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.
Patil
S
S
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.
Newman
D K
DK
Newman
P J
PJ
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