VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.
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.
['Fearnley|Gareth W|GW|', 'Smith|Gina A|GA|', 'Abdul-Zani|Izma|I|', 'Yuldasheva|Nadira|N|', 'Mughal|Nadeem A|NA|', 'Homer-Vanniasinkam|Shervanthi|S|', 'Kearney|Mark T|MT|', 'Zachary|Ian C|IC|', 'Tomlinson|Darren C|DC|', 'Harrison|Michael A|MA|', 'Wheatcroft|Stephen B|SB|', 'Ponnambalam|Sreenivasan|S|']
VEGF-A VEGFR2 Trafficking Endothelial