VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 27005951.
- Also identified by DOI 10.1038/ncomms11017 and PMC identifier 4814575.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Antigens, CD
- Cadherins
- Capillary Permeability
- Endothelial Cells
- Glioma
- Melanoma, Experimental
- Neoplasm Metastasis
- Proto-Oncogene Proteins pp60(c-src)
- Vascular Endothelial Growth Factor A
- Vascular Endothelial Growth Factor Receptor-2