title: VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.
abstract: Vascular endothelial growth factor A (VEGF-A) binding to the receptor tyrosine kinase VEGFR2 triggers multiple signal transduction pathways, which regulate endothelial cell responses that control vascular development. Multiple isoforms of VEGF-A can elicit differential signal transduction and endothelial responses. However, it is unclear how such cellular responses are controlled by isoform-specific VEGF-A-VEGFR2 complexes. Increasingly, there is the realization that the membrane trafficking of receptor-ligand complexes influences signal transduction and protein turnover. By building on these concepts, our study shows for the first time that three different VEGF-A isoforms (VEGF-A165, VEGF-A121 and VEGF-A145) promote distinct patterns of VEGFR2 endocytosis for delivery into early endosomes. This differential VEGFR2 endocytosis and trafficking is linked to VEGF-A isoform-specific signal transduction events. Disruption of clathrin-dependent endocytosis blocked VEGF-A isoform-specific VEGFR2 activation, signal transduction and caused substantial depletion in membrane-bound VEGFR1 and VEGFR2 levels. Furthermore, such VEGF-A isoforms promoted differential patterns of VEGFR2 ubiquitylation, proteolysis and terminal degradation. Our study now provides novel insights into how different VEGF-A isoforms can bind the same receptor tyrosine kinase and elicit diverse cellular outcomes.
authors.affiliation: Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Fearnley
authors.affiliation: Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Gina A
authors.initials: GA
authors.lastname: Smith
authors.affiliation: Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Izma
authors.initials: I
authors.lastname: Abdul-Zani
authors.affiliation: Leeds Institute of Cardiovascular Metabolism and Medicine, LIGHT Laboratories, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Nadira
authors.initials: N
authors.lastname: Yuldasheva
authors.affiliation: Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Nadeem A
authors.initials: NA
authors.lastname: Mughal
authors.affiliation: Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK.
authors.forename: Shervanthi
authors.initials: S
authors.lastname: Homer-Vanniasinkam
authors.affiliation: Leeds Institute of Cardiovascular Metabolism and Medicine, LIGHT Laboratories, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Kearney
authors.affiliation: Centre for Cardiovascular Biology and Medicine, Division of Medicine, University College London, London WC1E 6BT, UK.
authors.forename: Ian C
authors.initials: IC
authors.lastname: Zachary
authors.affiliation: Biomedical Health Research Centre, Astbury Building, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Darren C
authors.initials: DC
authors.lastname: Tomlinson
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Harrison
authors.affiliation: Leeds Institute of Cardiovascular Metabolism and Medicine, LIGHT Laboratories, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Wheatcroft
authors.affiliation: Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK s.ponnambalam@leeds.ac.uk.
authors.forename: Sreenivasan
authors.initials: S
authors.lastname: Ponnambalam
keywords: Endothelial; Trafficking; VEGF-A; VEGFR2