Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy
Anne Angelillo-Scherrer, … , Bernhard Wehrle-Haller, Peter Carmeliet
Anne Angelillo-Scherrer, … , Bernhard Wehrle-Haller, Peter Carmeliet
Published February 1, 2005
Citation Information: J Clin Invest. 2005;115(2):237-246. https://doi.org/10.1172/JCI22079.
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Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy

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 β3 integrin, thereby amplifying outside-in signaling via αIIbβ3. Blocking the Gas6-R–αIIbβ3 integrin cross-talk might be a novel approach to the reduction of thrombosis.

Authors

Anne Angelillo-Scherrer, Laurent Burnier, Nathalie Flores, Pierre Savi, Maria DeMol, Paul Schaeffer, Jean-Marc Herbert, Greg Lemke, Stephen P. Goff, Glenn K. Matsushima, H. Shelton Earp, Christian Vesin, Marc F. Hoylaerts, Stéphane Plaisance, Désiré Collen, Edward M. Conway, Bernhard Wehrle-Haller, Peter Carmeliet

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Figure 3

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Effect of the lack of Tyro3, Axl, or Mer on aggregation of WT, Tyro3–/–,...
Effect of the lack of Tyro3, Axl, or Mer on aggregation of WT, Tyro3–/–, Axl–/–, or Mer–/– PRP. (A) Response of WT or Tyro3–/– platelets to 5 μM and 50 μM ADP. (Similar results were obtained with Axl–/– and Mer–/– platelets; data not shown.) (B) Response of WT or Axl–/– platelets to 2 μg/ml and 10 μg/ml collagen. (Similar results were obtained with Tyro3–/– and Mer–/– platelets; data not shown.) (C) Response of WT or Mer–/– platelets to 1 μM and 7 μM TXA2 analogue U46619. (Similar results were obtained with Tyro3–/– and Axl–/– platelets; data not shown.) (D) Aggregation response to ADP (5 μM) of washed human platelets after preincubation with human Axl extracellular domain (hAxl-EC-Fc) or control IgG, revealing that hAxl-EC-Fc reduces platelet aggregation. A representative example of 3 independent experiments is shown. Arrows in A–D indicate addition of the platelet agonists.