Phosphorylation of VE-cadherin controls endothelial phenotypes via p120-catenin coupling and Rac1 activation

Am J Physiol Heart Circ Physiol. 2011 Jan;300(1):H162-72. doi: 10.1152/ajpheart.00650.2010. Epub 2010 Oct 29.

Abstract

To establish the role of vascular endothelial (VE)-cadherin in the regulation of endothelial cell functions, we investigated the effect of phosphorylation of a VE-cadherin site sought to be involved in p120-catenin binding on vascular permeability and endothelial cell migration. To this end, we introduced either wild-type VE-cadherin or Y658 phosphomimetic (Y658E) or dephosphomimetic (Y658F) VE-cadherin mutant constructs into an endothelial cell line (rat fat pad endothelial cells) lacking endogenous VE-cadherin. Remarkably, neither wild-type- nor Y658E VE-cadherin was retained at cell-cell contacts because of p120-catenin preferential binding to N-cadherin, resulting in the targeting of N-cadherin to cell-cell junctions and the exclusion of VE-cadherin. However, Y658F VE-cadherin was able to bind p120-catenin and to localize at adherence junctions displacing N-cadherin. This resulted in an enhanced barrier function and a complete abrogation of Rac1 activation and lamellipodia formation, thereby inhibiting cell migration. These findings demonstrate that VE-cadherin, through the regulation of Y658 phosphorylation, competes for junctional localization with N-cadherin and controls vascular permeability and endothelial cell migration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / metabolism
  • Animals
  • Antigens, CD / metabolism*
  • Blotting, Western
  • Cadherins / metabolism*
  • Capillary Permeability / physiology
  • Catenins / metabolism*
  • Cell Adhesion / physiology
  • Cell Line
  • Cell Movement / physiology
  • Cells, Cultured
  • Delta Catenin
  • Endothelial Cells / cytology
  • Endothelial Cells / metabolism*
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Fluorescent Antibody Technique
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Phosphorylation
  • RNA Interference
  • Rats
  • Signal Transduction
  • Umbilical Veins / cytology
  • Umbilical Veins / metabolism
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • Antigens, CD
  • Cadherins
  • Catenins
  • cadherin 5
  • rac1 GTP-Binding Protein
  • Delta Catenin