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The vitamin K–dependent anticoagulant factor, protein S, inhibits multiple VEGF-A–induced angiogenesis events in a Mer- and SHP2-dependent manner

Abstract : Protein S is a vitamin K-dependent glyco-protein, which, besides its anticoagulant function, acts as an agonist for the ty-rosine kinase receptors Tyro3, Axl, and Mer. The endothelium expresses Tyro3, Axl, and Mer and produces protein S. The interaction of protein S with endothelial cells and particularly its effects on angio-genesis have not yet been analyzed. Here we show that human protein S, at circulating concentrations, inhibited vascular en-dothelial growth factor (VEGF) receptor 2-dependent vascularization of Matrigel plugs in vivo and the capacity of endo-thelial cells to form capillary-like networks in vitro as well as VEGF-A-induced endothelial migration and proliferation. Furthermore, protein S inhibited VEGF-A-induced endothelial VEGFR2 phosphorylation and activation of mitogen-activated kinase-Erk1/2 and Akt. Protein S activated the tyrosine phos-phatase SHP2, and the SHP2 inhibitor NSC 87877 reversed the observed inhibition of VEGF-A-induced endothelial proliferation. Using siRNA directed against Tyro3, Axl, and Mer, we demonstrate that protein S-mediated SHP2 activation and inhibition of VEGF-A-stimulated proliferation were mediated by Mer. Our report provides the first evidence for the existence of a protein S/Mer/SHP2 axis, which inhibits VEGFR2 signaling, regulates en-dothelial function, and points to a role for protein S as an endogenous angiogen-esis inhibitor. (Blood. 2012;120(25): 5073-5083)
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Contributor : Sylvain Fraineau <>
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Sylvain Fraineau, Arnaud Monvoisin, Jonathan Clarhaut, Julie Talbot, Claire Simonneau, et al.. The vitamin K–dependent anticoagulant factor, protein S, inhibits multiple VEGF-A–induced angiogenesis events in a Mer- and SHP2-dependent manner. Blood, American Society of Hematology, 2012, 120 (25), pp.5073-5083. ⟨10.1182/blood-2012-05-429183⟩. ⟨inserm-02444598⟩

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