, spleen, and uterus of a normal adult mouse (H&E=hematoxylin and eosin counterstaining; ISH=in situ hybridization); [0068]
FIG. 17 illustrates the induction of FGFR-L MRNA in osteoblastic ST2 cells under conditions of osteoclastogenesis (i.e., 5-day exposure to vitamin D3 and dexamethasone); [0069]
FIG. 18 illustrates the results of Western blot analysis of [0070] E. coli-derived Des7-FGFR-L/ECD and CHO-derived FGFR-L/ECD-Fc proteins using FGFR-L polypeptide antiserum;
FIG. 19 illustrates the results of Western blot analysis of murine eye (lane 1) and adipose tissue (lane 2) using FGFR-L polypeptide antiserum; [0071]
FIGS. [0072] 20A-20B illustrate the results of FACS analysis on F4 and D3 bone marrow stromal cells using FGFR-L polypeptide antiserum;
FIGS. [0073] 21A-21D illustrate the results of proliferation assays using D3 bone marrow stromal cells (either untransduced or transduced with a construct encoding FGFR-L polypeptide) following 72 hour exposure to rhuPDGF (panel A), rhuFGF-2 (panel B), rhuFGF-4 (panel C), or rhuFGF-6 (panel D);
FIG. 22 illustrates the results of proliferation assays using A5-F bone marrow stromal cells following exposure to [0074] E. coli-derived Des7-FGFR-L/ECD protein and serum, PDGF, FGF-2, FGF-4, or FGF-6;
FIG. 23 illustrates the results of proliferation assays using A5-F bone marrow stromal cells following exposure to CHO-derived FGFR-L/ECD-Fc protein and serum, PDGF, FGF-4, or FGF-6; [0075]
FIG. 24 illustrates the expression of the neomycin resistance gene as detected by Northern blot analysis of peripheral blood mononuclear cell (PBMN) RNA from two FGFR-L/neo-transduced mice ([0076] lanes 1 and 2) and two neo-transduced control mice (lanes 3 and 4).

