VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis

Biology Open

卷:5

Darren C. Tomlinson¹  Ian C. Zachary²  Gareth W. Fearnley³  Nadeem A. Mughal³  Izma Abdul-Zani³  Sreenivasan Ponnambalam³  Gina A. Smith³  Mark T. Kearney⁴  Nadira Yuldasheva⁴  Stephen B. Wheatcroft⁴  Shervanthi Homer-Vanniasinkam⁵  Michael A. Harrison⁶ 

[1] Biomedical Health Research Centre, Astbury Building, University of Leeds, Leeds LS2 9JT, UK;

[2] Centre for Cardiovascular Biology and Medicine, Division of Medicine, University College London, London WC1E 6BT, UK;

[3] Endothelial Cell Biology Unit, School of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, UK;

[4] Leeds Institute of Cardiovascular Metabolism and Medicine, LIGHT Laboratories, University of Leeds, Leeds LS2 9JT, UK;

[5] Leeds Vascular Institute, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK;

[6] School of Biomedical Sciences, University of Leeds, Leeds LS2 9JT, UK;

关键词: VEGF-A;    VEGFR2;    Endothelial;    Trafficking;   

DOI  :  10.1242/bio.017434

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown