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Armin Maghsoudlou, Rosana D Meyer, Edward Hartsough, Nader Rahimi; Identification of Novel Endoplasmic Reticulum Ubiquitin E3 Ligase Involved in Regulation of Angiogenesis. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1326.
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Ocular angiogenesis is a hallmark of many debilitating eye diseases including wet age related macular degeneration and diabetic retinopathy. Vascular endothelial growth factor-A (VEGF-A), a principal mediator of neovascularization/angiogenesis, is a major cause of the disease's progression. Because of its central role in angiogenesis, the most successful CNV treatments have also relied on the blocking of the VEGF-A pathway. Activation of VEGFR-2 by VEGF family ligands mediates most of the known VEGF cellular responses leading to angiogenesis. The overall aim of this project is to understand the molecular mechanisms by which post - translational modifications on the VEGFR-2 control ocular angiogenesis, and how disruption of these post - translational modifications in pathological conditions contribute to aberrant angiogenesis.
We used various cell culture based assays including transfection and western blot analysis to establish the interaction of RNF-121 with VEGFR-2. Immunofluorescence microscopy was used to establish cellular localization of RNF-121. Western blotting and immunohistochemistry assays were used to analyze expression of RNF-121 in endothelial cells.
We have identified Ring Finger-121 (RNF-121) protein as a novel endoplasmic reticulum (ER) ubiquitin E3 ligase expressed in endothelial cells. RNF-121 directly associates with newly synthesized VEGFR-2 protein. RNF-121 mediates ubiquitination of VEGFR-2, a post-translational modification that targets VEGFR-2 to proteasomal degradation. RNF-121-dependnet degradation of VEGFR-2 reduces the presence of functional VEGFR-2 at the surface of endothelial cells and inhibits angiogenesis.
RNF-121 is a novel ubiquitin E3 ligase of VEGFR-2. RNF-121 plays an important role in angiogenesis by limiting the availability of VEGFR-2 at the surface endothelial cells and significantly reduces the angiogenic activity of VEGF-A.
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