R-Ras Inhibits Autophosphorylation of VEGF Receptor-2 in Endothelial Cells and Suppresses the Receptor Activation in Tumor Vasculature [Molecular Bases of Disease]

February 2nd, 2015 by Sawada, J., Li, F., Komatsu, M.

Abnormal angiogenesis is associated with a broad range of medical conditions including cancer. The formation of neovasculature with functionally defective blood vessels significantly impacts tumor progression, metastasis and the efficacy of anti-cancer therapies. Vascular endothelial growth factor (VEGF) potently induces vascular permeability and vessel growth in the tumor microenvironment, and its inhibition normalizes tumor vasculature. In contrast, the signaling of small GTPase R-Ras inhibits excessive angiogenic growth and promotes the maturation of regenerating blood vessels. R-Ras signaling counteracts VEGFinduced vessel sprouting, permeability, and invasive activities of endothelial cells. In this study, we investigated the effect of R-Ras on VEGF receptor-2 (VEGFR2) activation by VEGF - the key mechanism for angiogenic stimulation. Here we show that tyrosine phosphorylation of VEGFR2 is significantly elevated in the tumor vasculature and dermal microvessels of VEGF-injected skin in R-Ras knockout mice. In cultured endothelial cells, RRas suppressed the internalization of VEGFR2 that is required for full activation of the receptor by VEGF. Consequently, R-Ras strongly suppressed autophosphorylation of the receptor at all five major tyrosine phosphorylation sites. Conversely, the silencing of R-Ras resulted in increased VEGFR2 phosphorylation. This effect of R-Ras on VEGFR2 was at least in part dependent on VEcadherin. These findings identify a novel function of R-Ras to control the response of endothelial cells to VEGF and suggest an underlying mechanism by which R-Ras regulates angiogenesis.
  • Posted in Journal of Biological Chemistry, Publications
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