Autophagy links beta-catenin and Smad signaling to promote epithelial-mesenchymal transition via upregulation of integrin linked kinase

作者：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^*

来源：International Journal of Biochemistry & Cell Biology, 2016, 76: 123-134.

DOI：10.1016/j.biocel.2016.05.010

• TGF-beta 1
• Autophagy
• EMT
• Smad2
• beta-catenin
• ILK

TGF-beta 1 induces epithelial-mesenchymal transition (EMT) and autophagy in a variety of cells. However, the role of autophagy in TGF-beta 1-induced EMT has not been clearly elucidated and the underlying mechanisms are unclear. In the present study, we found that TGF-beta 1 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-beta 1-induced increase of vimentin and decreased E-cadherin expression. In contrast, rapamycin-associated enhancement of TGF-beta 1-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 beta-catenin at Y-654 leading to pY654-beta-cateninip-Smad2 complex formation. Chromatin immunoprecipitation assay demonstrated binding by the pY654-beta-cateninip-Smad2 complex to ILK promoter thus increasing ILK expression. Taken together, our results demonstrate that TGF-beta 1-induced autophagy links beta-catenin and Smad signaling to promote EMT in C1.1 cells through a novel pY654-13-catenin/p-Smad2/ILK pathway. The pathway delineated links disruption of E-cadherin/beta-catenin-mediated cell-cell contact to induction of EMT via upregulation of ILK.

• 出版日期2016-7
• 单位河北医科大学; 山西医科大学