title: VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread.
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.
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Xiujuan
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Narendra
authors.initials: N
authors.lastname: Padhan
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Elisabet O
authors.initials: EO
authors.lastname: Sjöström
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Francis P
authors.initials: FP
authors.lastname: Roche
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Chiara
authors.initials: C
authors.lastname: Testini
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Naoki
authors.initials: N
authors.lastname: Honkura
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Miguel
authors.initials: M
authors.lastname: Sáinz-Jaspeado
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Gordon
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.|Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Bentley
authors.affiliation: Centre for Computational Neuroscience and Robotics, University of Sussex, Chichester 1 CI 104, Brighton BN1 9RH, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Philippides
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Tolmachev
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.|c/o IFOM-IEO Campus, Via Adamello, 16, 20139 Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
authors.affiliation: Department of Pathology, Dartmouth College, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.
authors.forename: Radu V
authors.identifier: http://orcid.org/0000-0003-2969-1725
authors.initials: RV
authors.lastname: Stan
authors.affiliation: Department of Vascular Cell Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstraße 20, 48149 Münster, Germany.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.affiliation: Biomolecular Research, Molecular Cell Biology, Paul-Scherrer Institute, 5232 Villigen-PSI, Switzerland.
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer-Hofer
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.|Karolinska Institutet, Dept. Medical Biochemistry and Biophysics, Div. Vascular Biology, 17177 Stockholm, Sweden.
authors.forename: Christer
authors.initials: C
authors.lastname: Betsholtz
authors.affiliation: Translational Cancer Research, Medicon Village, Lund University, Building 404:A3, 22381 Lund, Sweden.
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
authors.affiliation: Department of Medical Cell Biology, Biomedical Center, Uppsala University, Box 571, 751 23 Uppsala, Sweden.
authors.forename: Leif
authors.initials: L
authors.lastname: Jansson
authors.affiliation: Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Science for Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
authors.forename: Lena
authors.initials: L
authors.lastname: Claesson-Welsh
mesh_terms: D022005:Adherens Junctions; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability / Q000235:genetics*; D004487:Edema; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D005910:Glioma / Q000473:pathology*; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008863:Microspheres; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics*; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000235:genetics; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics* / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D016392:Proto-Oncogene Proteins pp60(c-src); D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C000592875:Kdr protein, mouse