VE-cadherin is a critical endothelial regulator of TGF-beta signalling

EMBO J. 2008 Apr 9;27(7):993-1004. doi: 10.1038/emboj.2008.46. Epub 2008 Mar 13.

Abstract

VE-cadherin is an endothelial-specific transmembrane protein concentrated at cell-to-cell adherens junctions. Besides promoting cell adhesion and controlling vascular permeability, VE-cadherin transfers intracellular signals that contribute to vascular stabilization. However, the molecular mechanism by which VE-cadherin regulates vascular homoeostasis is still poorly understood. Here, we report that VE-cadherin expression and junctional clustering are required for optimal transforming growth factor-beta (TGF-beta) signalling in endothelial cells (ECs). TGF-beta antiproliferative and antimigratory responses are increased in the presence of VE-cadherin. ECs lacking VE-cadherin are less responsive to TGF-beta/ALK1- and TGF-beta/ALK5-induced Smad phosphorylation and target gene transcription. VE-cadherin coimmunoprecipitates with all the components of the TGF-beta receptor complex, TbetaRII, ALK1, ALK5 and endoglin. Clustered VE-cadherin recruits TbetaRII and may promote TGF-beta signalling by enhancing TbetaRII/TbetaRI assembly into an active receptor complex. Taken together, our data indicate that VE-cadherin is a positive and EC-specific regulator of TGF-beta signalling. This suggests that reduction or inactivation of VE-cadherin may contribute to progression of diseases where TGF-beta signalling is impaired.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type II / metabolism
  • Allantois / cytology
  • Allantois / drug effects
  • Allantois / metabolism
  • Animals
  • Antigens, CD / metabolism*
  • Cadherins / deficiency
  • Cadherins / metabolism*
  • Cell Movement / drug effects
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Proliferation / drug effects
  • Dimerization
  • Embryo, Mammalian / cytology
  • Embryo, Mammalian / drug effects
  • Embryo, Mammalian / metabolism
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Humans
  • Kinetics
  • Mice
  • Models, Biological
  • Phosphorylation / drug effects
  • Protein Binding / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction / drug effects*
  • Smad2 Protein / metabolism
  • Smad3 Protein / metabolism
  • Transcription, Genetic / drug effects
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Antigens, CD
  • Cadherins
  • Receptors, Transforming Growth Factor beta
  • Smad2 Protein
  • Smad3 Protein
  • Transforming Growth Factor beta
  • cadherin 5
  • Protein-Serine-Threonine Kinases
  • ACVRL1 protein, human
  • Activin Receptors, Type II
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptor, Transforming Growth Factor-beta Type II
  • TGFBR1 protein, human
  • Tgfbr1 protein, mouse