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 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.
Angelillo-Scherrer
Anne
A
Division of Angiology and Hemostasis, Department of Internal Medicine, Faculty of Medicine and University Hospitals of Geneva, Geneva, Switzerland. Anne.Angelillo@medecine.unige.ch
Burnier
Laurent
L
Flores
Nathalie
N
Savi
Pierre
P
DeMol
Maria
M
Schaeffer
Paul
P
Herbert
Jean-Marc
JM
Lemke
Greg
G
Goff
Stephen P
SP
Matsushima
Glenn K
GK
Earp
H Shelton
HS
Vesin
Christian
C
Hoylaerts
Marc F
MF
Plaisance
Stéphane
S
Collen
Désiré
D
Conway
Edward M
EM
Wehrle-Haller
Bernhard
B
Carmeliet
Peter
P
D000818:Animals; D039661:Integrin beta3 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010974:Platelet Aggregation / Q000235:genetics / Q000502:physiology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013927:Thrombosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000099255:Growth Arrest-Specific Protein 6
D039661:Integrin beta3; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D000099255:Growth Arrest-Specific Protein 6