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Nat Commun. 2016 Mar 23;7:11017. doi: 10.1038/ncomms11017.

VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread.

Author information

1
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
2
Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
3
Centre for Computational Neuroscience and Robotics, University of Sussex, Chichester 1 CI 104, Brighton BN1 9RH, UK.
4
c/o IFOM-IEO Campus, Via Adamello, 16, 20139 Milan, Italy.
5
Department of Pathology, Dartmouth College, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
6
Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
7
Biomolecular Research, Molecular Cell Biology, Paul-Scherrer Institute, 5232 Villigen-PSI, Switzerland.
8
Karolinska Institutet, Dept. Medical Biochemistry and Biophysics, Div. Vascular Biology, 17177 Stockholm, Sweden.
9
Translational Cancer Research, Medicon Village, Lund University, Building 404:A3, 22381 Lund, Sweden.
10
Department of Medical Cell Biology, Biomedical Center, Uppsala University, Box 571, 751 23 Uppsala, Sweden.

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 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.

PMID:
27005951
PMCID:
PMC4814575
DOI:
10.1038/ncomms11017
[Indexed for MEDLINE]
Free PMC Article
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