Lyn and PECAM-1 function as interdependent inhibitors of platelet aggregation

Blood. 2011 Apr 7;117(14):3903-6. doi: 10.1182/blood-2010-09-304816. Epub 2011 Feb 4.

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

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Drug Synergism
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / physiology
  • Platelet Aggregation / genetics*
  • Platelet Aggregation Inhibitors* / metabolism
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Platelet Endothelial Cell Adhesion Molecule-1 / physiology*
  • Platelet Membrane Glycoproteins / agonists
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / physiology
  • src-Family Kinases / genetics
  • src-Family Kinases / metabolism
  • src-Family Kinases / physiology*

Substances

  • Multiprotein Complexes
  • Platelet Aggregation Inhibitors
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Platelet Membrane Glycoproteins
  • platelet membrane glycoprotein VI
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse