Platelet endothelial cell adhesion molecule-1 serves as an inhibitory receptor that modulates platelet responses to collagen.
Platelet responses to collagen are mediated by the combined actions of the integrin alpha2beta1, which serves as a major collagen-binding receptor, and the GPVI/FcRgamma-chain complex, which transmits collagen-specific activation signals into the cell interior through the action of an immunoreceptor tyrosine-based activation motif within the cytoplasmic domain of the FcRgamma-chain. Despite much progress in identifying components of the signaling pathway responsible for collagen-induced platelet activation, virtually nothing is known about the regulatory elements that modulate this important hemostatic event. PECAM-1, a recently recognized member of the inhibitory receptor family, contains a functional immunoreceptor tyrosine-based inhibitory motif within its cytoplasmic domain that, when tyrosine phosphorylated, recruits and activates the protein-tyrosine phosphatase, SHP-2. To test the hypothesis that PECAM-1 functions to regulate GPVI/FcRgamma-chain-mediated platelet activation, the responses of wild-type versus PECAM-1-deficient murine platelets to GPVI-specific agonists were compared. Four distinct GPVI/FcRgamma-chain-dependent responses were found to be significantly exaggerated in platelets derived from PECAM-1-deficient mice, including Mg++-independent adhesion to immobilized fibrillar collagen, collagen-induced platelet aggregation, platelet aggregation induced by the GPVI-specific agonist collagen-related peptide, and GPVI/FcRgamma-chain-induced dense granule secretion. Together, these data provide compelling evidence that PECAM-1 modulates platelet responses to collagen, and they implicate this novel member of the inhibitory receptor family in the regulation of primary hemostasis.
Blood Research Institute, The Blood Center of Southeastern Wisconsin, and the Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, WI 53233, USA.
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D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002097:C-Reactive Protein / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006736:Horses; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology; D010980:Platelet Membrane Glycoproteins / Q000819:agonists / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; D000255:Adenosine Triphosphate; D003094:Collagen; D002097:C-Reactive Protein; D013917:Thrombin