DETAILED DESCRIPTION OF THE INVENTION

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All references cited in this application are expressly incorporated by reference herein. [0077]
Definitions [0078]
The terms “FGFR-L gene” or “FGFR-L nucleic acid molecule” or “FGFR-L polynucleotide” refer to a nucleic acid molecule comprising or consisting of a nucleotide sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4, a nucleotide sequence encoding the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, a nucleotide sequence of the DNA insert in ATCC Deposit No. ______, and nucleic acid molecules as defined herein. [0079]
The term “FGFR-L polypeptide allelic variant” refers to one of several possible naturally occurring alternate forms of a gene occupying a given locus on a chromosome of an organism or a population of organisms. [0080]
The term “FGFR-L polypeptide splice variant” refers to a nucleic acid molecule, usually RNA, which is generated by alternative processing of intron sequences in an RNA transcript of FGFR-L polypeptide amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. [0081]
The term “isolated nucleic acid molecule” refers to a nucleic acid molecule of the invention that (1) has been separated from at least about 50 percent of proteins, lipids, carbohydrates, or other materials with which it is naturally found when total nucleic acid is isolated from the source cells, (2) is not linked to all or a portion of a polynucleotide to which the “isolated nucleic acid molecule” is linked in nature, (3) is operably linked to a polynucleotide which it is not linked to in nature, or (4) does not occur in nature as part of a larger polynucleotide sequence. Preferably, the isolated nucleic acid molecule of the present invention is substantially free from any other contaminating nucleic acid molecule(s) or other contaminants that are found in its natural environment that would interfere with its use in polypeptide production or its therapeutic, diagnostic, prophylactic or research use. [0082]
The term “nucleic acid sequence” or “nucleic acid molecule” refers to a DNA or RNA sequence. The term encompasses molecules formed from any of the known base analogs of DNA and RNA such as, but not limited to 4-acetylcytosine, 8-hydroxy-N6-methyladenosine, aziridinyl-cytosine, pseudoisocytosine, 5-(carboxyhydroxylmethyl) uracil, 5-fluorouracil, 5-bromouracil, 5-carboxymethylaminomethyl-2-thiouracil, 5-carboxy-methylaminomethyluracil, dihydrouracil, inosine, N6-iso-pentenyladenine, 1-methyladenine, 1-methylpseudouracil, 1-methylguanine, 1-methylinosine, 2,2-dimethyl-guanine, 2-methyladenine, -2-methylguanine, 3-methylcytosine, 5-methylcytosine, N6-methyladenine, 7-methylguanine, 5-methylaminomethyluracil, 5-methoxyamino-methyl-2-thiouracil, beta-D-mannosylqueosine, 5′-methoxycarbonyl-methyluracil, 5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, oxybutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyluracil, N-uracil-5-oxyacetic acid methylester, uracil-5-oxyacetic acid, pseudouracil, queosine, 2-thiocytosine, and 2,6-diaminopurine. [0083]
The term “vector” is used to refer to any molecule (e.g., nucleic acid, plasmid, or virus) used to transfer coding information to a host cell. [0084]
The term “expression vector” refers to a vector that is suitable for transformation of a host cell and contains nucleic acid sequences that direct and/or control the expression of inserted heterologous nucleic acid sequences. Expression includes, but is not limited to, processes such as transcription, translation, and RNA splicing, if introns are present. [0085]
The term “operably linked” is used herein to refer to an arrangement of flanking sequences wherein the flanking sequences so described are configured or assembled so as to perform their usual function. Thus, a flanking sequence operably linked to a coding sequence may be capable of effecting the replication, transcription and/or translation of the coding sequence. For example, a coding sequence is operably linked to a promoter when the promoter is capable of directing transcription of that coding sequence. A flanking sequence need not be contiguous with the coding sequence, so long as it functions correctly. Thus, for example, intervening untranslated yet transcribed sequences can be present between a promoter sequence and the coding sequence and the promoter sequence can still be considered “operably linked” to the coding sequence. [0086]
The term “host cell” is used to refer to a cell which has been transformed, or is capable of being transformed with a nucleic acid sequence and then of expressing a selected gene of interest. The term includes the progeny of the parent cell, whether or not the progeny is identical in morphology or in genetic make-up to the original parent, so long as the selected gene is present. [0087]
The term “FGFR-L polypeptide” refers to a polypeptide comprising the amino acid sequence of either SEQ ID NO.: 2 or SEQ ID NO: 5 and related polypeptides. Related polypeptides include FGFR-L polypeptide fragments, FGFR-L polypeptide orthologs, FGFR-L polypeptide variants, and FGFR-L polypeptide derivatives, which possess at least one activity of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. FGFR-L polypeptides may be mature polypeptides, as defined herein, and may or may not have an amino-terminal methionine residue, depending on the method by which they are prepared. [0088]
The term “FGFR-L polypeptide fragment” refers to a polypeptide that comprises a truncation at the amino-terminus (with or without a leader sequence) and/or a truncation at the carboxyl-terminus of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. The term “FGFR-L polypeptide fragment” also refers to amino-terminal and/or carboxyl-terminal truncations of FGFR-L polypeptide orthologs, FGFR-L polypeptide derivatives, or FGFR-L polypeptide variants, or to amino-terminal and/or carboxyl-terminal truncations of the polypeptides encoded by FGFR-L polypeptide allelic variants or FGFR-L polypeptide splice variants. FGFR-L polypeptide fragments may result from alternative RNA splicing or from in vivo protease activity. Membrane-bound forms of an FGFR-L polypeptide are also contemplated by the present invention. In preferred embodiments, truncations and/or deletions comprise about 10 amino acids, or about 20 amino acids, or about 50 amino acids, or about 75 amino acids, or about 100 amino acids, or more than about 100 amino acids. The polypeptide fragments so produced will comprise about 25 contiguous amino acids, or about 50 amino acids, or about 75. amino acids, or about 100 amino acids, or about 150 amino acids, or about 200 amino acids, or more than about 200 amino acids. Such FGFR-L polypeptide fragments may optionally comprise an amino-terminal methionine residue. It will be appreciated that such fragments can be used, for example, to generate antibodies to FGFR-L polypeptides. [0089]
The term “FGFR-L polypeptide ortholog” refers to a polypeptide from another species that corresponds to FGFR-L polypeptide amino acid sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. For example, mouse and human FGFR-L polypeptides are considered orthologs of each other. [0090]
The term “FGFR-L polypeptide variants” refers to FGFR-L polypeptides comprising amino acid sequences having one or more amino acid sequence substitutions, deletions (such as internal deletions and/or FGFR-L polypeptide fragments), and/or additions (such as internal additions and/or FGFR-L fusion polypeptides) as compared to the FGFR-L polypeptide amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 (with or without a leader sequence). Variants may be naturally occurring (e.g., FGFR-L polypeptide allelic variants, FGFR-L polypeptide orthologs, and FGFR-L polypeptide splice variants) or artificially constructed. Such FGFR-L polypeptide variants may be prepared from the corresponding nucleic acid molecules having a DNA sequence that varies accordingly from the DNA sequence as set forth in either SEQ ID NO: 1 or SEQ ID NO: 4. In preferred embodiments, the variants have from 1 to 3, or from 1 to 5, or from 1 to 10, or from 1 to 15, or from 1 to 20, or from 1 to 25, or from 1 to 50, or from 1 to 75, or from 1 to 100, or more than 100 amino acid substitutions, insertions, additions and/or deletions, wherein the substitutions may be conservative, or non-conservative, or any combination thereof. [0091]
The term “FGFR-L polypeptide derivatives” refers to the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, FGFR-L polypeptide fragments, FGFR-L polypeptide orthologs, or FGFR-L polypeptide variants, as defined herein, that have been chemically modified. The term “FGFR-L polypeptide derivatives” also refers to the polypeptides encoded by FGFR-L polypeptide allelic variants or FGFR-L polypeptide splice variants, as defined herein, that have been chemically modified. [0092]
The term “mature FGFR-L polypeptide” refers to an FGFR-L polypeptide lacking a leader sequence. A mature FGFR-L polypeptide may also include other modifications such as proteolytic processing of the amino-terminus (with or without a leader sequence) and/or the carboxyl-terminus, cleavage of a smaller polypeptide from a larger precursor, N-linked and/or O-linked glycosylation, and the like. An exemplary mature FGFR-L polypeptide is depicted by the amino acid sequence of either SEQ ID NO: 3 or SEQ ID NO: 6. [0093]
The term “FGFR-L fusion polypeptide” refers to a fusion of one or more amino acids (such as a heterologous protein or peptide) at the amino- or carboxyl-terminus of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, FGFR-L polypeptide fragments, FGFR-L polypeptide orthologs, FGFR-L polypeptide variants, or FGFR-L derivatives, as defined herein. The term “FGFR-L fusion polypeptide” also refers to a fusion of one or more amino acids at the amino- or carboxyl-terminus of the polypeptide encoded by FGFR-L polypeptide allelic variants or FGFR-L polypeptide splice variants, as defined herein. [0094]
The term “biologically active FGFR-L polypeptides” refers to FGFR-L polypeptides having at least one activity characteristic of the polypeptide comprising the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5. In addition, an FGFR-L polypeptide may be active as an immunogen; that is, the FGFR-L polypeptide contains at least one epitope to which antibodies may be raised. [0095]
The term “isolated polypeptide” refers to a polypeptide of the present invention that (1) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is naturally found when isolated from the source cell, (2) is not linked (by covalent or noncovalent interaction) to all or a portion of a polypeptide to which the “isolated polypeptide” is linked in nature, (3) is operably linked (by covalent or noncovalent interaction) to a polypeptide with which it is not linked in nature, or (4) does not occur in nature. Preferably, the isolated polypeptide is substantially free from any other contaminating polypeptides or other contaminants that are found in its natural environment that would interfere with its therapeutic, diagnostic, prophylactic or research use. [0096]
The term “identity,” as known in the art, refers to a relationship between the sequences of two or more polypeptide molecules or two or more nucleic acid molecules, as determined by comparing the sequences. In the art, “identity” also means the degree of sequence relatedness between nucleic acid molecules or polypeptides, as the case may be, as determined by the match between strings of two or more nucleotide or two or more amino acid sequences. “Identity” measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”). [0097]
The term “similarity” is a related concept, but in contrast to “identity,” “similarity” refers to a measure of relatedness which includes both identical matches and conservative substitution matches. If two polypeptide sequences have, for example, {fraction (10/20)} identical amino acids, and the remainder are all non-conservative substitutions, then the percent identity and similarity would both be 50%. If in the same example, there are five more positions where there are conservative substitutions, then the percent identity remains 50%, but the percent similarity would be 75% ({fraction (15/20)}). Therefore, in cases where there are conservative substitutions, the percent similarity between two polypeptides will be higher than the percent identity between those two polypeptides. [0098]
The term “naturally occurring” or “native” when used in connection with biological materials such as nucleic acid molecules, polypeptides, host cells, and the like, refers to materials which are found in nature and are not manipulated by man. Similarly, “non-naturally occurring” or “non-native” as used herein refers to a material that is not found in nature or that has been structurally modified or synthesized by man. [0099]
The terms “effective amount” and “therapeutically effective amount” each refer to the amount of an FGFR-L polypeptide or FGFR-L nucleic acid molecule used to support an observable level of one or more biological activities of the FGFR-L polypeptides as set forth herein. [0100]
The term “pharmaceutically acceptable carrier” or “physiologically acceptable carrier” as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of the FGFR-L polypeptide, FGFR-L nucleic acid molecule, or FGFR-L selective binding agent as a pharmaceutical composition. [0101]
The term “antigen” refers to a molecule or a portion of a molecule capable of being bound by a selective binding agent, such as an antibody, and additionally capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. An antigen may have one or more epitopes. [0102]
The term “selective binding agent” refers to a molecule or molecules having specificity for an FGFR-L polypeptide. As used herein, the terms, “specific” and “specificity” refer to the ability of the selective binding agents to bind to human FGFR-L polypeptides and not to bind to human non-FGFR-L polypeptides. It will be appreciated, however, that the selective binding agents may also bind orthologs of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, that is, interspecies versions thereof, such as mouse and rat FGFR-L polypeptides. [0103]
The term “transduction” is used to refer to the transfer of genes from one bacterium to another, usually by a phage. “Transduction” also refers to the acquisition and transfer of eukaryotic cellular sequences by retroviruses. [0104]
The term “transfection” is used to refer to the uptake of foreign or exogenous DNA by a cell, and a cell has been “transfected” when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art and are disclosed herein. See, e.g., Graham et al., 1973[0105] , Virology 52:456; Sambrook et al., Molecular Cloning, A Laboratory Manual (Cold Spring Harbor Laboratories, 1989); Davis et al., Basic Methods in Molecular Biology (Elsevier, 1986); and Chu et al., 1981, Gene 13:197. Such techniques can be used to introduce one or more exogenous DNA moieties into suitable host cells.
The term “transformation” as used herein refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transfection or transduction, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell. [0106]
Relatedness of Nucleic Acid Molecules and/or Polypeptides [0107]
It is understood that related nucleic acid molecules include allelic or splice variants of the nucleic acid molecule of either SEQ ID NO: 1 or SEQ ID NO: 4, and include sequences which are complementary to any of the above nucleotide sequences. Related nucleic acid molecules also include a nucleotide sequence encoding a polypeptide comprising or consisting essentially of a substitution, modification, addition and/or deletion of one or more amino acid residues compared to the polypeptide in either SEQ ID NO: 2 or SEQ ID NO: 5. Such related FGFR-L polypeptides may comprise, for example, an addition and/or a deletion of one or more N-linked or O-linked glycosylation sites or an addition and/or a deletion of one or more cysteine residues. [0108]
Related nucleic acid molecules also include fragments of FGFR-L nucleic acid molecules which encode a polypeptide of at least about 25 contiguous amino acids, or about 50 amino acids, or about 75 amino acids, or about 100 amino acids, or about 150 amino acids, or about 200 amino acids, or more than about 200 amino acid residues of the FGFR-L polypeptide of either SEQ ID NO: 2 or SEQ ID NO: 5. [0109]
In addition, related FGFR-L nucleic acid molecules also include those molecules which comprise nucleotide sequences which hybridize under moderately or highly stringent conditions as defined herein with the fully complementary sequence of the FGFR-L nucleic acid molecule of either SEQ ID NO: 1 or SEQ ID NO: 4, or of a molecule encoding a polypeptide, which polypeptide comprises the amino acid sequence as shown in either SEQ ID NO: 2 or SEQ ID NO: 5, or of a nucleic acid fragment as defined herein, or of a nucleic acid fragment encoding a polypeptide as defined herein. Hybridization probes may be prepared using the FGFR-L sequences provided herein to screen cDNA, genomic or synthetic DNA libraries for related sequences. Regions of the DNA and/or amino acid sequence of FGFR-L polypeptide that exhibit significant identity to known sequences are readily determined using sequence alignment algorithms as described herein and those regions may be used to design probes for screening. [0110]
The term “highly stringent conditions” refers to those conditions that are designed to permit hybridization of DNA strands whose sequences are highly complementary, and to exclude hybridization of significantly mismatched DNAs. Hybridization stringency is principally determined by temperature, ionic strength, and the concentration of denaturing agents such as formamide. Examples of “highly stringent conditions” for hybridization and washing are 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate at 65-68° C. or 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate, and 50% formamide at 42° C. See Sambrook, Fritsch & Maniatis, [0111] Molecular Cloning: A Laboratory Manual (2nd ed., Cold Spring Harbor Laboratory, 1989); Anderson et al., Nucleic Acid Hybridisation: A Practical Approach Ch. 4 (IRL Press Limited).
More stringent conditions (such as higher temperature, lower ionic strength, higher formamide, or other denaturing agent) may also be used—however, the rate of hybridization will be affected. Other agents may be included in the hybridization and Washing buffers for the purpose of reducing non-specific and/or background hybridization. Examples are 0.1% bovine serum albumin, 0.1% polyvinyl-pyrrolidone, 0.1% sodium pyrophosphate, 0.1% sodium dodecylsulfate, NaDodSO[0112] ₄, (SDS), ficoll, Denhardt's solution, sonicated salmon sperm DNA (or another non-complementary DNA), and dextran sulfate, although other suitable agents can also be used. The concentration and types of these additives can be changed without substantially affecting the stringency of the hybridization conditions. Hybridization experiments are usually carried out at pH 6.8-7.4; however, at typical ionic strength conditions, the rate of hybridization is nearly independent of pH. See Anderson et al., Nucleic Acid Hybridisation: A Practical Approach Ch. 4 (IRL Press Limited).
Factors affecting the stability of DNA duplex include base composition, length, and degree of base pair mismatch. Hybridization conditions can be adjusted by one skilled in the art in order to accommodate these variables and allow DNAs of different sequence relatedness to form hybrids. The melting temperature of a perfectly matched DNA duplex can be estimated by the following equation: [0113]
T _m(° C.)=81.5+16.6(log[Na+])+0.41(% G+C)−600/N−0.72(% formamide)
where N is the length of the duplex formed, [Na+] is the molar concentration of the sodium ion in the hybridization or washing solution, % G+C is the percentage of (guanine+cytosine) bases in the hybrid. For imperfectly matched hybrids, the melting temperature is reduced by approximately 1° C. for each 1% mismatch. [0114]
The term “moderately stringent conditions” refers to conditions under which a DNA duplex with a greater degree of base pair mismatching than could occur under “highly stringent conditions” is able to form. Examples of typical “moderately stringent conditions” are 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate at 50-65° C. or 0.015 M sodium FGFR-Loride, 0.0015 M sodium citrate, and 20% formamide at 37-50° C. By way of example, “moderately stringent conditions” of 50° C. in 0.015 M sodium ion will allow about a 21% mismatch. [0115]
It will be appreciated by those skilled in the art that there is no absolute distinction between “highly stringent conditions” and “moderately stringent conditions.” For example, at 0.015 M sodium ion (no formamide), the melting temperature of perfectly matched long DNA is about 71° C. With a wash at 65° C. (at the same ionic strength), this would allow for approximately a 6% mismatch. To capture more distantly related sequences, one skilled in the art can simply lower the temperature or raise the ionic strength. [0116]
A good estimate of the melting temperature in 1M NaCl* for oligonucleotide probes up to about 20nt is given by: [0117]
Tm=2° C. per A−T base pair+4° C. per G−C base pair
*The sodium ion concentration in 6× salt sodium citrate (SSC) is 1M. See Suggs et al., [0118] Developmental Biology Using Purified Genes 683 (Brown and Fox, eds., 1981).
High stringency washing conditions for oligonucleotides are usually at a temperature of 0-5° C. below the Tm of the oligonucleotide in 6× SSC, 0.1% SDS. [0119]
In another embodiment, related nucleic acid molecules comprise or consist of a nucleotide sequence that is at least about 70 percent identical to the nucleotide sequence as shown in either SEQ ID NO: 1 or SEQ ID NO: 4, or comprise or consist essentially of a nucleotide sequence encoding a polypeptide that is at least about 70 percent identical to the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. In preferred embodiments, the nucleotide sequences are about 75 percent, or about 80 percent, or about 85 percent, or about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to the nucleotide sequence as shown in either SEQ ID NO: 1 or SEQ ID NO: 4, or the nucleotide sequences encode a polypeptide that is about 75 percent, or about 80 percent, or about 85 percent, or about 90 percent, or about 95, 96, 97, 98, or 99 percent identical to the polypeptide sequence as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. [0120]
Related nucleic acid molecules encode polypeptides possessing at least one activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. [0121]
Differences in the nucleic acid sequence may result in conservative and/or non-conservative modifications of the amino acid sequence relative to the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5. [0122]
Conservative modifications to the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5 (and the corresponding modifications to the encoding nucleotides) will produce a polypeptide having functional and chemical characteristics similar to those of FGFR-L polypeptides. In contrast, substantial modifications in the functional and/or chemical characteristics of FGFR-L polypeptides may be accomplished by selecting substitutions in the amino acid sequence of either SEQ ID NO: 2 or SEQ ID NO: 5 that differ significantly in their effect on maintaining (a) the structure of the molecular backbone in the area of the substitution, for example, as a sheet or helical conformation, (b) the charge or hydrophobicity of the molecule at the target site, or (c) the bulk of the side chain. [0123]
For example, a “conservative amino acid substitution” may involve a substitution of a native amino acid residue with a normative residue such that there is little or no effect on the polarity or charge of the amino acid residue at that position. Furthermore, any native residue in the polypeptide may also be substituted with alanine, as has been previously described for “alanine scanning mutagenesis.”[0124]
Conservative amino acid substitutions also encompass non-naturally occurring amino acid residues that are typically incorporated by chemical peptide synthesis rather than by synthesis in biological systems. These include peptidomimetics, and other reversed or inverted forms of amino acid moieties. [0125]
Naturally occurring residues may be divided into classes based on common side chain properties: [0126]
1) hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; [0127]
2) neutral hydrophilic: Cys, Ser, Thr; [0128]
3) acidic: Asp, Glu; [0129]
4) basic: Asn, Gln, His, Lys, Arg; [0130]
5) residues that influence chain orientation: Gly, Pro; and [0131]
6) aromatic: Trp, Tyr, Phe. [0132]
For example, non-conservative substitutions may involve the exchange of a member of one of these classes for a member from another class. Such substituted residues may be introduced into regions of the human FGFR-L polypeptide that are homologous with non-human FGFR-L polypeptides, or into the non-homologous regions of the molecule. [0133]
In making such changes, the hydropathic index of amino acids may be considered. [0134]
Each amino acid has been assigned a hydropathic index on the basis of its hydrophobicity and charge characteristics. The hydropathic indices are: isoleucine (+4.5); valine (+4.2); leucine (+3.8); phenylalanine (+2.8); cysteine/cystine (+2.5); methionine (+1.9); alanine (+1.8); glycine (−0.4); threonine (−0.7); serine (−0.8); tryptophan (−0.9); tyrosine (−1.3); proline (−1.6); histidine (−3.2); glutamate (−3.5); glutamine (−3.5); aspartate (−3.5); asparagine (−3.5); lysine (−3.9); and arginine (−4.5). [0135]
The importance of the hydropathic amino acid index in conferring interactive biological function on a protein is generally understood in the art (Kyte et al., 1982[0136] , J. Mol. Biol. 157:105-31). It is known that certain amino acids maybe substituted for other amino acids having a similar hydropathic index or score and still retain a similar biological activity. In making changes based upon the hydropathic index, the substitution of amino acids whose hydropathic indices are within ±2 is preferred, those which are within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred.
It is also understood in the art that the substitution of like amino acids can be made effectively on the basis of hydrophilicity, particularly where the biologically functionally equivalent protein or peptide thereby created is intended for use in immunological embodiments, as in the present case. The greatest local average hydrophilicity of a protein, as governed by the hydrophilicity of its adjacent amino acids, correlates with its immunogenicity and antigenicity, i.e., with a biological property of the protein. [0137]
The following hydrophilicity values have been assigned to these amino acid residues: arginine (+3.0); lysine (+3.0); aspartate (+3.0±1); glutamate (+3.0±1); serine (+0.3); asparagine (+0.2); glutamine (+0.2); glycine (0); threonine (−0.4); proline (−0.5±1); alanine (−0.5); histidine (−0.5); cysteine (−1.0); methionine (−1.3); valine (−1.5); leucine (−1.8); isoleucine (−1.8); tyrosine (−2.3); phenylalanine (−2.5); and tryptophan (−3.4). In making changes based upon similar hydrophilicity values, the substitution of amino acids whose hydrophilicity values are within ±2 is preferred, those which are within ±1 are particularly preferred, and those within ±0.5 are even more particularly preferred. One may also identify epitopes from primary amino acid sequences on the basis of hydrophilicity. These regions are also referred to as “epitopic core regions.”[0138]

Desired amino acid substitutions (whether conservative or non-conservative) can be determined by those skilled in the art at the time such substitutions are desired. For example, amino acid substitutions can be used to identify important residues of the FGFR-L polypeptide, or to increase or decrease the affinity of the FGFR-L polypeptides described herein. Exemplary amino acid substitutions are set forth in Table I.

TABLE I


Amino Acid Substitutions

Original Residues	Exemplary Substitutions	Preferred Substitutions

Ala	Val, Leu, Ile	Val
Arg	Lys, Gln, Asn	Lys
Asn	Gln	Gln
Asp	Glu	Glu
Cys	Ser, Ala	Ser
Gln	Asn	Asn
Glu	Asp	Asp
Gly	Pro, Ala	Ala
His	Asn, Gln, Lys, Arg	Arg
Ile	Leu, Val, Met, Ala,	Leu
	Phe, Norleucine
Leu	Norleucine, Ile,	Ile
	Val, Met, Ala, Phe
Lys	Arg, 1,4 Diamino-butyric	Arg
	Acid, Gln, Asn
Met	Leu, Phe, Ile	Leu
Phe	Leu, Val, Ile, Ala,	Leu
	Tyr
Pro	Ala	Gly
Ser	Thr, Ala, Cys	Thr
Thr	Ser	Ser
Trp	Tyr, Phe	Tyr
Tyr	Trp, Phe, Thr, Ser	Phe
Val	Ile, Met, Leu, Phe,	Leu
	Ala, Norleucine

A skilled artisan will be able to determine suitable variants of the polypeptide as set forth in either SEQ ID NO: 2 or SEQ ID NO: 5 using well-known techniques. For identifying suitable areas of the molecule that may be changed without destroying biological activity, one skilled in the art may target areas not believed to be important for activity. For example, when similar polypeptides with similar activities from the same species or from other species are known, one skilled in the art may compare the amino acid sequence of an FGFR-L polypeptide to such similar polypeptides. With such a comparison, one can identify residues and portions of the molecules that are conserved among similar polypeptides. It will be appreciated that changes in areas of the FGFR-L molecule that are not conserved relative to such similar polypeptides would be less likely to adversely affect the biological activity and/or structure of an FGFR-L polypeptide. One skilled in the art would also know that, even in relatively conserved regions, one may substitute chemically similar amino acids for the naturally occurring residues while retaining activity (conservative amino acid residue substitutions). Therefore, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure. [0140]
Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in an FGFR-L polypeptide that correspond to amino acid residues that are important for activity or structure in similar polypeptides. One skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues of FGFR-L polypeptides. [0141]
One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar polypeptides. In view of such information, one skilled in the art may predict the alignment of amino acid residues of FGFR-L polypeptide with respect to its three dimensional structure. One skilled in the art may choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues may be involved in important interactions with other molecules. Moreover, one skilled in the art may generate test variants containing a single amino acid substitution at each amino acid residue. The variants could be screened using activity assays known to those with skill in the art. Such variants could be used to gather information about suitable variants. For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, or unsuitable activity, variants with such a change would be avoided. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations. [0142]
A number of scientific publications have been devoted to the prediction of secondary structure. See Moult, 1996[0143] , Curr. Opin. Biotechnol. 7:422-27; Chou et al., 1974, Biochemistry 13:222-45; Chou et al., 1974, Biochemistry 113:211-22; Chou et al., 1978, Adv. Enzymol. Relat. Areas Mol. Biol. 47:45-48; Chou et al., 1978, Ann. Rev. Biochem. 47:251-276; and Chou et al., 1979, Biophys. J 26:367-84. Moreover, computer programs are currently available to assist with predicting secondary structure. One method of predicting secondary structure is based upon homology modeling. For example, two polypeptides or proteins which have a sequence identity of greater than 30%, or similarity greater than 40%, often have similar structural topologies. The recent growth of the protein structural database (PDB) has provided enhanced predictability of secondary structure, including the potential number of folds within the structure of a polypeptide or protein. See Holm et al., 1999, Nucleic Acids Res. 27:244-47. It has been suggested that there are a limited number of folds in a given polypeptide or protein and that once a critical number of structures have been resolved, structural prediction will become dramatically more accurate (Brenner et al., 1997, Curr. Opin. Struct. Biol. 7:369-76).
Additional methods of predicting secondary structure include “threading” (Jones, 1997[0144] , Curr. Opin. Struct. Biol. 7:377-87; Sippl et al., 1996, Structure 4:15-19), “profile analysis” (Bowie et al., 1991, Science, 253:164-70; Gribskov et al., 1990, Methods Enzymol. 183:146-59; Gribskov et al., 1987, Proc. Nat. Acad. Sci. U.S.A. 84:4355-58), and “evolutionary linkage” (See Holm et aL, supra, and Brenner et al., supra).
Preferred FGFR-L polypeptide variants include glycosylation variants wherein the number and/or type of glycosylation sites have been altered compared to the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. In one embodiment, FGFR-L polypeptide variants comprise a greater or a lesser number of N-linked glycosylation sites than the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X may be any amino acid residue except proline. The substitution of amino acid residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions that eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional preferred FGFR-L variants include cysteine variants, wherein one or more cysteine residues are deleted or substituted with another amino acid (e.g., serine) as compared to the amino acid sequence set forth in either SEQ ID NO: 2 or SEQ ID NO: 5. Cysteine variants are useful when FGFR-L polypeptides must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically have an even number to minimize interactions resulting from unpaired cysteines. [0145]
In other embodiments, related nucleic acid molecules comprise or consist of a nucleotide sequence encoding a polypeptide as set forth in either Seq Id No: 2 or SEQ ID NO: 5 with at least one amino acid insertion and wherein the polypeptide has an activity of the polypeptide set forth in either SEQ ID NO: 2 or SEQ ID NO: 5, or a [0146]

0

SEQUENCE LISTING

<160> NUMBER OF SEQ ID NOS: 22

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<213> ORGANISM: Mus musculus

<220> FEATURE:

<221> NAME/KEY: CDS

<222> LOCATION: (87)..(1673)

<221> NAME/KEY: sig_peptide

<222> LOCATION: (87)..(146)

<221> NAME/KEY: misc_feature

<222> LOCATION: (1208)..(1271)

<223> OTHER INFORMATION: predicted transmembrane domain

<400> SEQUENCE: 1

gacctgggtc ttgcgggcct gagccctgag tggcgtccag tccagctccc agtgaccgcg 60

cccctgcttc aggtccgacc ggcgag atg acg cgg agc ccc gcg ctg ctg ctg 113

Met Thr Arg Ser Pro Ala Leu Leu Leu

1 5

ctg cta ttg ggg gcc ctc ccg tcg gct gag gcg gcg cga gga ccc cca 161

Leu Leu Leu Gly Ala Leu Pro Ser Ala Glu Ala Ala Arg Gly Pro Pro

10 15 20 25

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Arg Met Ala Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg

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Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr

45 50 55

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Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe

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Arg Val Leu Pro Gln Gly Leu Lys Val Lys Glu Val Glu Ala Glu Asp

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Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser

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Val Asn Tyr Thr Leu Ile Ile Met Asp Asp Ile Ser Pro Gly Lys Glu

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Ser Pro Gly Pro Gly Gly Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser

125 130 135

cag cag tgg gca cgg cct cgc ttc aca cag ccc tcc aag atg agg cgc 545

Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg

140 145 150

cga gtg att gca cgg cct gtg ggt agc tct gtg cgg ctc aag tgt gtg 593

Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val

155 160 165

gcc agt ggg cac cca cgg cca gac atc atg tgg atg aag gat gac cag 641

Ala Ser Gly His Pro Arg Pro Asp Ile Met Trp Met Lys Asp Asp Gln

170 175 180 185

acc ttg acg cat cta gag gct agt gaa cac aga aag aag aag tgg aca 689

Thr Leu Thr His Leu Glu Ala Ser Glu His Arg Lys Lys Lys Trp Thr

190 195 200

ctg agc ttg aag aac ctg aag cct gaa gac agt ggc aag tac acg tgc 737

Leu Ser Leu Lys Asn Leu Lys Pro Glu Asp Ser Gly Lys Tyr Thr Cys

205 210 215

cgt gta tct aac aag gcc ggt gcc atc aac gcc acc tac aaa gtg gat 785

Arg Val Ser Asn Lys Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp

220 225 230

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Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro

235 240 245

gtg aac aca acg gtg gac ttc ggt ggg aca acg tcc ttc cag tgc aag 881

Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys

250 255 260 265

gtg cgc agt gac gtg aag cct gtg atc cag tgg ctg aag cgg gtg gag 929

Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu

270 275 280

tac ggc tcc gag gga cgc cac aac tcc acc att gat gtg ggt ggc cag 977

Tyr Gly Ser Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln

285 290 295

aag ttt gtg gtg ttg ccc acg ggt gat gtg tgg tca cgg cct gat ggc 1025

Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly

300 305 310

tcc tac ctc aac aag ctg ctc atc tct cgg gcc cgc cag gat gat gct 1073

Ser Tyr Leu Asn Lys Leu Leu Ile Ser Arg Ala Arg Gln Asp Asp Ala

315 320 325

ggc atg tac atc tgc cta ggt gca aat acc atg ggc tac agt ttc cgt 1121

Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg

330 335 340 345

agc gcc ttc ctc act gta tta cca gac ccc aaa cct cca ggg cct cct 1169

Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro

350 355 360

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Met Ala Ser Ser Ser Ser Ser Thr Ser Leu Pro Trp Pro Val Val Ile

365 370 375

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Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly Thr Val Leu Leu Trp

380 385 390

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Leu Cys Gln Thr Lys Lys Lys Pro Cys Ala Pro Ala Ser Thr Leu Pro

395 400 405

gtg cct ggg cat cgt ccc cca ggg aca tcc cga gaa cgc agt ggt gac 1361

Val Pro Gly His Arg Pro Pro Gly Thr Ser Arg Glu Arg Ser Gly Asp

410 415 420 425

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Lys Asp Leu Pro Ser Leu Ala Val Gly Ile Cys Glu Glu His Gly Ser

430 435 440

gcc atg gcc ccc cag cac atc ctg gcc tct ggc tca act gct ggc ccc 1457

Ala Met Ala Pro Gln His Ile Leu Ala Ser Gly Ser Thr Ala Gly Pro

445 450 455

aag ctg tac ccc aag cta tac aca gat gtg cac aca cac aca cat aca 1505

Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Val His Thr His Thr His Thr

460 465 470

cac acc tgc act cac acg ctc tca tgt gga ggg caa ggt tca tca aca 1553

His Thr Cys Thr His Thr Leu Ser Cys Gly Gly Gln Gly Ser Ser Thr

475 480 485

cca gca tgt cca cta tca gtg cta aat aca gcg aat ctc caa gca ctg 1601

Pro Ala Cys Pro Leu Ser Val Leu Asn Thr Ala Asn Leu Gln Ala Leu

490 495 500 505

tgt cct gag gta ggc ata tgg ggg cca agg caa cag gtt ggg aga att 1649

Cys Pro Glu Val Gly Ile Trp Gly Pro Arg Gln Gln Val Gly Arg Ile

510 515 520

gag aac aat gga gga aga gta tct tagggtgcct tatggtggac actcacaaac 1703

Glu Asn Asn Gly Gly Arg Val Ser

525

ttggccatat agatgtatgt actaccagat gaacagccag ccagattcac acacgcacat 1763

gtttaaacgt gtaaacgtgt gcacaactgc acacacaacc tgagaaacct tcaggaggat 1823

ttgtggtgtg actttgcagt gacatgtagc gatggctagt tgaaggaatc tccctcatgt 1883

cttagtggtc atggccactt ccccacccct gcccatctgt gttcctgcct ggccttggtg 1943

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<213> ORGANISM: Mus musculus

<400> SEQUENCE: 2

Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro

1 5 10 15

Ser Ala Glu Ala Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val

20 25 30

Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro

35 40 45

Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg

50 55 60

Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu

65 70 75 80

Lys Val Lys Glu Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys

85 90 95

Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile

100 105 110

Met Asp Asp Ile Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser

115 120 125

Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg

130 135 140

Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val

145 150 155 160

Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro

165 170 175

Asp Ile Met Trp Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala

180 185 190

Ser Glu His Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys

195 200 205

Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly

210 215 220

Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser

225 230 235 240

Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe

245 250 255

Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro

260 265 270

Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His

275 280 285

Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr

290 295 300

Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu

305 310 315 320

Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly

325 330 335

Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu

340 345 350

Pro Asp Pro Lys Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Ser Ser

355 360 365

Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val

370 375 380

Phe Ile Leu Gly Thr Val Leu Leu Trp Leu Cys Gln Thr Lys Lys Lys

385 390 395 400

Pro Cys Ala Pro Ala Ser Thr Leu Pro Val Pro Gly His Arg Pro Pro

405 410 415

Gly Thr Ser Arg Glu Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala

420 425 430

Val Gly Ile Cys Glu Glu His Gly Ser Ala Met Ala Pro Gln His Ile

435 440 445

Leu Ala Ser Gly Ser Thr Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr

450 455 460

Thr Asp Val His Thr His Thr His Thr His Thr Cys Thr His Thr Leu

465 470 475 480

Ser Cys Gly Gly Gln Gly Ser Ser Thr Pro Ala Cys Pro Leu Ser Val

485 490 495

Leu Asn Thr Ala Asn Leu Gln Ala Leu Cys Pro Glu Val Gly Ile Trp

500 505 510

Gly Pro Arg Gln Gln Val Gly Arg Ile Glu Asn Asn Gly Gly Arg Val

515 520 525

Ser

<210> SEQ ID NO 3

<211> LENGTH: 509

<212> TYPE: PRT

<213> ORGANISM: Mus musculus

<220> FEATURE:

<221> NAME/KEY: TRANSMEM

<222> LOCATION: (355)..(375)

<400> SEQUENCE: 3

Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val Pro Arg Gln Val

1 5 10 15

Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp

20 25 30

Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser

35 40 45

Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Glu

50 55 60

Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly

65 70 75 80

Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile Met Asp Asp Ile

85 90 95

Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser Ser Gly Gly Gln

100 105 110

Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro

115 120 125

Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val

130 135 140

Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Met Trp

145 150 155 160

Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala Ser Glu His Arg

165 170 175

Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys Pro Glu Asp Ser

180 185 190

Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly Ala Ile Asn Ala

195 200 205

Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu

210 215 220

Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr

225 230 235 240

Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp

245 250 255

Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His Asn Ser Thr Ile

260 265 270

Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp

275 280 285

Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Ser Arg Ala

290 295 300

Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met

305 310 315 320

Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys

325 330 335

Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Ser Ser Thr Ser Leu Pro

340 345 350

Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly

355 360 365

Thr Val Leu Leu Trp Leu Cys Gln Thr Lys Lys Lys Pro Cys Ala Pro

370 375 380

Ala Ser Thr Leu Pro Val Pro Gly His Arg Pro Pro Gly Thr Ser Arg

385 390 395 400

Glu Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Val Gly Ile Cys

405 410 415

Glu Glu His Gly Ser Ala Met Ala Pro Gln His Ile Leu Ala Ser Gly

420 425 430

Ser Thr Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Val His

435 440 445

Thr His Thr His Thr His Thr Cys Thr His Thr Leu Ser Cys Gly Gly

450 455 460

Gln Gly Ser Ser Thr Pro Ala Cys Pro Leu Ser Val Leu Asn Thr Ala

465 470 475 480

Asn Leu Gln Ala Leu Cys Pro Glu Val Gly Ile Trp Gly Pro Arg Gln

485 490 495

Gln Val Gly Arg Ile Glu Asn Asn Gly Gly Arg Val Ser

500 505

<210> SEQ ID NO 4

<211> LENGTH: 1450

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: CDS

<222> LOCATION: (33)..(1448)

<221> NAME/KEY: sig_peptide

<222> LOCATION: (33)..(104)

<221> NAME/KEY: misc_feature

<222> LOCATION: (1167)..(1229)

<400> SEQUENCE: 4

gcggccgcga ccccaggtcc ggacaggccg ag atg acg ccg agc ccc ctg ttg 53

Met Thr Pro Ser Pro Leu Leu

1 5

ctg ctc ctg ctg ccg ccg ctg ctg ctg ggg gcc ttc cca ccg gcc gcc 101

Leu Leu Leu Leu Pro Pro Leu Leu Leu Gly Ala Phe Pro Pro Ala Ala

10 15 20

gcc gcc cga ggc ccc cca aag atg gcg gac aag gtg gtc cca cgg cag 149

Ala Ala Arg Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln

25 30 35

gtg gcc cgg ctg ggc cgc act gtg cgg ctg cag tgc cca gtg gag ggg 197

Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly

40 45 50 55

gac ccg ccg ccg ctg acc atg tgg acc aag gat ggc cgc acc atc cac 245

Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His

60 65 70

agc ggc tgg agc cgc ttc cgc gtg ctg ccg cag ggg ctg aag gtg aag 293

Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys

75 80 85

cag gtg gag cgg gag gat gcc ggc gtg tac gtg tgc aag gcc acc aac 341

Gln Val Glu Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn

90 95 100

ggc ttc ggc agc ctg agc gtc aac tac acc ctc gtc gtg ctg gat gac 389

Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp

105 110 115

att agc cca ggg aag gag agc ctg ggg ccc gac agc tcc tct ggg ggt 437

Ile Ser Pro Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly

120 125 130 135

caa gag gac ccc gcc agc cag cag tgg gca cga ccg cgc ttc aca cag 485

Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln

140 145 150

ccc tcc aag atg agg cgc cgg gtg atc gca cgg ccc gtg ggt agc tcc 533

Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser

155 160 165

gtg cgg ctc aag tgc gtg gcc agc ggg cac cct cgg ccc gac atc acg 581

Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr

170 175 180

tgg atg aag gac gac cag gcc ttg acg cgc cca gag gcc gct gag ccc 629

Trp Met Lys Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro

185 190 195

agg aag aag aag tgg aca ctg agc ctg aag aac ctg cgg ccg gag gac 677

Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp

200 205 210 215

agc ggc aaa tac acc tgc cgc gtg tcg aac cgc gcg ggc gcc atc aac 725

Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn

220 225 230

gcc acc tac aag gtg gat gtg atc cag cgg acc cgt tcc aag ccc gtg 773

Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val

235 240 245

ctc aca ggc acg cac ccc gtg aac acg acg gtg gac ttc ggg ggg acc 821

Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr

250 255 260

acg tcc ttc cag tgc aag gtg cgc agc gac gtg aag ccg gtg atc cag 869

Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln

265 270 275

tgg ctg aag cgc gtg gag tac ggc gct gag ggc cgc cac aac tcc acc 917

Trp Leu Lys Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr

280 285 290 295

atc gat gtg ggc ggc cag aag ttt gtg gtg ctg ccc acg ggt gac gtg 965

Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val

300 305 310

tgg tcg cgg ccc gac ggc tcc tac ctc aat aag ctg ctc atc acc cgt 1013

Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg

315 320 325

gcc cgc cag gac gat gcg ggc atg tac atc tgc ctt ggc gcc aac acc 1061

Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr

330 335 340

atg ggc tac agc ttc cgc agc gcc ttc ctc acc gtg ctg cca gac cca 1109

Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro

345 350 355

aaa ccg cca ggg cca cct gtg gcc tcc tcg tcc tcg gcc act agc ctg 1157

Lys Pro Pro Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu

360 365 370 375

ccg tgg ccc gtg gtc atc ggc atc cca gcc ggc gct gtc ttc atc ctg 1205

Pro Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu

380 385 390

ggc acc ctg ctc ctg tgg ctt tgc cag gcc cag aag aag ccg tgc acc 1253

Gly Thr Leu Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr

395 400 405

ccc gcg cct gcc cct ccc ctg cct ggg cac cgc ccg ccg ggg acg gcc 1301

Pro Ala Pro Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala

410 415 420

cgc gac cgc agc gga gac aag gac ctt ccc tcg ttg gcc gcc ctc agc 1349

Arg Asp Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser

425 430 435

gct ggc cct ggt gtg ggg ctg tgt gag gag cat ggg tct ccg gca gcc 1397

Ala Gly Pro Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala

440 445 450 455

ccc cag cac tta ctg ggc cca ggc cca gtt gct ggc cct aag ttg tac 1445

Pro Gln His Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr

460 465 470

ccc ta 1450

Pro

<210> SEQ ID NO 5

<211> LENGTH: 472

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQUENCE: 5

Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu

1 5 10 15

Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala

20 25 30

Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg

35 40 45

Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr

50 55 60

Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu

65 70 75 80

Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val

85 90 95

Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr

100 105 110

Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly

115 120 125

Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp

130 135 140

Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile

145 150 155 160

Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly

165 170 175

His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr

180 185 190

Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu

195 200 205

Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser

210 215 220

Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln

225 230 235 240

Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr

245 250 255

Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser

260 265 270

Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala

275 280 285

Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val

290 295 300

Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu

305 310 315 320

Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr

325 330 335

Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe

340 345 350

Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Val Ala Ser

355 360 365

Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro

370 375 380

Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln

385 390 395 400

Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly

405 410 415

His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu

420 425 430

Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu

435 440 445

Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro

450 455 460

Val Ala Gly Pro Lys Leu Tyr Pro

465 470

<210> SEQ ID NO 6

<211> LENGTH: 448

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: TRANSMEM

<222> LOCATION: (355)..(375)

