E-Cadherin Antagonizes Transforming Growth Factor β1 Gene Induction in Hepatic Stellate Cells by Inhibiting RhoA-Dependent Smad3 Phosphorylation

Cadherins mediate cell-cell adhesion and catenin (ctn)-related signaling pathways Liver fibrosis is accompanied by the loss of E-cadherin (ECAD), which promotes the process of epithelial-mesenchymal transition Currently, no information is available about the inhibitory role of ECAD in hepatic stellate cell activation Because of ECAD's potential for inhibiting the induction of transforming growth factor beta 1 (TGF beta 1), we investigated whether ECAD overexpression prevents TGF beta 1 gene induction, we also examined what the molecular basis could be Forced expression of ECAD decreased a-smooth muscle actin and vimentin levels and caused decreases in the constitutive and inducible expression of the TGF beta 1 gene and its downstream genes ECAD overexpression decreased Smad3 phosphorylation, weakly decreased Smad2 phosphorylation, and thus inhibited Smad reporter activity induced by either treatment with TGF beta 1 or Smad3 overexpression Overexpression of a dominant negative mutant of ras homolog gene family A (RhoA) diminished the ability of TGF beta 1 to elicit its own gene induction Consistently, transfection with a constitutively active mutant of RhoA reversed the inhibition of TGF beta 1-inducible or Smad3-inducible reporter activity by ECAD Studies using the mutant constructs of ECAD revealed that the p120-ctn binding domain of ECAD was responsible for TGF beta 1 repression Consistently, ECAD was capable of binding p120-ctn, which recruited RhoA, this prevented TGF beta 1 from increasing RhoA-mediated Smad3 phosphorylation In the liver samples of patients with mild or severe fibrosis, ECAD expression reciprocally correlated with the severity of fibrosis Conclusion Our results demonstrate that ECAD inhibits Smad3/2 phosphorylation by recruiting RhoA to p120-ctn at the p120-ctn binding domain, whereas the loss of ECAD due to cadherin switching promotes the up-regulation of TGF beta 1 and its target genes, and facilitates liver fibrosis (HEPATOLOGY 2010,52 2053-2064)