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Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy
Anne Angelillo-Scherrer1, Laurent Burnier1, Nathalie Flores1, Pierre Savi2, Maria DeMol3, Paul Schaeffer2, Jean-Marc Herbert2, Greg Lemke4, Stephen P. Goff5, Glenn K. Matsushima6, H. Shelton Earp7, Christian Vesin8, Marc F. Hoylaerts3, Stéphane Plaisance3, Désiré Collen3, Edward M. Conway3, Bernhard Wehrle-Haller8 and Peter Carmeliet3
1Division of Angiology and Hemostasis, Department of Internal Medicine, Faculty of Medicine and University Hospitals of Geneva, Geneva, Switzerland.
2Department of Cardiovascular Research, Sanofi-Synth–labo Recherche, Toulouse, France.
3Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, and Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.
4The Salk Institute for Biological Studies, San Diego, California, USA.
5Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.
6University of North Carolina Neuroscience Center, and
7Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
8Department of Cellular Physiology and Metabolism, University of Geneva Medical School, Geneva, Switzerland.
Address correspondence to: Anne Angelillo-Scherrer, Division of Angiology and Hemostasis, University Medical Center, 1 rue Michel-Servet, CH-1211 Geneva 14, Switzerland. Phone: 41-22-379-55-67; Fax: 41-22-372-92-99; E-mail: Received for publication May 5, 2004, and accepted in revised form November 23, 2004.
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 ß3 integrin, thereby amplifying outside-in signaling via IIbß3. Blocking the Gas6-R–IIbß3 integrin cross-talk might be a novel approach to the reduction of thrombosis.