<400> SEQUENCE: 6

Ala Arg Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln Val

1 5 10 15

Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp

20 25 30

Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser

35 40 45

Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Gln

50 55 60

Val Glu Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly

65 70 75 80

Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp Ile

85 90 95

Ser Pro Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly Gln

100 105 110

Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro

115 120 125

Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val

130 135 140

Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr Trp

145 150 155 160

Met Lys Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro Arg

165 170 175

Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp Ser

180 185 190

Gly Lys Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn Ala

195 200 205

Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu

210 215 220

Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr

225 230 235 240

Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp

245 250 255

Leu Lys Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr Ile

260 265 270

Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp

275 280 285

Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg Ala

290 295 300

Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met

305 310 315 320

Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys

325 330 335

Pro Pro Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu Pro

340 345 350

Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly

355 360 365

Thr Leu Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr Pro

370 375 380

Ala Pro Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala Arg

385 390 395 400

Asp Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser Ala

405 410 415

Gly Pro Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala Pro

420 425 430

Gln His Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr Pro

435 440 445

<210> SEQ ID NO 7

<211> LENGTH: 574

<212> TYPE: PRT

<213> ORGANISM: Pleurodeles waltlii

<400> SEQUENCE: 7

Met Gly Val Gln Lys Asp Ser Arg Asp Ile Arg Trp Asn Arg Thr Thr

1 5 10 15

Arg Pro Leu Ala Leu Leu Leu Cys Gly Leu Leu Ala Phe Ser Ala Leu

20 25 30

Ser Cys Ala Arg Thr Leu Pro Glu Gly Arg Lys Ala Asn Leu Ala Glu

35 40 45

Leu Val Ser Glu Glu Glu Glu His Phe Leu Leu Asp Pro Gly Asn Ala

50 55 60

Leu Arg Leu Phe Cys Asp Thr Asn Gln Thr Thr Ile Val Asn Trp Tyr

65 70 75 80

Thr Glu Ser Thr Arg Leu Gln His Gly Gly Arg Ile Arg Leu Thr Asp

85 90 95

Thr Val Leu Glu Ile Ala Asp Val Thr Tyr Glu Asp Ser Gly Leu Tyr

100 105 110

Leu Cys Val Val Pro Gly Thr Gly His Ile Leu Arg Asn Phe Thr Ile

115 120 125

Ser Val Val Asp Ser Leu Ala Ser Gly Asp Asp Asp Asp Glu Asp His

130 135 140

Gly Arg Glu Asp Ser Ala Gly Asp Met Gly Glu Asp Pro Pro Tyr Ser

145 150 155 160

Thr Ser Tyr Arg Ala Pro Phe Trp Ser Gln Pro Gln Arg Met Asp Lys

165 170 175

Lys Leu Tyr Ala Val Pro Ala Gly Asn Thr Val Lys Phe Arg Cys Pro

180 185 190

Ser Ala Gly Asn Pro Thr Pro Gly Ile Arg Trp Leu Lys Asn Gly Arg

195 200 205

Glu Phe Gly Gly Glu His Arg Ile Gly Gly Ile Arg Leu Arg His Gln

210 215 220

His Trp Ser Leu Val Met Glu Ser Val Val Pro Ser Asp Arg Gly Asn

225 230 235 240

Tyr Thr Cys Leu Val Glu Asn Lys Phe Gly Ser Ile Ser Tyr Ser Tyr

245 250 255

Leu Leu Asp Val Leu Glu Arg Ser Pro His Arg Pro Ile Leu Gln Ala

260 265 270

Gly Leu Pro Ala Asn Thr Thr Ala Met Leu Gly Ser Asp Val Gln Phe

275 280 285

Phe Cys Lys Val Tyr Ser Asp Ala Gln Pro His Ile Gln Trp Leu Lys

290 295 300

His Ile Glu Val Asn Gly Ser Arg Tyr Gly Pro Asp Gly Val Pro Phe

305 310 315 320

Val Gln Val Leu Lys Thr Ala Asp Ile Asn Ser Ser Glu Val Glu Val

325 330 335

Leu Tyr Leu His Asn Val Ser Phe Glu Asp Ala Gly Glu Tyr Thr Cys

340 345 350

Leu Ala Gly Asn Ser Ile Gly Leu Ser Tyr Gln Ser Ala Trp Leu Thr

355 360 365

Val Leu Pro Glu Glu Asp Phe Ala Lys Glu Ala Glu Gly Pro Glu Thr

370 375 380

Arg Tyr Thr Asp Ile Ile Ile Tyr Thr Ser Gly Ser Leu Ala Leu Leu

385 390 395 400

Met Ala Ala Val Ile Val Val Leu Cys Arg Met Gln Leu Pro Pro Thr

405 410 415

Lys Thr His Leu Glu Pro Ala Thr Val His Lys Leu Ser Arg Phe Pro

420 425 430

Leu Met Arg Gln Phe Ser Leu Glu Ser Ser Ser Ser Gly Lys Ser Ser

435 440 445

Thr Ser Leu Val Arg Val Thr Arg Leu Ser Ser Ser Cys Thr Pro Met

450 455 460

Leu Pro Gly Val Leu Glu Phe Asp Leu Pro Leu Asp Ser Lys Trp Glu

465 470 475 480

Phe Pro Arg Glu Arg Leu Val Leu Gly Lys Pro Leu Gly Glu Gly Cys

485 490 495

Phe Gly Gln Val Val Arg Ala Glu Ala Tyr Gly Ile Asn Lys Asp Gln

500 505 510

Pro Asp Lys Ala Ile Thr Val Ala Ile Lys Ile Val Lys Asp Lys Gly

515 520 525

Thr Asp Lys Glu Leu Ser Asp Leu Ile Ser Glu Met Glu Leu Met Lys

530 535 540

Leu Met Gly Lys His Lys Asn Ile Ile Asn Leu Leu Gly Val Cys Thr

545 550 555 560

Gln Asp Gly Pro Leu Tyr Met Ile Val Glu Tyr Ala Ser Lys

565 570

<210> SEQ ID NO 8

<211> LENGTH: 504

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence: virtual

human FGFR-L amino acid sequence comprising residues

1-472 of SEQ ID NO: 5 and residues 473-504 of

GenBank accession no. AJ277437

<400> SEQUENCE: 8

Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu

1 5 10 15

Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala

20 25 30

Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg

35 40 45

Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr

50 55 60

Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu

65 70 75 80

Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val

85 90 95

Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr

100 105 110

Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly

115 120 125

Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp

130 135 140

Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile

145 150 155 160

Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly

165 170 175

His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr

180 185 190

Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu

195 200 205

Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser

210 215 220

Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln

225 230 235 240

Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr

245 250 255

Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser

260 265 270

Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala

275 280 285

Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val

290 295 300

Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu

305 310 315 320

Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr

325 330 335

Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe

340 345 350

Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Val Ala Ser

355 360 365

Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro

370 375 380

Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln

385 390 395 400

Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly

405 410 415

His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu

420 425 430

Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu

435 440 445

Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro

450 455 460

Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr

465 470 475 480

His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val

485 490 495

His Gln His Ile His Tyr Gln Cys

500

<210> SEQ ID NO 9

<211> LENGTH: 11

<212> TYPE: PRT

<213> ORGANISM: Human immunodeficiency virus type 1

<400> SEQUENCE: 9

Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg

1 5 10

<210> SEQ ID NO 10

<211> LENGTH: 15

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence:

internalizing domain derived from HIV tat protein

<400> SEQUENCE: 10

Gly Gly Gly Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg

1 5 10 15

<210> SEQ ID NO 11

<211> LENGTH: 20

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence: predicted

signal peptide of murine FGFR-L polypeptide

<400> SEQUENCE: 11

Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro

1 5 10 15

Ser Ala Glu Ala

20

<210> SEQ ID NO 12

<211> LENGTH: 25

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence: predicted

transmmebrane domain for murine FRL polypeptide

<400> SEQUENCE: 12

Leu Pro Trp Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile

1 5 10 15

Leu Gly Thr Val Leu Leu Trp Leu Cys

20 25

<210> SEQ ID NO 13

<211> LENGTH: 24

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence:

oligonucleotide; PCR primer

<400> SEQUENCE: 13

cgctgaccat gtggaccaag gatg 24

<210> SEQ ID NO 14

<211> LENGTH: 24

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence:

oligonucleotide; PCR primer

<400> SEQUENCE: 14

cttgacccca gaaggagctg tcgg 24

<210> SEQ ID NO 15

<211> LENGTH: 504

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQUENCE: 15

Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu

1 5 10 15

Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala

20 25 30

Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg

35 40 45

Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr

50 55 60

Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu

65 70 75 80

Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val

85 90 95

Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr

100 105 110

Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly

115 120 125

Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp

130 135 140

Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile

145 150 155 160

Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly

165 170 175

His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr

180 185 190

Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu

195 200 205

Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser

210 215 220

Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln

225 230 235 240

Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr

245 250 255

Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser

260 265 270

Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala

275 280 285

Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val

290 295 300

Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu

305 310 315 320

Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr

325 330 335

Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe

340 345 350

Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Val Ala Ser

355 360 365

Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro

370 375 380

Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln

385 390 395 400

Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly

405 410 415

His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu

420 425 430

Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu

435 440 445

Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro

450 455 460

Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr

465 470 475 480

His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val

485 490 495

His Gln His Ile His Tyr Gln Cys

500

<210> SEQ ID NO 16

<211> LENGTH: 3112

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: CDS

<222> LOCATION: (25)..(1536)

