VEGFR2 Trafficking,Signaling and Proteolysis is Regulated by the Ubiquitin Isopeptidase USP8 |
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| Authors: | Gina A. Smith Gareth W. Fearnley Izma Abdul‐Zani Stephen B. Wheatcroft Darren C. Tomlinson Michael A. Harrison Sreenivasan Ponnambalam |
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| Affiliation: | 1. Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds, UK;2. Leeds Institute of Cardiovascular & Metabolic Medicine, University of Leeds, Leeds, UK;3. Biomedical Health Research Centre & Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK;4. School of Biomedical Sciences, University of Leeds, Leeds, UK |
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| Abstract: | Vascular endothelial growth factor A (VEGF‐A) regulates many aspects of vascular function. VEGF‐A binding to vascular endothelial growth factor receptor 2 (VEGFR2) stimulates endothelial signal transduction and regulates multiple cellular responses. Activated VEGFR2 undergoes ubiquitination but the enzymes that regulate this post‐translational modification are unclear. In this study, the de‐ubiquitinating enzyme, USP8, is shown to regulate VEGFR2 trafficking, de‐ubiquitination, proteolysis and signal transduction. USP8‐depleted endothelial cells displayed altered VEGFR2 ubiquitination and production of a unique VEGFR2 extracellular domain proteolytic fragment caused by VEGFR2 accumulation in the endosome–lysosome system. In addition, perturbed VEGFR2 trafficking impaired VEGF‐A‐stimulated signal transduction in USP8‐depleted cells. Thus, regulation of VEGFR2 ubiquitination and de‐ubiquitination has important consequences for the endothelial cell response and vascular physiology.  |
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| Keywords: | de‐ubiquitination proteolysis signal transduction trafficking USP8 VEGF‐A VEGFR2 |
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