Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function

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 angiog...
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Autor*in:	Gina A. Smith [verfasserIn] Gareth W. Fearnley [verfasserIn] Izma Abdul-Zani [verfasserIn] Stephen B. Wheatcroft [verfasserIn] Darren C. Tomlinson [verfasserIn] Michael A. Harrison [verfasserIn] Sreenivasan Ponnambalam [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	Endothelial VEGF-A VEGFR2 UBA1 Ubiquitination Signal transduction Angiogenesis

Übergeordnetes Werk:	In: Biology Open - The Company of Biologists, 2012, 6(2017), 10, Seite 1404-1415
Übergeordnetes Werk:	volume:6 ; year:2017 ; number:10 ; pages:1404-1415

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1242/bio.027896

Katalog-ID:	DOAJ068689268

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authorswithroles_txt_mv	Gina A. Smith @@aut@@ Gareth W. Fearnley @@aut@@ Izma Abdul-Zani @@aut@@ Stephen B. Wheatcroft @@aut@@ Darren C. Tomlinson @@aut@@ Michael A. Harrison @@aut@@ Sreenivasan Ponnambalam @@aut@@
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callnumber-first	Q - Science
author	Gina A. Smith
spellingShingle	Gina A. Smith misc QH301-705.5 misc Endothelial misc VEGF-A misc VEGFR2 misc UBA1 misc Ubiquitination misc Signal transduction misc Angiogenesis misc Science misc Q misc Biology (General) Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function
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topic_title	QH301-705.5 Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function Endothelial VEGF-A VEGFR2 UBA1 Ubiquitination Signal transduction Angiogenesis
topic	misc QH301-705.5 misc Endothelial misc VEGF-A misc VEGFR2 misc UBA1 misc Ubiquitination misc Signal transduction misc Angiogenesis misc Science misc Q misc Biology (General)
topic_unstemmed	misc QH301-705.5 misc Endothelial misc VEGF-A misc VEGFR2 misc UBA1 misc Ubiquitination misc Signal transduction misc Angiogenesis misc Science misc Q misc Biology (General)
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title	Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function
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title_full	Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function
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author_browse	Gina A. Smith Gareth W. Fearnley Izma Abdul-Zani Stephen B. Wheatcroft Darren C. Tomlinson Michael A. Harrison Sreenivasan Ponnambalam
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title_sort	ubiquitination of basal vegfr2 regulates signal transduction and endothelial function
callnumber	QH301-705.5
title_auth	Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function
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.
abstractGer	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.
abstract_unstemmed	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.
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title_short	Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function
url	https://doi.org/10.1242/bio.027896 https://doaj.org/article/0083afd86eff426b9d979f5c7df686ce http://bio.biologists.org/content/6/10/1404 https://doaj.org/toc/2046-6390
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author2	Gareth W. Fearnley Izma Abdul-Zani Stephen B. Wheatcroft Darren C. Tomlinson Michael A. Harrison Sreenivasan Ponnambalam
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Ubiquitination of basal VEGFR2 regulates signal transduction and endothelial function

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