Critchley, William R; Smith, Gina A; Zachary, Ian C; Harrison, Michael A; Ponnambalam, Sreenivasan; (2023) E2 ubiquitin-conjugating enzymes, UBE2D1 and UBE2D2, regulate VEGFR2 dynamics and endothelial function. Journal of Cell Science , Article jcs.260657. 10.1242/jcs.260657.

Preview

Text jcs260657.pdf - Other Download (4MB) | Preview

Abstract

Vascular endothelial growth factor receptor 2 (VEGFR2) regulates endothelial function and angiogenesis. VEGFR2 undergoes ubiquitination which programs this receptor for trafficking and proteolysis but the ubiquitin-modifying enzymes involved are ill-defined. Herein, we used a reverse genetics screen of the human E2 family of ubiquitin-conjugating enzymes to identify gene products which regulate VEGFR2 ubiquitination and proteolysis. We find that depletion of either UBE2D1 or UBE2D2 in endothelial cells cause a rise in steady-state VEGFR2 levels. This rise in plasma membrane VEGFR2 levels impact on VEGF-A-stimulated signalling, with increased activation of canonical MAPK, phospholipase C1, and Akt pathways. Analysis of biosynthetic VEGFR2 is consistent with a role for UBE2D enzymes in influencing plasma membrane VEGFR2 levels. Cell surface biotinylation and recycling studies show an increase in VEGFR2 recycling to the plasma membrane upon reduction in UBE2D levels. Depletion of either UBE2D1 or UBE2D2 stimulates endothelial tubulogenesis which is consistent with increased VEGFR2 plasma membrane levels promoting the cellular response to exogenous VEGF-A. Our studies identify a key role for UBE2D1 and UBE2D2 in regulating VEGFR2 function in angiogenesis.

Download activity - last month

Export as JSONXMLCSV

Download activity - last 12 months

Export as JSONCSVXML

Downloads by country - last 12 months

Export as JSONXMLCSV

Archive Staff Only

View Item