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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Integrin beta3 / metabolism
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism*
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Mice
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Mice, Knockout
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Phosphatidylinositol 3-Kinases / metabolism
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Platelet Aggregation / genetics
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Platelet Aggregation / physiology*
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Platelet Glycoprotein GPIIb-IIIa Complex / metabolism
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-akt
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Receptor Protein-Tyrosine Kinases / administration & dosage
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism
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Signal Transduction / genetics
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Signal Transduction / physiology*
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Thrombosis / drug therapy
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Thrombosis / genetics
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Thrombosis / metabolism*
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Thrombosis / pathology
Substances
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Integrin beta3
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Intercellular Signaling Peptides and Proteins
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Platelet Glycoprotein GPIIb-IIIa Complex
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Proto-Oncogene Proteins
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growth arrest-specific protein 6
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Receptor Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt