ncomms11017.pdf (4.79 MB)
VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
journal contribution
posted on 2023-06-09, 00:58 authored by Xiujuan Li, Narendra Padhan, Elisabet O Sjöström, Francis P Roche, Chiara Testini, Naoki Honkura, Miguel Sáinz-Jaspeado, Emma Gordon, Katie Bentley, Andy PhilippidesAndy Philippides, Vladimir Tolmachev, Elisabetta Dejana, Radu V Stan, Dietmar Vestweber, Kurt Ballmer-Hofer, Christer Betsholtz, Kristian Pietras, Leif Jansson, Lena Claesson-WelshThe 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 VEGFAinduced 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.
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- Published
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- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Nature Publishing GroupExternal DOI
Issue
1Volume
7Article number
a11017Department affiliated with
- Informatics Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2016-04-19First Open Access (FOA) Date
2016-04-19First Compliant Deposit (FCD) Date
2016-04-19Usage metrics
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