VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

Summary, in English

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 Vegfr2(Y949F/Y949F) leads to VEGFA-resistant endothelial adherens junctions and a block in molecular extravasation. Vessels in Vegfr2(Y949F/Y949F) mice remain sensitive to inflammatory cytokines, and vascular morphology, blood pressure and flow parameters are normal. Tumour-bearing Vegfr2(Y949F/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 VEGFA-induced 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.

• Author: Xiujuan Li; Narendra Padhan; Elisabet O Sjöström; Francis P Roche; Chiara Testini; Naoki Honkura; Miguel Sáinz-Jaspeado; Emma Gordon; Katie Bentley; Andrew Philippides; Vladimir Tolmachev; Elisabetta Dejana; Radu V Stan; Dietmar Vestweber; Kurt Ballmer-Hofer; Christer Betsholtz; Kristian Pietras; Leif Jansson; Lena Claesson-Welsh
• Department/s: Experimental oncology; Division of Translational Cancer Research; BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
• Publishing year: 2016-03-23
• Language: English
• Publication/Series: Nature Communications
• Volume: 7
• Links: http://dx.doi.org/10.1038/ncomms11017
• Document type: Journal article
• Publisher: Nature Publishing Group
• Topic: Cell and Molecular Biology
• Status: Published
• Research group: Experimental oncology
• ISBN/ISSN/Other: ISSN: 2041-1723