Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy

J Clin Invest. 2005 Feb;115(2):237-46. doi: 10.1172/JCI22079.

Abstract

Mechanisms regulating thrombus stabilization remain largely unknown. Here, we report that loss of any 1 of the Gas6 receptors (Gas6-Rs), i.e., Tyro3, Axl, or Mer, or delivery of a soluble extracellular domain of Axl that traps Gas6 protects mice against life-threatening thrombosis. Loss of a Gas6-R does not prevent initial platelet aggregation but impairs subsequent stabilization of platelet aggregates, at least in part by reducing "outside-in" signaling and platelet granule secretion. Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the beta3 integrin, thereby amplifying outside-in signaling via alphaIIbbeta3. Blocking the Gas6-R-alphaIIbbeta3 integrin cross-talk might be a novel approach to the reduction of thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Integrin beta3 / metabolism
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Phosphatidylinositol 3-Kinases / metabolism
  • Platelet Aggregation / genetics
  • Platelet Aggregation / physiology*
  • Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Receptor Protein-Tyrosine Kinases / administration & dosage
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Thrombosis / drug therapy
  • Thrombosis / genetics
  • Thrombosis / metabolism*
  • Thrombosis / pathology

Substances

  • Integrin beta3
  • Intercellular Signaling Peptides and Proteins
  • Platelet Glycoprotein GPIIb-IIIa Complex
  • Proto-Oncogene Proteins
  • growth arrest-specific protein 6
  • Phosphatidylinositol 3-Kinases
  • Receptor Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt