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

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...

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Bibliographic Details
Published in:The Journal of clinical investigation 2005-02, Vol.115 (2), p.237-246
Main Authors: Angelillo-Scherrer, Anne, Burnier, Laurent, Flores, Nathalie, Savi, Pierre, DeMol, Maria, Schaeffer, Paul, Herbert, Jean-Marc, Lemke, Greg, Goff, Stephen P, Matsushima, Glenn K, Earp, H Shelton, Vesin, Christian, Hoylaerts, Marc F, Plaisance, Stéphane, Collen, Désiré, Conway, Edward M, Wehrle-Haller, Bernhard, Carmeliet, Peter
Format: Article
Language:English
Subjects:
Animals
Biomedical research
Blood clots
Blood platelets
Integrin beta3 - metabolism
Intercellular Signaling Peptides and Proteins - genetics
Intercellular Signaling Peptides and Proteins - metabolism
Ligands
Mice
Mice, Knockout
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
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
Pulmonary embolisms
Receptor Protein-Tyrosine Kinases - administration & dosage
Receptor Protein-Tyrosine Kinases - genetics
Receptor Protein-Tyrosine Kinases - metabolism
Signal Transduction - genetics
Signal Transduction - physiology
Thromboembolism
Thrombosis
Thrombosis - drug therapy
Thrombosis - genetics
Thrombosis - metabolism
Thrombosis - pathology
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci22079