VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

作者：Xiujuan Li, Narendra Padhan, Elisabet Ohlin Sjöström, Francis P. Roche, Chiara Testini, Naoki Honkura, Miguel Sáinz‐Jaspeado, Emma J. Gordon, Katie Bentley, Andrew O. Philippides, Vladimir Tolmachev, Elisabetta Dejana, Radu V. Stan, Dietmar Vestweber, Kurt Ballmer‐Hofer, Christer Betsholtz, Kristian Pietras, Leif E. Jansson, Lena Claesson‐Welsh · 发表于：Nature Communications · 年份：2016 · DOI：10.1038/ncomms11017 · 被引用次数：170 · 研究领域：Angiogenesis and VEGF in Cancer、Hippo pathway signaling and YAP/TAZ、Cancer, Hypoxia, and Metabolism

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.