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E‐cadherin antagonizes TGFbeta1 gene induction in hepatic stellate cells by inhibiting RhoA‐dependent Smad3/2 phosphorylation
Author(s) -
Kim Sang Geon,
Cho Je,
Kim Young Woo
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.946.3
Subject(s) - rhoa , cadherin , hepatic stellate cell , phosphorylation , transforming growth factor , microbiology and biotechnology , smad , epithelial–mesenchymal transition , fibrosis , cancer research , signal transduction , chemistry , biology , downregulation and upregulation , gene , cell , medicine , endocrinology , biochemistry
Cadherins mediate cell‐cell adhesion and catenin (ctn)‐related signaling pathways. Liver fibrosis is accompanied by the loss of E‐cadherin that promotes the process of epithelial mesenchymal transition. This study investigated whether E‐cadherin overexpression inhibits transforming growth factor‐beta1 (TGFbeta1) gene induction and, if so, what molecular basis. Forced expression of E‐cadherin decreased the level of mesenchymal markers, and the constitutive or inducible expression of the TGFbeta1 gene and its downstream genes. E‐cadherin overexpression decreased Smad3/2 phosphorylations, and consequent its transcriptional activity. The ability of E‐cadherin to inhibit TGFbeta1‐inducible Smad activity was reversed by RhoA activation. Molecular approaches revealed that the p120‐ctn binding domain of E‐cadherin was responsible for TGFbeta1 repression. E‐cadherin was capable of binding p120‐ctn, which recruited RhoA, preventing the ability of TGFbeta1 to increase RhoA‐mediated Smad3 phosphorylation. In the liver tissues of patients with liver fibrosis, E‐cadherin expression reciprocally correlated with the severity of fibrosis. In conclusion, E‐cadherin inhibits Smad3/2 phosphorylations by recruiting RhoA to p120‐ctn, supporting the notion that the loss of E‐cadherin due to cadherin switch promotes TGFbeta1 and target gene induction, and facilitates liver fibrosis.