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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >E-cadherin antagonizes transforming growth factor beta1 gene induction in hepatic stellate cells by inhibiting RhoA-dependent Smad3 phosphorylation.
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E-cadherin antagonizes transforming growth factor beta1 gene induction in hepatic stellate cells by inhibiting RhoA-dependent Smad3 phosphorylation.

机译：E-钙黏着蛋白通过抑制RhoA依赖性Smad3磷酸化来拮抗肝星状细胞中的转化生长因子beta1基因诱导。

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摘要

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 beta1 (TGFbeta1), we investigated whether ECAD overexpression prevents TGFbeta1 gene induction; we also examined what the molecular basis could be. Forced expression of ECAD decreased alpha-smooth muscle actin and vimentin levels and caused decreases in the constitutive and inducible expression of the TGFbeta1 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 TGFbeta1 or Smad3 overexpression. Overexpression of a dominant negative mutant of ras homolog gene family A (RhoA) diminished the ability of TGFbeta1 to elicit its own gene induction. Consistently, transfection with a constitutively active mutant of RhoA reversed the inhibition of TGFbeta1-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 TGFbeta1 repression. Consistently, ECAD was capable of binding p120-ctn, which recruited RhoA; this prevented TGFbeta1 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 TGFbeta1 and its target genes, and facilitates liver fibrosis.
机译：钙黏着蛋白介导细胞间粘附和连环蛋白（ctn）相关的信号通路。肝纤维化伴有E-钙粘蛋白（ECAD）的丢失，这促进了上皮-间质转化的过程。目前，尚无关于ECAD在肝星状细胞激活中的抑制作用的信息。由于ECAD具有抑制转化生长因子beta1（TGFbeta1）诱导的潜力，因此我们研究了ECAD是否过表达阻止TGFbeta1基因诱导。我们还研究了分子基础是什么。 ECAD的强迫表达降低了α平滑肌肌动蛋白和波形蛋白的水平，并导致TGFbeta1基因及其下游基因的组成型和诱导型表达下降。 ECAD过表达降低了Smad3的磷酸化，弱地降低了Smad2的磷酸化，因此抑制了用TGFbeta1或Smad3过表达处理诱导的Smad报告基因活性。 ras同源基因家族A（RhoA）的显性负突变体的过表达减少了TGFbeta1引发其自身基因诱导的能力。一致地，用RhoA的组成型活性突变体转染可逆转ECAD对TGFbeta1诱导型或Smad3诱导的报告基因活性的抑制作用。使用ECAD的突变体构建物进行的研究表明，ECAD的p120-ctn结合域负责TGFbeta1的抑制。一致地，ECAD能够结合p120-ctn，从而招募了RhoA。这阻止了TGFbeta1增加RhoA介导的Smad3磷酸化。在轻度或重度纤维化患者的肝样本中，ECAD表达与纤维化的严重程度呈正相关。结论：我们的结果表明，ECAD通过在p120-ctn结合域将RhoA募集到p120-ctn来抑制Smad3 / 2磷酸化，而由于钙黏着蛋白转换导致的ECAD丢失促进TGFbeta1及其靶基因的上调，并促进肝纤维化。

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