Journal
BIOLOGY OPEN
Volume 5, Issue 5, Pages 571-583Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/bio.017434
Keywords
VEGF-A; VEGFR2; Endothelial; Trafficking
Categories
Funding
- Heart Research UK [TRP11/11]
- Brunei Government
- British Heart Foundation [FS/12/20/29462, PG/14/54/30939]
- Circulation Foundation George Davies Surgeon Scientist Award
- BHF [RG/15/7/31521, RG/11/11/29050]
- European Research Council [ERC-2012-StG 310747-BP-CarDiO]
- MRC [MR/L009625/1] Funding Source: UKRI
- British Heart Foundation [FS/12/71/29747, RG/09/010/28087, RG/11/11/29050, RG/06/003/21131, PG/12/56/29748, FS/12/20/29462, PG/14/54/30939] Funding Source: researchfish
- Medical Research Council [MR/L009625/1] Funding Source: researchfish
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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-A(165), VEGF-A(121) and VEGF-A(145)) 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.
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