Glycoprotein VI and uses thereof

Abstract

The invention provides isolated nucleic acid molecules and polypeptide molecules that encode glycoprotein VI, a platelet membrane glycoprotein that is involved platelet-collagen interactions. The invention also provides antisense nucleic acid molecules, expression vectors containing the nucleic acid molecules of the invention, host cells into which the expression vectors have been introduced, and non-human transgenic animals in which a nucleic acid molecule of the invention has been introduced or disrupted. The invention still further provides isolated polypeptides, fusion polypeptides, antigenic peptides and antibodies. Diagnostic, screening and therapeutic methods utilizing compositions of the invention are also provided.

1 . An isolated nucleic acid molecule selected from the group consisting of: 
 a) a nucleic acid molecule comprising a nucleotide sequence which is at least 45% identical to the nucleotide sequence of SEQ ID NO:1, 2, 14 or 15, the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225, or a complement thereof;    b) a nucleic acid molecule comprising a fragment of at least 300 nucleotides of the nucleotide sequence of SEQ ID NO:1, 2, 14 or 15, the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225, or a complement thereof;    c) a nucleic acid molecule which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225; and    d) a nucleic acid molecule which encodes a fragment of a polypeptide comprising the amino acid sequence of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225;    
     
     
         2 . The isolated nucleic acid molecule of  claim 1 , which is selected from the group consisting of: 
 a) a nucleic acid comprising the nucleotide sequence of SEQ ID NO:1, 2, 14 or 15, the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225, or a complement thereof; and    b) a nucleic acid molecule which encodes a polypeptide comprising the amino acid sequence of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225;    
     
     
         3 . The nucleic acid molecule of  claim 1  further comprising vector nucleic acid sequences.  
     
     
         4 . The nucleic acid molecule of  claim 1  further comprising nucleic acid sequences encoding a heterologous polypeptide.  
     
     
         5 . A host cell which contains the nucleic acid molecule of  claim 1 .  
     
     
         6 . The host cell of  claim 5  which is a mammalian host cell.  
     
     
         7 . A non-human mammalian host cell containing the nucleic acid molecule of  claim 1 .  
     
     
         8 . An isolated polypeptide selected from the group consisting of: 
 a) a fragment of a polypeptide comprising the amino acid sequence of SEQ ID NO:3 or 16, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:3 or 16;    b) a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of plasmids deposited with the ATCC as Accession Number 207180 or PTA-225, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule comprising SEQ ID NO:2 or 15, or a complement thereof under stringent conditions; and    c) a polypeptide which is encoded by a nucleic acid molecule comprising a nucleotide sequence which is at least 45% identical to a nucleic acid comprising the nucleotide sequence of SEQ ID NO:2 or 15, or at least 98% to a nucleic acid comprising the nucleotide sequence of SEQ ID NO:2 or 15, or a complement thereof.    
     
     
         9 . The isolated polypeptide of  claim 8  comprising the amino acid sequence of SEQ ID NO:3 or 16.  
     
     
         10 . The polypeptide of  claim 8 , further comprising heterologous amino acid sequences.  
     
     
         11 . An antibody which selectively binds to a polypeptide of  claim 8 .  
     
     
         12 . A method for producing a polypeptide selected from the group consisting of: 
 a) a polypeptide comprising the amino acid sequence of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225,    b) a polypeptide comprising a fragment of the amino acid sequence of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225, wherein the fragment comprises at least 15 contiguous amino acids of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225; and    c) a naturally occurring allelic variant of a polypeptide comprising the amino acid sequence of SEQ ID NO:3 or 16, or the amino acid sequence encoded by the cDNA insert of the plasmid deposited with the ATCC as Accession Number 207180 or PTA-225, wherein the polypeptide is encoded by a nucleic acid molecule which hybridizes to a nucleic acid molecule comprising SEQ ID NO:1 or 14, or a complement thereof under stringent conditions;    comprising culturing the host cell of  claim 5  under conditions in which the nucleic acid molecule is expressed.    
     
     
         13 . A method for detecting the presence of a polypeptide of  claim 8  in a sample, comprising: 
 a) contacting the sample with a compound which selectively binds to a polypeptide of  claim 8;  and    b) determining whether the compound binds to the polypeptide in the sample.    
     
     
         14 . A method for detecting the presence of a nucleic acid molecule of  claim 1  in a sample, comprising the steps of: 
 a) contacting the sample with a nucleic acid probe or primer which selectively hybridizes to the nucleic acid molecule; and    b) determining whether the nucleic acid probe or primer binds to a nucleic acid molecule in the sample.    
     
     
         15 . A kit comprising a compound which selectively hybridizes to a nucleic acid molecule of  claim 1  and instructions for use.  
     
     
         16 . A method for identifying a compound which binds to a polypeptide of  claim 8  comprising the steps of: 
 a) contacting a polypeptide, or a cell expressing a polypeptide of  claim 8  with a test compound; and    b) determining whether the polypeptide binds to the test compound.    
     
     
         17 . The method of  claim 16 , wherein the binding of the test compound to the polypeptide is detected by a method selected from the group consisting of: 
 a) detection of binding by direct detecting of test compound/polypeptide binding;    b) detection of binding using a competition binding assay;    c) detection of binding using an assay for TANGO 268-mediated signal transduction.    
     
     
         18 . A method for modulating the activity of a polypeptide of  claim 8  comprising contacting a polypeptide or a cell expressing a polypeptide of  claim 8  with a compound which binds to the polypeptide in a sufficient concentration to modulate the activity of the polypeptide.  
     
     
         19 . A method for identifying a compound which modulates the activity of a polypeptide of  claim 8 , comprising: 
 a) contacting a polypeptide of  claim 8  with a test compound; and    b) determining the effect of the test compound on the activity of the polypeptide to thereby identify a compound which modulates the activity of the polypeptide.    
     
     
         20 . A method for modulating an activity of a TANG0268 polypeptide in a subject comprising administering an anti-TANG0268 antibody to the subject to thereby modulate an activity of a TANG0268 polypeptide.  
     
     
         21 . The method of  claim 20 , wherein the TANG0268 activity is selected from the group consisting of: 
 a) the ability to modulate the host immune response;    b) the ability to modulate the proliferation, differentiation and/or activity of megakaryocytes and/or platelets;    c) the ability to modulate immunoregulatory functions;    d) the ability to modulate platelet morphology, migration, aggregation, degranulation and/or function;    e) the ability to modulate collagen binding to platelets;    f) the ability modulate collagen-induced platelet adhesion and aggregation;    g) the ability to interact with convulxin;    h) the ability to bind to an antibody from a patient with idiopathic thrombocytopenic purpura (ITP); and    i) the ability to associate and/or co-express with FcRγ.    
     
     
         22 . A method for treating a subject having a disorder associated with aberrant expression or activity of a TANGO268 polypeptide, comprising administering an anti-TANGO268 antibody to the subject, thereby treating said subject having a disorder associated with aberrant expression or activity of a TANGO0268 polypeptide.  
     
     
         23 . The method of  claim 22 , wherein the disorder associated with aberrant expression or activity of a TANGO268 polypeptide is selected from the group consisting of: 
 a) immunologic disorders; b) developmental disorders; c) embryonic disorders; d) liver disorders; e) cerebral vascular diseases; f) venous thromboembolism diseases; g) thrombotic disorders; h) coronary diseases; and i) metastatic cancers.