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VEGFR2 Trafficking, Signaling and Proteolysis is Regulated by the Ubiquitin Isopeptidase USP8
Author(s) -
Smith Gina A.,
Fearnley Gareth W.,
AbdulZani Izma,
Wheatcroft Stephen B.,
Tomlinson Darren C.,
Harrison Michael A.,
Ponnambalam Sreenivasan
Publication year - 2016
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/tra.12341
Subject(s) - ubiquitin , biology , microbiology and biotechnology , proteolysis , ubiquitin ligase , signal transduction , deubiquitinating enzyme , biochemistry , gene , enzyme
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.