VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

Li, Xiujuan, Padhan, Narendra, Sjöström, Elisabet O, Roche, Francis P, Testini, Chiara, Honkura, Naoki, Sáinz-Jaspeado, Miguel, Gordon, Emma, Bentley, Katie, Philippides, Andrew, Tolmachev, Vladimir, Dejana, Elisabetta, Stan, Radu V, Vestweber, Dietmar, Ballmer-Hofer, Kurt, Betsholtz, Christer, Pietras, Kristian, Jansson, Leif and Claesson-Welsh, Lena (2016) VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications, 7. p. 11017. ISSN 2041-1723

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Abstract

The specific role of VEGFA-induced permeability and vascular leakage in physiology and pathology has remained unclear. Here we show that VEGFA-induced vascular leakage depends on signalling initiated via the VEGFR2 phosphosite Y949, regulating dynamic c-Src and VE-cadherin phosphorylation. Abolished Y949 signalling in the mouse mutant Vegfr2Y949F/Y949F leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2Y949F/Y949F mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2Y949F/Y949F mice display reduced vascular leakage and oedema, improved response to chemotherapy and, importantly, reduced metastatic spread. The inflammatory infiltration in the tumour micro-environment is unaffected. Blocking VEGFAinduced disassembly of endothelial junctions, thereby suppressing tumour oedema and metastatic spread, may be preferable to full vascular suppression in the treatment of certain cancer forms.

Item Type: Article
Schools and Departments: School of Engineering and Informatics > Informatics
Depositing User: Catrina Hey
Date Deposited: 19 Apr 2016 14:54
Last Modified: 07 Mar 2017 09:19
URI: http://sro.sussex.ac.uk/id/eprint/60546

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