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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents



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ID: 732127.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread
Authors:Li, X.; Padhan, N.; Sjostrom, E. O.; Roche, F. P.; Testini, C.; Honkura, N.; Sainz-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.
Date of Publication (YYYY-MM-DD):2016-03-23
Title of Journal:Nat Commun
Volume:7
Start Page:11017
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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.
Free Keywords:Adherens Junctions; Animals; Antigens, CD/*metabolism; Cadherins/*metabolism; Capillary Permeability/*genetics; Edema; Endothelial Cells/*metabolism; Endothelium, Vascular/metabolism; Glioma/*pathology; Melanoma, Experimental/*pathology; Mice; Microspheres; Mutation; Neoplasm Metastasis/*genetics; Neoplasm Transplantation; Phosphorylation/genetics; Proto-Oncogene Proteins pp60(c-src)/*metabolism; Signal Transduction; Vascular Endothelial Growth Factor A/*metabolism; Vascular Endothelial Growth Factor Receptor-2/*genetics/metabolism
External Publication Status:published
Document Type:Article
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Centre for Computational Neuroscience and Robotics, University of Sussex, Chichester 1 CI 104, Brighton BN1 9RH, UK. c/o IFOM-IEO Campus, Via Adamello, 16, 20139 Milan, Italy. Department of Pathology, Dartmouth College, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA. Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Rontgenstrasse 20, 48149 Munster, Germany. Biomolecular Research, Molecular Cell Biology, Paul-Scherrer Institute, 5232 Villigen-PSI, Switzerland. Karolinska Institutet, Dept. Medical Biochemistry and Biophysics, Div. Vascular Biology, 17177 Stockholm, Sweden. Translational Cancer Research, Medicon Village, Lund University, Building 404:A3, 22381 Lund, Sweden. Department of Medical Cell Biology, Biomedical Center, Uppsala University, Box 571, 751 23 Uppsala, Sweden.
Identifiers:ISSN:2041-1723 (Electronic) 2041-1723 (Linking) %R 10.1... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/pubmed/27005951 [ID No:2]
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