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Biol Open. 2017 Oct 15;6(10):1404-1415. doi: 10.1242/bio.027896.

Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function.

Author information

1
Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
2
Leeds Institute of Cardiovascular & Metabolic Medicine, Faculty of Medicine & Health, University of Leeds, Leeds LS2 9JT, UK.
3
School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
4
Endothelial Cell Biology Unit, School of Molecular & Cellular Biology, University of Leeds, Leeds LS2 9JT, UK s.ponnambalam@leeds.ac.uk.

Abstract

Cell surface receptors can undergo recycling or proteolysis but the cellular decision-making events that sort between these pathways remain poorly defined. Vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGFR2) regulate signal transduction and angiogenesis, but how signaling and proteolysis is regulated is not well understood. Here, we provide evidence that a pathway requiring the E1 ubiquitin-activating enzyme UBA1 controls basal VEGFR2 levels, hence metering plasma membrane receptor availability for the VEGF-A-regulated endothelial cell response. VEGFR2 undergoes VEGF-A-independent constitutive degradation via a UBA1-dependent ubiquitin-linked pathway. Depletion of UBA1 increased VEGFR2 recycling from endosome-to-plasma membrane and decreased proteolysis. Increased membrane receptor availability after UBA1 depletion elevated VEGF-A-stimulated activation of key signaling enzymes such as PLCγ1 and ERK1/2. Although UBA1 depletion caused an overall decrease in endothelial cell proliferation, surviving cells showed greater VEGF-A-stimulated responses such as cell migration and tubulogenesis. Our study now suggests that a ubiquitin-linked pathway regulates the balance between receptor recycling and degradation which in turn impacts on the intensity and duration of VEGF-A-stimulated signal transduction and the endothelial response.

KEYWORDS:

Angiogenesis; Endothelial; Signal transduction; UBA1; Ubiquitination; VEGF-A; VEGFR2

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