Journal Article

VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

Pietras, Kristian, Stan, Radu V., Dejana, Elisabetta, Roche, Francis P., Philippides, Andrew, Tolmachev, Vladimir, Li, Xiujuan, Gordon, Emma, Testini, Chiara, Betsholtz, Christer, Vestweber, Dietmar, Bentley, Katie, Ballmer-Hofer, Kurt, Honkura, Naoki, Padhan, Narendra, Jansson, Leif, Sjöström, Elisabet O., Sáinz-Jaspeado, Miguel, Claesson-Welsh, Lena

2016

Overview

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. Signals through VEGF receptor 2 (VEGFR2) increase vascular permeability, promoting cancer progression. Here the authors show that a point mutation in VEGFR2 preventing its auto-phosphorylation leads to reduced metastatic spread and improved response to chemotherapy in tumor-bearing mice, without affecting tumor inflammation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/67/1059 / 631/67/322 / 631/80/79/2028 / 631/80/86 / Adherens Junctions / Animals / Antigens, CD - metabolism / Basic Medicine / Blood pressure / Cadherins - metabolism / Capillary Permeability - genetics / Cell and Molecular Biology / Cell- och molekylärbiologi / Edema / Endothelial Cells - metabolism / Endothelium, Vascular - metabolism / Glioma - pathology / Humanities and Social Sciences / Medical and Health Sciences / Medicin och hälsovetenskap / Medicinska och farmaceutiska grundvetenskaper / Melanoma, Experimental - pathology / Mice / Microspheres / multidisciplinary / Mutation / Neoplasm Metastasis - genetics / Neoplasm Transplantation / Phosphorylation - genetics / Proto-Oncogene Proteins pp60(c-src) - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Vascular Endothelial Growth Factor A - metabolism / Vascular Endothelial Growth Factor Receptor-2 - genetics / Vascular Endothelial Growth Factor Receptor-2 - metabolism