VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
Open accessAbstract
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.
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Self-citationSALM4 regulates angiogenic functions in endothelial cells through VEGFR2 phosphorylation at Tyr1175
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- Authors
- Li, X., Padhan, N., Sjöström, E. O., Roche, F. P., Testini, C., Honkura, N., Sáinz-Jaspeado, M., Gordon, E., Bentley, K., Philippides, A., Tolmachev, V., Dejana, E., Stan, R. V., Vestweber, D., Ballmer-Hofer, K., Betsholtz, C., Pietras, K., Jansson, L., & Claesson-Welsh, L.
- Affiliations
- Uppsala University (SE)
- University of Sussex (GB)
- Dartmouth College (US)
- Max Planck Institute for Molecular Biomedicine (DE)
- Lund University (SE)
- ORCID
- Venue
- Nature Communications
- Published
- 2016-03-23
- Volume
- 7
- Issue
- 1
- Pages
- 11017-11017
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4814575
- OpenAlex
- W2306875942
- Cited by
- 149
- References
- 49
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 19 · 2023: 13 · 2022: 19 · 2021: 8 · 2020: 14 · 2019: 20 · 2018: 14 · 2017: 13 · 2016: 10
- FWCI
- 9.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DORA PSI (Paul Scherrer Institute) (submittedVersion, cc-by)
- Sussex Research Online (University of Sussex) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Uppsala University Publications (Uppsala University) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Research Portal (King's College London) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Science Foundation
- Fondation Leducq
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A, 130463)
- Cancerfonden (130463)
- Knut och Alice Wallenbergs Stiftelse
- Oncosuisse
- Science for Life Laboratory
- Uppsala Multidisciplinary Center for Advanced Computational Science
- National Cancer Institute (CA175592, R21CA172983, CA172983, R21CA175592)
- FP7 Ideas: European Research Council (294556)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- VEGFR2, VEGF-A, vascular leakage, endothelial adherens junctions, VE-cadherin, Src kinase, metastasis, chemotherapy response, tumor microenvironment, inflammatory cytokines
- MeSH terms
- Cadherin 5, Animals, Capillary Permeability, Edema, Endothelium, Vascular, Glioma, Melanoma, Experimental, Microspheres, Mutation, Neoplasm Metastasis, Neoplasm Transplantation, Phosphorylation, Signal Transduction, Antigens, CD, Cadherins, Proto-Oncogene Proteins pp60(c-src), Adherens Junctions, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Endothelial Cells, Mice
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