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.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Drug Synergism
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Female
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Multiprotein Complexes / genetics
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Multiprotein Complexes / physiology
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Platelet Aggregation / genetics*
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Platelet Aggregation Inhibitors* / metabolism
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Platelet Endothelial Cell Adhesion Molecule-1 / genetics
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Platelet Endothelial Cell Adhesion Molecule-1 / physiology*
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Platelet Membrane Glycoproteins / agonists
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
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Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology
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src-Family Kinases / genetics
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src-Family Kinases / metabolism
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src-Family Kinases / physiology*
Substances
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Multiprotein Complexes
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Platelet Aggregation Inhibitors
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Platelet Endothelial Cell Adhesion Molecule-1
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Platelet Membrane Glycoproteins
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platelet membrane glycoprotein VI
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lyn protein-tyrosine kinase
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src-Family Kinases
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Protein Tyrosine Phosphatase, Non-Receptor Type 11
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Ptpn11 protein, mouse