Modulation de la signalisation du récepteur de type 2 du facteur de croissance de l’endothélium vasculaire (VEGFR-2) par l’ubiquitination
Abstract Angiogenesis is one of the most important processes to maintain oxygen homeostasis throughout the different tissues. The different signaling pathways of the vascular endothelial growth factor receptor 2, VEGFR-2, play a primordial role in the angiogenic response induced by different angiogenic factors, one of which is the vascular endothelial growth factor, VEGF. Following VEGFR-2 activation, many signaling cascades are triggered in endothelial cells; in order to attenuate this response, VEGFR-2 undergoes multi ubiquitination on lysine residues and in this fashion it is brought into the degradation pathways, mainly through the lysosomes. This ubiquitination is induced by the association of the ubiquitin ligase (E3) c-Cbl to a phosphorylated tyrosine residue in the c-terminal domain of VEGFR-2. In this study, we identified tyrosine residue 1319 as being necessary for the association of c-Cbl to VEGFR-2 and for its ubiquitination. Our results show as well that overexpression of the mutant Y1319F version of VEGFR-2 in bovine aortic endothelial cells, BAEC, slows down the degradation process of VEGFR-2 and at the same time increases and prolongs the activation of endothelial nitric oxide synthase, eNOS. These results allow us to better understand the process of VEGFR-2 signaling regulation at the intracellular level. Keywords: [Angiogenesis, VEGFR-2, VEGF, c-Cbl, Ubiquitination, Tyrosine 1319, Degradation]
VEGFR-2 VEGF c-Cbl Ubiquitination Tyrosine 1319 Angiogenesis