VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

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 and Lena Claesson-Welsh ()
Additional contact information
Xiujuan Li: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Narendra Padhan: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Elisabet O. Sjöström: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Francis P. Roche: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Chiara Testini: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Naoki Honkura: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Miguel Sáinz-Jaspeado: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Emma Gordon: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Katie Bentley: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Andrew Philippides: Centre for Computational Neuroscience and Robotics, University of Sussex
Vladimir Tolmachev: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Elisabetta Dejana: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Radu V. Stan: Dartmouth College, Geisel School of Medicine at Dartmouth
Dietmar Vestweber: Max Planck Institute for Molecular Biomedicine
Kurt Ballmer-Hofer: Biomolecular Research, Molecular Cell Biology, Paul-Scherrer Institute
Christer Betsholtz: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University
Kristian Pietras: Translational Cancer Research, Medicon Village, Lund University
Leif Jansson: Biomedical Center, Uppsala University
Lena Claesson-Welsh: Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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 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.

Date: 2016
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DOI: 10.1038/ncomms11017

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