title: R-Ras protein inhibits autophosphorylation of vascular endothelial growth factor receptor 2 in endothelial cells and suppresses receptor activation in tumor vasculature.
abstract: 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 anticancer 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 the small GTPase R-Ras inhibits excessive angiogenic growth and promotes the maturation of regenerating blood vessels. R-Ras signaling counteracts VEGF-induced 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. 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, R-Ras suppressed the internalization of VEGFR2, which 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, silencing of R-Ras resulted in increased VEGFR2 phosphorylation. This effect of R-Ras on VEGFR2 was, at least in part, dependent on vascular endothelial cadherin. 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.
authors: From the Cardiovascular Pathobiology Program and Tumor Microenvironment and Metastasis Program, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida 32827.
authors: Junko
authors: J
authors: Sawada
authors: From the Cardiovascular Pathobiology Program and Tumor Microenvironment and Metastasis Program, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida 32827.
authors: Fangfei
authors: F
authors: Li
authors: From the Cardiovascular Pathobiology Program and Tumor Microenvironment and Metastasis Program, Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, Florida 32827 mkomatsu@sanfordburnham.org.
authors: Masanobu
authors: M
authors: Komatsu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000378:metabolism*; D045744:Cell Line, Tumor; D020405:Dermis / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D008546:Melanoma, Experimental / Q000098:blood supply / Q000378:metabolism*; D018345:Mice, Knockout; D055806:Microvessels / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D018631:ras Proteins / Q000502:physiology*; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D040301:Vascular Endothelial Growth Factor Receptor-2; D018631:ras Proteins; D000099152:Cadherin 5; C000592875:Kdr protein, mouse; C513254:Rras protein, mouse
keywords: Angiogenesis; Cancer Biology; Endothelial Cell; Endothelium; Ras Protein; Tumor; Tumor Microenvironment; VEGF; Vascular Biology
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