Phosphorylation sur tyrosine de la VE-cadhérine en réponse au VEGF : mécanismes moléculaires et implications physiopathologiques

Abstract : Tyrosine phosphorylation of VE-cadherin in response to VEGF : molecular mechanisms and physiopathologic implications. Vascular integrity deeply depends on endothelial cell-cell junction stability. VE- (Vascular Endothelial)-cadherin is a key component of this junctions, and its tyrosine phosphorylation is thought to be a potent mechanism that controls vascular permeability. In this report, we demonstrated the existence of a tyrosine phosphorylated form of VE-cadherin in vivo. Remarkably, VE-cadherin tyrosine phosphorylation was strongly increased in ovary and uterus during hormone-induced angiogenesis, but not in other adult quiescent tissues. For the first time, we demonstrated that Src had a permanent association with VE-cadherin, in vivo and in vitro. Moreover, in agreement with other in vitro data, we found a transient association between VEGFR-2 and VE-cadherin in vivo in angiogenic tissues. Using several approaches, we demonstrated that VE-cadherin is a direct substrate for Src kinase in VEGF signaling pathway, and that tyrosine 685 is the unique phosphorylated site. In vitro wound healing test suggested that phosphorylation of Y685 in response to VEGF may be a key event in the intracellular signaling involved in migration process of endothelial cells. Finally, studying human breast carcinoma we also demonstrated the existence of a tyrosine phosphorylated form of VE-cadherin in tumor angiogenesis and its association with a PI3K and Src family kinase activity. Overall, this data concluded that Src kinase directly phosphorylates VE-cadherin on tyrosine 685 in response to VEGF, and this phosphorylation may be in vivo a sign of an angiogenic endothelium.
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Submitted on : Wednesday, March 5, 2008 - 10:53:03 PM
Last modification on : Thursday, March 6, 2008 - 8:41:48 AM
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Yann Wallez. Phosphorylation sur tyrosine de la VE-cadhérine en réponse au VEGF : mécanismes moléculaires et implications physiopathologiques. Biologie cellulaire. Université Joseph-Fourier - Grenoble I, 2007. Français. ⟨tel-00260975⟩

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