VEGFR2 Trafficking, Signaling and Proteolysis is Regulated by the Ubiquitin Isopeptidase USP8

Traffic. 2016 Jan;17(1):53-65. doi: 10.1111/tra.12341. Epub 2015 Dec 2.

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.

Keywords: USP8; VEGF-A; VEGFR2; de-ubiquitination; proteolysis; signal transduction; trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endopeptidases / metabolism*
  • Endosomal Sorting Complexes Required for Transport / metabolism*
  • Endosomes / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Protein Transport
  • Proteolysis*
  • Signal Transduction*
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*

Substances

  • Endosomal Sorting Complexes Required for Transport
  • KDR protein, human
  • Vascular Endothelial Growth Factor Receptor-2
  • Endopeptidases
  • USP8 protein, human
  • Ubiquitin Thiolesterase