<400> SEQUENCE: 16

gaccccaggt ccggacaggc cgag atg acg ccg agc ccc ctg ttg ctg ctc 51

Met Thr Pro Ser Pro Leu Leu Leu Leu

1 5

ctg ctg ccg ccg ctg ctg ctg ggg gcc ttc cca ccg gcc gcc gcc gcc 99

Leu Leu Pro Pro Leu Leu Leu Gly Ala Phe Pro Pro Ala Ala Ala Ala

10 15 20 25

cga ggc ccc cca aag atg gcg gac aag gtg gtc cca cgg cag gtg gcc 147

Arg Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln Val Ala

30 35 40

cgg ctg ggc cgc act gtg cgg ctg cag tgc cca gtg gag ggg gac ccg 195

Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro

45 50 55

ccg ccg ctg acc atg tgg acc aag gat ggc cgc acc atc cac agc ggc 243

Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly

60 65 70

tgg agc cgc ttc cgc gtg ctg ccg cag ggg ctg aag gtg aag cag gtg 291

Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Gln Val

75 80 85

gag cgg gag gat gcc ggc gtg tac gtg tgc aag gcc acc aac ggc ttc 339

Glu Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe

90 95 100 105

ggc agc ctt agc gtc aac tac acc ctc gtc gtg ctg gat gac att agc 387

Gly Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp Ile Ser

110 115 120

cca ggg aag gag agc ctg ggg ccc gac agc tcc tct ggg ggt caa gag 435

Pro Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly Gln Glu

125 130 135

gac ccc gcc agc cag cag tgg gca cga ccg cgc ttc aca cag ccc tcc 483

Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser

140 145 150

aag atg agg cgc cgg gtg atc gca cgg ccc gtg ggt agc tcc gtg cgg 531

Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg

155 160 165

ctc aag tgc gtg gcc agc ggg cac cct cgg ccc gac atc acg tgg atg 579

Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr Trp Met

170 175 180 185

aag gac gac cag gcc ttg acg cgc cca gag gcc gct gag ccc agg aag 627

Lys Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro Arg Lys

190 195 200

aag aag tgg aca ctg agc ctg aag aac ctg cgg ccg gag gac agc ggc 675

Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp Ser Gly

205 210 215

aaa tac acc tgc cgc gtg tcg aac cgc gcg ggc gcc atc aac gcc acc 723

Lys Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn Ala Thr

220 225 230

tac aag gtg gat gtg atc cag cgg acc cgt tcc aag ccc gtg ctc aca 771

Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr

235 240 245

ggc acg cac ccc gtg aac acg acg gtg gac ttc ggg ggg acc acg tcc 819

Gly Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser

250 255 260 265

ttc cag tgc aag gtg cgc agc gac gtg aag ccg gtg atc cag tgg ctg 867

Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu

270 275 280

aag cgc gtg gag tac ggc gcc gag ggc cgc cac aac tcc acc atc gat 915

Lys Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr Ile Asp

285 290 295

gtg ggc ggc cag aag ttt gtg gtg ctg ccc acg ggt gac gtg tgg tcg 963

Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser

300 305 310

cgg ccc gac ggc tcc tac ctc aat aag ctg ctc atc acc cgt gcc cgc 1011

Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg Ala Arg

315 320 325

cag gac gat gcg ggc atg tac atc tgc ctt ggc gcc aac acc atg ggc 1059

Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly

330 335 340 345

tac agc ttc cgc agc gcc ttc ctc acc gtg ctg cca gac cca aaa ccg 1107

Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro

350 355 360

caa ggg cca cct gtg gcc tcc tcg tcc tcg gcc act agc ctg ccg tgg 1155

Gln Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu Pro Trp

365 370 375

ccc gtg gtc atc ggc atc cca gcc ggc gct gtc ttc atc ctg ggc acc 1203

Pro Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly Thr

380 385 390

ctg ctc ctg tgg ctt tgc cag gcc cag aag aag ccg tgc acc ccc gcg 1251

Leu Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr Pro Ala

395 400 405

cct gcc cct ccc ctg cct ggg cac cgc ccg ccg ggg acg gcc ctc gac 1299

Pro Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala Leu Asp

410 415 420 425

cgc agc gga gac aag gac ctt ccc tcg ttg gcc gcc ctc agc gct ggc 1347

Arg Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser Ala Gly

430 435 440

cct ggt gtg ggg ctg tgt gag gag cat ggg tct ccg gca gcc ccc cag 1395

Pro Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala Pro Gln

445 450 455

cac tta ctg ggc cca ggc cca gtt gct ggc cct aag ttg tac ccc aaa 1443

His Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr Pro Lys

460 465 470

ctc tac aca gac atc cac aca cac aca cac aca cac tct cac aca cac 1491

Leu Tyr Thr Asp Ile His Thr His Thr His Thr His Ser His Thr His

475 480 485

tca cac gtg gag ggc aag gtc cac cag cac atc cac tat cag tgc 1536

Ser His Val Glu Gly Lys Val His Gln His Ile His Tyr Gln Cys

490 495 500

tagacggcac cgtatctgca gtgggcacgg gggggccggc cagacaggca gactgggagg 1596

atggaggacg gagctgcaga cgaaggcagg ggacccatgg cgaggaggaa tggccagcac 1656

cccaggcagt ctgtgtgtga ggcatagccc ctggacacac acacacagac acacacacta 1716

cctggatgca tgtatgcaca cacatgcgcg cacacgtgct ccctgaaggc acacgtacgc 1776

acacacgcac atgcacagat atgccgcctg ggcacacaga taagctgccc aaatgcacgc 1836

acacgcacag agacatgcca gaacatacaa ggacatgctg cctgaacata cacacgcaca 1896

cccatgcgca gatgtgctgc ctggacacac acacacacac ggatatgctg tctggacgca 1956

cacacgtgca gatatggtat ccggacacac acgtgcacag atatgctgcc tggacacaca 2016

gataatgctg ccttgacaca cacatgcacg gatattgcct ggacacacac acacacacgc 2076

gtgcacagat atgctgtctg gacaggcaca cacatgcaga tatgctgcct ggacacacac 2136

ttccagacac acgtgcacag gcgcagatat gctgcctgga cacacgcaga tatgctgtct 2196

agtcacacac acacgcagac atgctgtccg gacacacaca cgcatgcaca gatatgctgt 2256

ccggacacac acacgcacgc agatatgctg cctggacaca cacacagata atgctgcctc 2316

aacactcaca cacgtgcaga tattgcctgg acacacacat gtgcacagat atgctgtctg 2376

gacatgcaca cacgtgcaga tatgctgtcc ggatacacac gcacgcacac atgcagatat 2436

gctgcctggg cacacacttc cggacacaca tgcacacaca ggtgcagata tgctgcctgg 2496

acacacgcag actgacgtgc ttttgggagg gtgtgccgtg aagcctgcag tacgtgtgcc 2556

gtgaggctca tagttgatga gggactttcc ctgctccacc gtcactcccc caactctgcc 2616

cgcctctgtc cccgcctcag tccccgcctc catccccgcc tctgtcccct ggccttggcg 2676

gctatttttg ccacctgcct tgggtgccca ggagtcccct actgctgtgg gctggggttg 2736

ggggcacagc agccccaagc ctgagaggct ggagcccatg gctagtggct catccccact 2796

gcattctccc cctgacacag agaaggggcc ttggtattta tatttaagaa atgaagataa 2856

tattaataat gatggaagga agactgggtt gcagggactg tggtctctcc tggggcccgg 2916

gacccgcctg gtctttcagc catgctgatg accacacccc gtccaggcca gacaccaccc 2976

cccaccccac tgtcgtggtg gccccagatc tctgtaattt tatgtagagt ttgagctgaa 3036

gccccgtata tttaatttat tttgttaaac atgaaagtgc atcctttccc tccaaaaaaa 3096

aaaaaaaaaa aaaaaa 3112

<210> SEQ ID NO 17

<211> LENGTH: 504

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQUENCE: 17

Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu

1 5 10 15

Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala

20 25 30

Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg

35 40 45

Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr

50 55 60

Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu

65 70 75 80

Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val

85 90 95

Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr

100 105 110

Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly

115 120 125

Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp

130 135 140

Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile

145 150 155 160

Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly

165 170 175

His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr

180 185 190

Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu

195 200 205

Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser

210 215 220

Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln

225 230 235 240

Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr

245 250 255

Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser

260 265 270

Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala

275 280 285

Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val

290 295 300

Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu

305 310 315 320

Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr

325 330 335

Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe

340 345 350

Leu Thr Val Leu Pro Asp Pro Lys Pro Gln Gly Pro Pro Val Ala Ser

355 360 365

Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro

370 375 380

Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln

385 390 395 400

Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly

405 410 415

His Arg Pro Pro Gly Thr Ala Leu Asp Arg Ser Gly Asp Lys Asp Leu

420 425 430

Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu

435 440 445

Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro

450 455 460

Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr

465 470 475 480

His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val

485 490 495

His Gln His Ile His Tyr Gln Cys

500

<210> SEQ ID NO 18

<211> LENGTH: 3080

<212> TYPE: DNA

<213> ORGANISM: Homo sapiens

<220> FEATURE:

<221> NAME/KEY: CDS

<222> LOCATION: (23)..(1534)

