title: Lyn and PECAM-1 function as interdependent inhibitors of platelet aggregation.
abstract: Inhibition of platelet responsiveness is important to control pathologic thrombus formation. Platelet-endothelial cell adhesion molecule-1 (PECAM-1) and the Src family kinase Lyn inhibit platelet activation by the glycoprotein VI (GPVI) collagen receptor; however, it is not known whether PECAM-1 and Lyn function in the same or different inhibitory pathways. In these studies, we found that, relative to wild-type platelets, platelets derived from PECAM-1-deficient, Lyn-deficient, or PECAM-1/Lyn double-deficient mice were equally hyperresponsive to stimulation with a GPVI-specific agonist, indicating that PECAM-1 and Lyn participate in the same inhibitory pathway. Lyn was required for PECAM-1 tyrosine phosphorylation and subsequent binding of the Src homology 2 domain-containing phosphatase-2, SHP-2. These results support a model in which PECAM-1/SHP-2 complexes, formed in a Lyn-dependent manner, suppress GPVI signaling.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
authors.forename: Zhangyin
authors.initials: Z
authors.lastname: Ming
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.forename: Jizhou
authors.initials: J
authors.lastname: Xiang
authors.forename: Peter
authors.initials: P
authors.lastname: Polewski
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Newman
authors.forename: Debra K
authors.initials: DK
authors.lastname: Newman
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000502:physiology; D010974:Platelet Aggregation / Q000235:genetics*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000819:agonists; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism / Q000502:physiology; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D046912:Multiprotein Complexes; D010975:Platelet Aggregation Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse