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Papers In Press, published online ahead of print November 26, 2001
Medicine, University of Pennsylvania, Philadelphia, PA 19104
Corresponding Author: markkahn{at}mail.med.upenn.edu
The platelet response to collagen is a primary event in hemostasis and thrombosis but the precise roles of the numerous identified platelet collagen receptors remain incompletely defined. Attention has recently focused on glycoprotein VI (GPVI), a receptor which is expressed on platelets in association with a signaling adaptor, the Fc receptor gamma chain (FcRg). Genetic and pharmacologic loss of GPVI function results in loss of collagen signaling in platelets but studies to date have failed to demonstrate that GPVI- Fc Rg expression is sufficient to confer collagen signaling responses. These results have led to the hypothesis that collagen responses mediated by GPVI-Fc Rg may require the collagen-binding integrin a2b1 as a co-receptor but this model has not been supported by a recent study of mouse platelets lacking a2b1. In the present study we have used a novel anti-GPVI monoclonal antibody to measure the level of GPVI on human platelets and to guide the development of GPVI-expressing cell lines to assess the role of GPVI in mediating platelet collagen responses. GPVI receptor density on human platelets appears tightly regulated, is independent of the level of a2b1 expression and significantly exceeds that on previously characterized GPVI-expressing RBL-2H3 cells. Using newly generated GPVI-expressing RBL-2H3 cells with receptor densities equivalent to that on human platelets we demonstrate that GPVI expression confers both adhesive and signaling responses to collagen in a graded fashion that is proportional to the GPVI receptor density. These results resolve some of the conflicting data regarding GPVI-collagen interactions and demonstrate that (1) GPVI-Fc Rg expression is sufficient to confer both adhesion and signaling responses to collagen, and (2) GPVI-mediated collagen responses are receptor density dependent at the receptor levels expressed on human platelets.
J. Biol. Chem, 10.1074/jbc.M109714200
Submitted on October 9, 2001
Revised on November 26, 2001
Accepted on November 23, 2001
The platelet receptor GPVI mediates both adhesion and signaling responses to collagen in a receptor density-dependent fashion
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