Smith, GA, Fearnley, G, Abdul Zani, I et al. (4 more authors) (2017) Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function. Biology Open, 6 (10). pp. 1404-1415. ISSN 2046-6390
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
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
Keywords: | Endothelial; VEGF-A; VEGFR2; UBA1; ubiquitination; signal transduction; angiogenesis |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Cardiovascular Science (Leeds) The University of Leeds > Faculty of Medicine and Health (Leeds) |
Funding Information: | Funder Grant number British Heart Foundation FS/12/20/29462 |
Depositing User: | Symplectic Publications |
Date Deposited: | 16 Aug 2017 14:42 |
Last Modified: | 09 Jul 2019 09:50 |
Published Version: | http://www.biologists.com/ |
Status: | Published |
Publisher: | Company of Biologists |
Identification Number: | 10.1242/bio.027896 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:120202 |