<400> SEQUENCE: 18

ccccaggtcc ggacaggccg ag atg acg ccg agc ccc ctg ttg ctg ctc ctg 52

Met Thr Pro Ser Pro Leu Leu Leu Leu Leu

1 5 10

ctg ccg ccg ctg ctg ctg ggg gcc ttc cca ccg gcc gcc gcc gcc cga 100

Leu Pro Pro Leu Leu Leu Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg

15 20 25

ggc ccc cca aag atg gcg gac aag gtg gtc cca cgg cag gtg gcc cgg 148

Gly Pro Pro Lys Met Ala Asp Lys Val Val Pro Arg Gln Val Ala Arg

30 35 40

ctg ggc cgc act gtg cgg ctg cag tgc cca gtg gag ggg gac ccg ccg 196

Leu Gly Arg Thr Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro Pro

45 50 55

ccg ctg acc atg tgg acc aag gat ggc cgc acc atc cac agc ggc tgg 244

Pro Leu Thr Met Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly Trp

60 65 70

agc cgc ttc cgc gtg ctg ccg cag ggg ctg aag gtg aag cag gtg gag 292

Ser Arg Phe Arg Val Leu Pro Gln Gly Leu Lys Val Lys Gln Val Glu

75 80 85 90

cgg gag gat gcc ggc gtg tac gtg tgc aag gcc acc aac ggc ttc ggc 340

Arg Glu Asp Ala Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly

95 100 105

agc ctt agc gtc aac tac acc ctc gtc gtg ctg gat gac att agc cca 388

Ser Leu Ser Val Asn Tyr Thr Leu Val Val Leu Asp Asp Ile Ser Pro

110 115 120

ggg aag gag agc ctg ggg ccc gac agc tcc tct ggg ggt caa gag gac 436

Gly Lys Glu Ser Leu Gly Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp

125 130 135

ccc gcc agc cag cag tgg gca cga ccg cgc ttc aca cag ccc tcc aag 484

Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys

140 145 150

atg agg cgc cgg gtg atc gca cgg ccc gtg ggt agc tcc gtg cgg ctc 532

Met Arg Arg Arg Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg Leu

155 160 165 170

aag tgc gtg gcc agc ggg cac cct cgg ccc gac atc acg tgg atg aag 580

Lys Cys Val Ala Ser Gly His Pro Arg Pro Asp Ile Thr Trp Met Lys

175 180 185

gac gac cag gcc ttg acg cgc cca gag gcc gct gag ccc agg aag aag 628

Asp Asp Gln Ala Leu Thr Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys

190 195 200

aag tgg aca ctg agc ctg aag aac ctg cgg ccg gag gac agc ggc aaa 676

Lys Trp Thr Leu Ser Leu Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys

205 210 215

tac acc tgc cgc gtg tcg aac cgc gcg ggc gcc atc aac gcc acc tac 724

Tyr Thr Cys Arg Val Ser Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr

220 225 230

aag gtg gat gtg atc cag cgg acc cgt tcc aag ccc gtg ctc aca ggc 772

Lys Val Asp Val Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr Gly

235 240 245 250

acg cac ccc gtg aac acg acg gtg gac ttc ggg ggg acc acg tcc ttc 820

Thr His Pro Val Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser Phe

255 260 265

cag tgc aag gtg cgc agc gac gtg aag ccg gtg atc cag tgg ctg aag 868

Gln Cys Lys Val Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu Lys

270 275 280

cgc gtg gag tac ggc gcc gag ggc cgc cac aac tcc acc atc gat gtg 916

Arg Val Glu Tyr Gly Ala Glu Gly Arg His Asn Ser Thr Ile Asp Val

285 290 295

ggc ggc cag aag ttt gtg gtg ctg ccc acg ggt gac gtg tgg tcg cgg 964

Gly Gly Gln Lys Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser Arg

300 305 310

ccc gac ggc tcc tac ctc aat aag ctg ctc atc acc cgt gcc cgc cag 1012

Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln

315 320 325 330

gac gat gcg ggc atg tac atc tgc ctt ggc gcc aac acc atg ggc tac 1060

Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr

335 340 345

agc ttc cgc agc gcc ttc ctc acc gtg ctg cca gac cca aaa ccg caa 1108

Ser Phe Arg Ser Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro Gln

350 355 360

ggg cca cct gtg gcc tcc tcg tcc tcg gcc act agc ctg ccg tgg ccc 1156

Gly Pro Pro Val Ala Ser Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro

365 370 375

gtg gtc atc ggc atc cca gcc ggc gct gtc ttc atc ctg ggc acc ctg 1204

Val Val Ile Gly Ile Pro Ala Gly Ala Val Phe Ile Leu Gly Thr Leu

380 385 390

ctc ctg tgg ctt tgc cag gcc cag aag aag ccg tgc acc ccc gcg cct 1252

Leu Leu Trp Leu Cys Gln Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro

395 400 405 410

gcc cct ccc ctg cct ggg cac cgc ccg ccg ggg acg gcc cgc gac cgc 1300

Ala Pro Pro Leu Pro Gly His Arg Pro Pro Gly Thr Ala Arg Asp Arg

415 420 425

agc gga gac aag gac ctt ccc tcg ttg gcc gcc ctc agc gct ggc cct 1348

Ser Gly Asp Lys Asp Leu Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro

430 435 440

ggt gtg ggg ctg tgt gag gag cat ggg tct ccg gca gcc ccc cag cac 1396

Gly Val Gly Leu Cys Glu Glu His Gly Ser Pro Ala Ala Pro Gln His

445 450 455

tta ctg ggc cca ggc cca gtt gct ggc cct aag ttg tac ccc aaa ctc 1444

Leu Leu Gly Pro Gly Pro Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu

460 465 470

tac aca gac atc cac aca cac aca cac aca cac tct cac aca cac tca 1492

Tyr Thr Asp Ile His Thr His Thr His Thr His Ser His Thr His Ser

475 480 485 490

cac gtg gag ggc aag gtc cac cag cac atc cac tat cag tgc 1534

His Val Glu Gly Lys Val His Gln His Ile His Tyr Gln Cys

495 500

tagacggcac cgtatctgca gtgggcacgg gggggccggc cagacaggca gactgggagg 1594

atggaggacg gagctgcaga cgaaggcagg ggacccatgg cgaggaggaa tggccagcac 1654

cccaggcagt ctgtgtgtga ggcatagccc ctggacacac acacacagac acacacacta 1714

cctggatgca tgtatgcaca cacatgcgcg cacacgtgct ccctgaaggc acacgtacgc 1774

acacacgcac atgcacagat atgccgcctg ggcacacaga taagctgccc aaatgcacgc 1834

acacgcacag agacatgcca gaacatacaa ggacatgctg cctgaacata cacacgcaca 1894

cccatgcgca gatgtgctgc ctggacacac acacacacac ggatatgctg tctggacgca 1954

cacacgtgca gatatggtat ccggacacac acgtgcacag atatgctgcc tggacacaca 2014

gataatgctg ccttgacaca cacatgcacg gatattgcct ggacacacac acacacacgc 2074

gtgcacagat atgctgtctg gacaggcaca cacatgcaga tatgctgcct ggacacacac 2134

ttccagacac acgtgcacag gcgcagatat gctgcctgga cacacgcaga tatgctgtct 2194

agtcacacac acacgcagac atgctgtccg gacacacaca cgcatgcaca gatatgctgt 2254

ccggacacac acacgcacgc agatatgctg cctggacaca cacacagata atgctgcctc 2314

aacactcaca cacgtgcaga tattgcctgg acacacacat gtgcacagat atgctgtctg 2374

gacatgcaca cacgtgcaga tatgctgtcc ggatacacac gcacgcacac atgcagatat 2434

gctgcctggg cacacacttc cggacacaca tgcacacaca ggtgcagata tgctgcctgg 2494

acacacgcag actgacgtgc ttttgggagg gtgtgccgtg aagcctgcag tacgtgtgcc 2554

gtgaggctca tagttgatga gggactttcc ctgctccacc gtcactcccc caactctgcc 2614

cgcctctgtc cccgcctcag tccccgcctc catccccgcc tctgtcccct ggccttggcg 2674

gctatttttg ccacctgcct tgggtgccca ggagtcccct actgctgtgg gctggggttg 2734

ggggcacagc agccccaagc ctgagaggct ggagcccatg gctagtggct catccccact 2794

gcattctccc cctgacacag agaaggggcc ttggtattta tatttaagaa atgaagataa 2854

tattaataat gatggaagga agactgggtt gcagggactg tggtctctcc tggggcccgg 2914

gacccgcctg gtctttcagc catgctgatg accacacccc gtccaggcca gacaccaccc 2974

cccaccccac tgtcgtggtg gccccagatc tctgtaattt tatgtagagt ttgagctgaa 3034

gccccgtata tttaatttat tttgttaaac atgaaagtgc atcctt 3080

<210> SEQ ID NO 19

<211> LENGTH: 504

<212> TYPE: PRT

<213> ORGANISM: Homo sapiens

<400> SEQUENCE: 19

Met Thr Pro Ser Pro Leu Leu Leu Leu Leu Leu Pro Pro Leu Leu Leu

1 5 10 15

Gly Ala Phe Pro Pro Ala Ala Ala Ala Arg Gly Pro Pro Lys Met Ala

20 25 30

Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg

35 40 45

Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr

50 55 60

Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu

65 70 75 80

Pro Gln Gly Leu Lys Val Lys Gln Val Glu Arg Glu Asp Ala Gly Val

85 90 95

Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr

100 105 110

Thr Leu Val Val Leu Asp Asp Ile Ser Pro Gly Lys Glu Ser Leu Gly

115 120 125

Pro Asp Ser Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp

130 135 140

Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile

145 150 155 160

Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly

165 170 175

His Pro Arg Pro Asp Ile Thr Trp Met Lys Asp Asp Gln Ala Leu Thr

180 185 190

Arg Pro Glu Ala Ala Glu Pro Arg Lys Lys Lys Trp Thr Leu Ser Leu

195 200 205

Lys Asn Leu Arg Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser

210 215 220

Asn Arg Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln

225 230 235 240

Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr

245 250 255

Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser

260 265 270

Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ala

275 280 285

Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val

290 295 300

Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu

305 310 315 320

Asn Lys Leu Leu Ile Thr Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr

325 330 335

Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe

340 345 350

Leu Thr Val Leu Pro Asp Pro Lys Pro Gln Gly Pro Pro Val Ala Ser

355 360 365

Ser Ser Ser Ala Thr Ser Leu Pro Trp Pro Val Val Ile Gly Ile Pro

370 375 380

Ala Gly Ala Val Phe Ile Leu Gly Thr Leu Leu Leu Trp Leu Cys Gln

385 390 395 400

Ala Gln Lys Lys Pro Cys Thr Pro Ala Pro Ala Pro Pro Leu Pro Gly

405 410 415

His Arg Pro Pro Gly Thr Ala Arg Asp Arg Ser Gly Asp Lys Asp Leu

420 425 430

Pro Ser Leu Ala Ala Leu Ser Ala Gly Pro Gly Val Gly Leu Cys Glu

435 440 445

Glu His Gly Ser Pro Ala Ala Pro Gln His Leu Leu Gly Pro Gly Pro

450 455 460

Val Ala Gly Pro Lys Leu Tyr Pro Lys Leu Tyr Thr Asp Ile His Thr

465 470 475 480

His Thr His Thr His Ser His Thr His Ser His Val Glu Gly Lys Val

485 490 495

His Gln His Ile His Tyr Gln Cys

500

<210> SEQ ID NO 20

<211> LENGTH: 342

<212> TYPE: PRT

<213> ORGANISM: Mus musculus

<400> SEQUENCE: 20

Met Ala Asp Lys Val Val Pro Arg Gln Val Ala Arg Leu Gly Arg Thr

1 5 10 15

Val Arg Leu Gln Cys Pro Val Glu Gly Asp Pro Pro Pro Leu Thr Met

20 25 30

Trp Thr Lys Asp Gly Arg Thr Ile His Ser Gly Trp Ser Arg Phe Arg

35 40 45

Val Leu Pro Gln Gly Leu Lys Val Lys Glu Val Glu Ala Glu Asp Ala

50 55 60

Gly Val Tyr Val Cys Lys Ala Thr Asn Gly Phe Gly Ser Leu Ser Val

65 70 75 80

Asn Tyr Thr Leu Ile Ile Met Asp Asp Ile Ser Pro Gly Lys Glu Ser

85 90 95

Pro Gly Pro Gly Gly Ser Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln

100 105 110

Gln Trp Ala Arg Pro Arg Phe Thr Gln Pro Ser Lys Met Arg Arg Arg

115 120 125

Val Ile Ala Arg Pro Val Gly Ser Ser Val Arg Leu Lys Cys Val Ala

130 135 140

Ser Gly His Pro Arg Pro Asp Ile Met Trp Met Lys Asp Asp Gln Thr

145 150 155 160

Leu Thr His Leu Glu Ala Ser Glu His Arg Lys Lys Lys Trp Thr Leu

165 170 175

Ser Leu Lys Asn Leu Lys Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg

180 185 190

Val Ser Asn Lys Ala Gly Ala Ile Asn Ala Thr Tyr Lys Val Asp Val

195 200 205

Ile Gln Arg Thr Arg Ser Lys Pro Val Leu Thr Gly Thr His Pro Val

210 215 220

Asn Thr Thr Val Asp Phe Gly Gly Thr Thr Ser Phe Gln Cys Lys Val

225 230 235 240

Arg Ser Asp Val Lys Pro Val Ile Gln Trp Leu Lys Arg Val Glu Tyr

245 250 255

Gly Ser Glu Gly Arg His Asn Ser Thr Ile Asp Val Gly Gly Gln Lys

260 265 270

Phe Val Val Leu Pro Thr Gly Asp Val Trp Ser Arg Pro Asp Gly Ser

275 280 285

Tyr Leu Asn Lys Leu Leu Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly

290 295 300

Met Tyr Ile Cys Leu Gly Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser

305 310 315 320

Ala Phe Leu Thr Val Leu Pro Asp Pro Lys Pro Pro Gly Pro Pro Met

325 330 335

Ala Ser Ser Ser Ser Ser

340

<210> SEQ ID NO 21

<211> LENGTH: 1788

<212> TYPE: DNA

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence: murine

FGFR-L extracellular domain-Fc fusion polypeptide

<221> NAME/KEY: CDS

<222> LOCATION: (1)..(1782)

