VEGF-induced vascular permeability is mediated by FAK.
Dev Cell
; 22(1): 146-57, 2012 Jan 17.
Article
en En
| MEDLINE
| ID: mdl-22264731
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 ß-catenin at tyrosine-142 (Y142) facilitating VE-cadherin-ß-catenin dissociation and EC junctional breakdown. Kinase inhibited FAK is in a closed conformation that prevents VE-cadherin association and limits VEGF-stimulated ß-catenin Y142 phosphorylation. Our studies establish a role for FAK as an essential signaling switch within ECs regulating adherens junction dynamics.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Permeabilidad Capilar
/
Endotelio Vascular
/
Movimiento Celular
/
Neovascularización Fisiológica
/
Factor A de Crecimiento Endotelial Vascular
/
Quinasa 1 de Adhesión Focal
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Dev Cell
Asunto de la revista:
EMBRIOLOGIA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos