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VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

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
Publishing year: 2016-03-23
Language: English
Publication/Series: Nature Communications
Volume: 7
Document type: Journal article
Publisher: Nature Publishing Group

Abstract 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.

Keywords

  • Cell and Molecular Biology

Other

Published
  • Experimental oncology
  • ISSN: 2041-1723
Kristian Pietras
E-mail: kristian [dot] pietras [at] med [dot] lu [dot] se

Professor

Division of Translational Cancer Research

+46 46 222 64 29

MV404 A31B1

90

Project manager

Experimental oncology