<400> SEQUENCE: 21

atg acg cgg agc ccc gcg ctg ctg ctg ctg cta ttg ggg gcc ctc ccg 48

Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro

1 5 10 15

tcg gct gag gcg gcg cga gga ccc cca aga atg gca gac aaa gtg gtc 96

Ser Ala Glu Ala Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val

20 25 30

cca cgg cag gtg gcc cgc ctg ggc cgc act gtg cgg cta cag tgc cca 144

Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro

35 40 45

gtg gag ggg gac cca cca ccg ttg acc atg tgg acc aaa gat ggc cgc 192

Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg

50 55 60

aca atc cac agt ggc tgg agc cgc ttc cgt gtg ctg ccc cag ggt ctg 240

Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu

65 70 75 80

aag gtg aag gag gtg gag gcc gag gat gcc ggt gtt tat gtg tgc aag 288

Lys Val Lys Glu Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys

85 90 95

gcc acc aat ggc ttt ggc agc ctc agc gtc aac tac act ctc atc atc 336

Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile

100 105 110

atg gat gat att agt cca ggg aag gag agc cct ggg cca ggt ggt tct 384

Met Asp Asp Ile Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser

115 120 125

tcg ggg ggc cag gag gac cca gcc agc cag cag tgg gca cgg cct cgc 432

Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg

130 135 140

ttc aca cag ccc tcc aag atg agg cgc cga gtg att gca cgg cct gtg 480

Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val

145 150 155 160

ggt agc tct gtg cgg ctc aag tgt gtg gcc agt ggg cac cca cgg cca 528

Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro

165 170 175

gac atc atg tgg atg aag gat gac cag acc ttg acg cat cta gag gct 576

Asp Ile Met Trp Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala

180 185 190

agt gaa cac aga aag aag aag tgg aca ctg agc ttg aag aac ctg aag 624

Ser Glu His Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys

195 200 205

cct gaa gac agt ggc aag tac acg tgc cgt gta tct aac aag gcc ggt 672

Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly

210 215 220

gcc atc aac gcc acc tac aaa gtg gat gta atc cag cgg act cgt tcc 720

Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser

225 230 235 240

aag cct gtg ctc aca ggg aca cac cct gtg aac aca acg gtg gac ttc 768

Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe

245 250 255

ggt ggg aca acg tcc ttc cag tgc aag gtg cgc agt gac gtg aag cct 816

Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro

260 265 270

gtg atc cag tgg ctg aag cgg gtg gag tac ggc tcc gag gga cgc cac 864

Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His

275 280 285

aac tcc acc att gat gtg ggt ggc cag aag ttt gtg gtg ttg ccc acg 912

Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr

290 295 300

ggt gat gtg tgg tca cgg cct gat ggc tcc tac ctc aac aag ctg ctc 960

Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu

305 310 315 320

atc tct cgg gcc cgc cag gat gat gct ggc atg tac atc tgc cta ggt 1008

Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly

325 330 335

gca aat acc atg ggc tac agt ttc cgt agc gcc ttc ctc act gta tta 1056

Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu

340 345 350

cca gac ccc aaa cct cca ggg cct cct atg gct tct tca tcg gtc gac 1104

Pro Asp Pro Lys Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Val Asp

355 360 365

aaa act cac aca tgc cca ccg tgc cca gca cct gaa ctc ctg ggg gga 1152

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

370 375 380

ccg tca gtc ttc ctc ttc ccc cca aaa ccc aag gac acc ctc atg atc 1200

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

385 390 395 400

tcc cgg acc cct gag gtc aca tgc gtg gtg gtg gac gtg agc cac gaa 1248

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

405 410 415

gac cct gag gtc aag ttc aac tgg tac gtg gac ggc gtg gag gtg cat 1296

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

420 425 430

aat gcc aag aca aag ccg cgg gag gag cag tac aac agc acg tac cgt 1344

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

435 440 445

gtg gtc agc gtc ctc acc gtc ctg cac cag gac tgg ctg aat ggc aag 1392

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

450 455 460

gag tac aag tgc aag gtc tcc aac aaa gcc ctc cca gcc ccc atc gag 1440

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

465 470 475 480

aaa acc atc tcc aaa gcc aaa ggg cag ccc cga gaa cca cag gtg tac 1488

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

485 490 495

acc ctg ccc cca tcc cgg gat gag ctg acc aag aac cag gtc agc ctg 1536

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

500 505 510

acc tgc ctg gtc aaa ggc ttc tat ccc agc gac atc gcc gtg gag tgg 1584

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

515 520 525

gag agc aat ggg cag ccg gag aac aac tac aag acc acg cct ccc gtg 1632

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

530 535 540

ctg gac tcc gac ggc tcc ttc ttc ctc tac agc aag ctc acc gtg gac 1680

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

545 550 555 560

aag agc agg tgg cag cag ggg aac gtc ttc tca tgc tcc gtg atg cat 1728

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

565 570 575

gag gct ctg cac aac cac tac acg cag aag agc ctc tcc ctg tct ccg 1776

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

580 585 590

ggt aaa tgataa 1788

Gly Lys

<210> SEQ ID NO 22

<211> LENGTH: 594

<212> TYPE: PRT

<213> ORGANISM: Artificial Sequence

<220> FEATURE:

<223> OTHER INFORMATION: Description of Artificial Sequence: murine

FGFR-L extracellular domain-Fc fusion polypeptide

<400> SEQUENCE: 22

Met Thr Arg Ser Pro Ala Leu Leu Leu Leu Leu Leu Gly Ala Leu Pro

1 5 10 15

Ser Ala Glu Ala Ala Arg Gly Pro Pro Arg Met Ala Asp Lys Val Val

20 25 30

Pro Arg Gln Val Ala Arg Leu Gly Arg Thr Val Arg Leu Gln Cys Pro

35 40 45

Val Glu Gly Asp Pro Pro Pro Leu Thr Met Trp Thr Lys Asp Gly Arg

50 55 60

Thr Ile His Ser Gly Trp Ser Arg Phe Arg Val Leu Pro Gln Gly Leu

65 70 75 80

Lys Val Lys Glu Val Glu Ala Glu Asp Ala Gly Val Tyr Val Cys Lys

85 90 95

Ala Thr Asn Gly Phe Gly Ser Leu Ser Val Asn Tyr Thr Leu Ile Ile

100 105 110

Met Asp Asp Ile Ser Pro Gly Lys Glu Ser Pro Gly Pro Gly Gly Ser

115 120 125

Ser Gly Gly Gln Glu Asp Pro Ala Ser Gln Gln Trp Ala Arg Pro Arg

130 135 140

Phe Thr Gln Pro Ser Lys Met Arg Arg Arg Val Ile Ala Arg Pro Val

145 150 155 160

Gly Ser Ser Val Arg Leu Lys Cys Val Ala Ser Gly His Pro Arg Pro

165 170 175

Asp Ile Met Trp Met Lys Asp Asp Gln Thr Leu Thr His Leu Glu Ala

180 185 190

Ser Glu His Arg Lys Lys Lys Trp Thr Leu Ser Leu Lys Asn Leu Lys

195 200 205

Pro Glu Asp Ser Gly Lys Tyr Thr Cys Arg Val Ser Asn Lys Ala Gly

210 215 220

Ala Ile Asn Ala Thr Tyr Lys Val Asp Val Ile Gln Arg Thr Arg Ser

225 230 235 240

Lys Pro Val Leu Thr Gly Thr His Pro Val Asn Thr Thr Val Asp Phe

245 250 255

Gly Gly Thr Thr Ser Phe Gln Cys Lys Val Arg Ser Asp Val Lys Pro

260 265 270

Val Ile Gln Trp Leu Lys Arg Val Glu Tyr Gly Ser Glu Gly Arg His

275 280 285

Asn Ser Thr Ile Asp Val Gly Gly Gln Lys Phe Val Val Leu Pro Thr

290 295 300

Gly Asp Val Trp Ser Arg Pro Asp Gly Ser Tyr Leu Asn Lys Leu Leu

305 310 315 320

Ile Ser Arg Ala Arg Gln Asp Asp Ala Gly Met Tyr Ile Cys Leu Gly

325 330 335

Ala Asn Thr Met Gly Tyr Ser Phe Arg Ser Ala Phe Leu Thr Val Leu

340 345 350

Pro Asp Pro Lys Pro Pro Gly Pro Pro Met Ala Ser Ser Ser Val Asp

355 360 365

Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly

370 375 380

Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile

385 390 395 400

Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu

405 410 415

Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His

420 425 430

Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg

435 440 445

Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys

450 455 460

Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu

465 470 475 480

Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr

485 490 495

Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu

500 505 510

Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp

515 520 525

Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val

530 535 540

Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp

545 550 555 560

Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His

565 570 575

Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro

580 585 590

Gly Lys

Claims

What is claimed is:

1. An isolated nucleic acid molecule comprising:

(a) the nucleotide sequence as set forth in SEQ ID NO: 4;

(b) a nucleotide sequence encoding the polypeptide as set forth in SEQ ID NO: 5;

(c) a nucleotide sequence which hybridizes under at least moderately stringent conditions to the complement of the nucleotide sequence of either (a) or (b), wherein the encoded polypeptide has an activity of the polypeptide as set forth in SEQ ID NO: 5; or

(d) a nucleotide sequence complementary to the nucleotide sequence of any of (a)-(c).

2. An isolated nucleic acid molecule comprising:

(a) a nucleotide sequence encoding a polypeptide that is at least about 70 percent identical to the polypeptide as set forth in SEQ ID NO: 5, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5;

(b) a nucleotide sequence encoding an allelic variant or splice variant of the nucleotide sequence as set forth in SEQ ID NO: 4, or the nucleotide sequence of (a);

(c) a region of the nucleotide sequence of SEQ ID NO: 4, or the nucleotide sequence of either (a) or (b), encoding a polypeptide fragment of at least about 25 amino acid residues, wherein the polypeptide fragment has an activity of the encoded polypeptide as set forth in SEQ ID NO: 5, or is antigenic;

(d) a region of the nucleotide sequence of SEQ ID NO: 4, or the nucleotide sequence of any of (a)-(c) comprising a fragment of at least about 16 nucleotides;

(e) a nucleotide sequence that hybridizes under at least moderately stringent conditions to the complement of the nucleotide sequence of any of (a)-(d), wherein the encoded polypeptide has an activity of the polypeptide as set forth in SEQ ID NO: 5; or

(f) a nucleotide sequence complementary to the nucleotide sequence of any of (a)-(e).

3. An isolated nucleic acid molecule comprising:

(a) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one conservative amino acid substitution, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5;

(b) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one amino acid insertion, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5;

(c) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one amino acid deletion, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5;

(d) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 which has a C- and/or N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5;

(e) a nucleotide sequence encoding a polypeptide as set forth in SEQ ID NO: 5 with at least one modification that is an amino acid substitution, amino acid insertion, amino acid deletion, C-terminal truncation, or N-terminal truncation, wherein the encoded polypeptide has an activity of the polypeptide set forth in SEQ ID NO: 5;

(g) a nucleotide sequence that hybridizes under at least moderately stringent conditions to the complement of the nucleotide sequence of any of (a)-(f), wherein the encoded polypeptide has an activity of the polypeptide as set forth in SEQ ID NO: 5; or

(h) a nucleotide sequence complementary to any of (a)-(g).

4. A vector comprising the nucleic acid molecule of any of claims 1, 2, or 3.

5. A host cell comprising the vector of claim 4.

6. The host cell of claim 5 that is a eukaryotic cell.

7. The host cell of claim 5 that is a prokaryotic cell.

8. A process of producing an FGFR-L polypeptide comprising culturing the host cell of claim 5 under suitable conditions to express the polypeptide, and optionally isolating the polypeptide from the culture.

9. The process of claim 8, wherein the nucleic acid molecule comprises promoter DNA other than the promoter DNA for the native FGFR-L polypeptide operatively linked to the DNA encoding the FGFR-L polypeptide.

10. The isolated nucleic acid molecule according to claim 2, wherein the percent identity is determined using a computer program that is GAP, BLASTN, FASTA, BLASTA, BLASTX, BestFit, or the Smith-Waterman algorithm.