Cloning, characterization, and functional studies of human and mouse glycoprotein VI: a platelet-specific collagen receptor from the immunoglobulin superfamily.
Injuries to the vessel wall and subsequent exposure of collagen from the subendothelial matrix result in thrombus formation. In physiological conditions, the platelet plug limits blood loss. However, in pathologic conditions, such as rupture of atherosclerotic plaques, platelet-collagen interactions are associated with cardiovascular and cerebral vascular diseases. Platelet glycoprotein VI (GPVI) plays a crucial role in collagen-induced activation and aggregation of platelets, and people who are deficient in GPVI suffer from bleeding disorders. Based on the fact that GPVI is coupled to the Fc receptor (FcR)-gamma chain and thus should share homology with the FcR chains, the genes encoding human and mouse GPVI were identified. They belong to the immunoglobulin (Ig) superfamily and share 64% homology at the protein level. Functional evidence demonstrating the identity of the recombinant protein with GPVI was shown by binding to its natural ligand collagen; binding to convulxin (Cvx), a GPVI-specific ligand from snake venom; binding of anti-GPVI IgG isolated from a patient; and association to the FcR-gamma chain. The study also demonstrated that the soluble protein blocks Cvx and collagen-induced platelet aggregation and that GPVI expression is restricted to megakaryocytes and platelets. Finally, human GPVI was mapped to chromosome 19, long arm, region 1, band 3 (19q13), in the same region as multiple members of the Ig superfamily. This work offers the opportunity to explore the involvement of GPVI in thrombotic disease, to develop alternative antithrombotic compounds, and to characterize the mechanism involved in GPVI genetic deficiencies. (Blood. 2000;96:1798-1807)
Jandrot-Perrus
M
M
Institut National de la Santé et de la Recherche Médicale (INSERM) E9907, Faculté Xavier Bichat, Paris, France.
Busfield
S
S
Lagrue
A H
AH
Xiong
X
X
Debili
N
N
Chickering
T
T
Le Couedic
J P
JP
Goodearl
A
A
Dussault
B
B
Fraser
C
C
Vainchenker
W
W
Villeval
J L
JL
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001792:Blood Platelets / Q000378:metabolism; D015152:Blotting, Northern; D016466:CHO Cells; D002448:Cell Adhesion; D002460:Cell Line; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism / Q000494:pharmacology; D006224:Cricetinae; D003435:Crotalid Venoms / Q000378:metabolism / Q000494:pharmacology; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005260:Female; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000494:pharmacology; D007136:Immunoglobulins / Q000235:genetics; D016023:Integrins / Q000235:genetics; D020014:K562 Cells; D037181:Lectins, C-Type; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D015539:Platelet Activation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000235:genetics* / Q000494:pharmacology; D011485:Protein Binding; D012313:RNA / Q000235:genetics / Q000378:metabolism; D038981:Receptors, Collagen; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured; D020298:U937 Cells
D003435:Crotalid Venoms; D018076:DNA, Complementary; D007141:Immunoglobulin Fc Fragments; D007136:Immunoglobulins; D016023:Integrins; D037181:Lectins, C-Type; D010980:Platelet Membrane Glycoproteins; D038981:Receptors, Collagen; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; C098341:platelet membrane glycoprotein VI; C028890:convulxin; D012313:RNA; D003094:Collagen