title: 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 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.
authors.affiliation: Division of Angiology and Hemostasis, Department of Internal Medicine, Faculty of Medicine and University Hospitals of Geneva, Geneva, Switzerland. Anne.Angelillo@medecine.unige.ch
authors.forename: Anne
authors.initials: A
authors.lastname: Angelillo-Scherrer
authors.forename: Laurent
authors.initials: L
authors.lastname: Burnier
authors.forename: Nathalie
authors.initials: N
authors.lastname: Flores
authors.forename: Pierre
authors.initials: P
authors.lastname: Savi
authors.forename: Maria
authors.initials: M
authors.lastname: DeMol
authors.forename: Paul
authors.initials: P
authors.lastname: Schaeffer
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Herbert
authors.forename: Greg
authors.initials: G
authors.lastname: Lemke
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Goff
authors.forename: Glenn K
authors.initials: GK
authors.lastname: Matsushima
authors.forename: H Shelton
authors.initials: HS
authors.lastname: Earp
authors.forename: Christian
authors.initials: C
authors.lastname: Vesin
authors.forename: Marc F
authors.initials: MF
authors.lastname: Hoylaerts
authors.forename: Stéphane
authors.initials: S
authors.lastname: Plaisance
authors.forename: Désiré
authors.initials: D
authors.lastname: Collen
authors.forename: Edward M
authors.initials: EM
authors.lastname: Conway
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wehrle-Haller
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: 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
chemical_list: 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