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Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function.
- Source :
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Biology open [Biol Open] 2017 Oct 15; Vol. 6 (10), pp. 1404-1415. Date of Electronic Publication: 2017 Oct 15. - Publication Year :
- 2017
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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 PLCĪ³1 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.<br />Competing Interests: Competing interestsThe authors declare no competing or financial interests.<br /> (© 2017. Published by The Company of Biologists Ltd.)
Details
- Language :
- English
- ISSN :
- 2046-6390
- Volume :
- 6
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Biology open
- Publication Type :
- Academic Journal
- Accession number :
- 28798148
- Full Text :
- https://doi.org/10.1242/bio.027896