title: VEGF-induced vascular permeability is mediated by FAK.
abstract: Endothelial cells (ECs) form cell-cell adhesive junctional structures maintaining vascular integrity. This barrier is dynamically regulated by vascular endothelial growth factor (VEGF) receptor signaling. We created an inducible knockin mouse model to study the contribution of the integrin-associated focal adhesion tyrosine kinase (FAK) signaling on vascular function. Here we show that genetic or pharmacological FAK inhibition in ECs prevents VEGF-stimulated permeability downstream of VEGF receptor or Src tyrosine kinase activation in vivo. VEGF promotes tension-independent FAK activation, rapid FAK localization to cell-cell junctions, binding of the FAK FERM domain to the vascular endothelial cadherin (VE-cadherin) cytoplasmic tail, and direct FAK phosphorylation of β-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-β-catenin dissociation and EC junctional breakdown. Kinase inhibited FAK is in a closed conformation that prevents VE-cadherin association and limits VEGF-stimulated β-catenin Y142 phosphorylation. Our studies establish a role for FAK as an essential signaling switch within ECs regulating adherens junction dynamics.
authors.affiliation: Department of Reproductive Medicine, Moores UCSD Cancer Center, La Jolla, CA 92093, USA.
authors.forename: Xiao Lei
authors.initials: XL
authors.lastname: Chen
authors.forename: Ju-Ock
authors.initials: JO
authors.lastname: Nam
authors.forename: Christine
authors.initials: C
authors.lastname: Jean
authors.forename: Christine
authors.initials: C
authors.lastname: Lawson
authors.forename: Colin T
authors.initials: CT
authors.lastname: Walsh
authors.forename: Erik
authors.initials: E
authors.lastname: Goka
authors.forename: Ssang-Taek
authors.initials: ST
authors.lastname: Lim
authors.forename: Alok
authors.initials: A
authors.lastname: Tomar
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tancioni
authors.forename: Sean
authors.initials: S
authors.lastname: Uryu
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Guan
authors.forename: Lisette M
authors.initials: LM
authors.lastname: Acevedo
authors.forename: Sara M
authors.initials: SM
authors.lastname: Weis
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
authors.forename: David D
authors.initials: DD
authors.lastname: Schlaepfer
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000502:physiology*; D002448:Cell Adhesion; D002450:Cell Communication; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000502:physiology*; D022001:Focal Adhesions / Q000502:physiology; D006321:Heart / Q000502:physiology; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051417:Focal Adhesion Kinase 1; D019426:Integrases; D014443:Tyrosine; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D019061:src-Family Kinases; D000099152:Cadherin 5; C467480:vascular endothelial growth factor A, mouse; C496051:Ptk2 protein, mouse; C045073:Cre recombinase