Autophagy links β-catenin and Smad signaling to promote epithelial-mesenchymal transition via upregulation of integrin linked kinase. (July 2016)

• Record Type: Journal Article
• Authors: Pang, Min; Wang, Hailong; Rao, Padmashree; Zhao, Ye; Xie, Jun; Cao, Qi; Wang, Yiping; Wang, Yuan Min; Lee, Vincent W.; Alexander, Stephen I.; Harris, David C.H.; Zheng, Guoping
• Is Part Of: International journal of biochemistry & cell biology. Volume 76(2016:Jul.)
• Page Start: 123
• Page End: 134
• Publication Date: 2016-07
• Subjects: TGF-β1 -- Autophagy -- EMT -- Smad2 -- β-catenin -- ILK; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2016.05.010
• Languages: English
• ISSNs: 1357-2725

Abstract

Highlights: TGF-β1 induces both autophagy and epithelial mesenchymal transition (EMT). Inhibition of autophagy reverses EMT. Autophagic disruption of E-cadherin/β-catenin promotes EMT by pY654-β-catenin/p-Smad2-mediated upregulation of ILK. Abstract: TGF-β1 induces epithelial-mesenchymal transition (EMT) and autophagy in a variety of cells. However, the role of autophagy in TGF-β1-induced EMT has not been clearly elucidated and the underlying mechanisms are unclear. In the present study, we found that TGF-β1 induced both autophagy and EMT in mouse tubular epithelial C1.1 cells. Inhibition of autophagy by 3-methyladenine or siRNA knockdown of Beclin 1 reduced TGF-β1-induced increase of vimentin and decreased E-cadherin expression. In contrast, rapamycin-associated enhancement of TGF-β1-induced autophagy increased EMT of C1.1 cells. Serum rescue inhibited autophagy followed by reversal of EMT. Blocking of autophagosome-lysosomal but not proteosomal degradation reduced the decrease of E-cadherin, demonstrating a role for autophagy in degradation of E-cadherin during EMT. Autophagy promoted the activation of Src and Src-associated phosphorylation of β-catenin at Y-654 leading to pY654-β-catenin/p-Smad2 complex formation. Chromatin immunoprecipitation assay demonstrated binding by the pY654-β-catenin/p-Smad2 complex to ILK promoter thus increasing ILK expression. Taken together, our results demonstrate that TGF-β1-induced autophagy links β-catenin and Smad signaling to promote EMT in C1.1 cells through a novel pY654-β-catenin/p-Smad2/ILK pathway. The pathway delineated links disruption of E-cadherin/β-catenin-mediated cell–cell contact to induction of EMT via upregulation of ILK.