Cited by 149Angiogenesis and VEGF in CancerLymphatic System and DiseasesBarrier Structure and Function Studies

VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread

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Li, Xiujuan, Padhan, Narendra, Sjöström, Elisabet O., Roche, Francis P., Testini, Chiara, Honkura, Naoki, Sáinz-Jaspeado, Miguel, Gordon, Emma +11 more·2016·Nature Communications

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 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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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)
Venue
Nature Communications
Published
2016-03-23
Volume
7
Issue
1
Pages
11017-11017
ISSN
2041-1723 (ISSN-L)
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
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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