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

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.

Mammalian autophagy and the plasma membrane

“…Focal adhesion disassembly is mediated by autophagy by increased paxillin degradation through either (4a) direct paxillin‐ NBR 1 interaction or (4b) direct paxillin‐ LC 3 interaction upon Src activation . Autophagy upregulation also degrades (5) tight junction proteins (claudin2) and (6) adherens junctions proteins (E‐cadherins) through yet unclarified routes. Autophagy inhibition increases the levels of p62 which stabilize Twist1 in the nucleus to transcriptionally repress E‐cadherin expression .…”

miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1

“…Autophagy is closely related to tumor metastasis, EMT, apoptosis and drug resistance (49–51). For instance, autophagy was able to degrade the epithelial marker E-cadherin and promoted EMT of tumors (52,53). Inhibition of autophagy could promote apoptosis of tumor cells (54).…”

LncRNA ENST00000453774.1 contributes to oxidative stress defense dependent on autophagy mediation to reduce extracellular matrix and alleviate renal fibrosis

“…Renal interstitial fibrosis is an inevitable outcome of all causes of progressive chronic kidney disease (CKD). EMT (Pang et al, ), chronic inflammation (Xiao et al, ), oxidative stress (Qin et al, ), and autophagy (Kawaoka et al, ) are reported to be key mechanisms in the pathogenesis and progression of renal interstitial fibrosis. To study renal fibrosis in vivo and in vitro, UUO and TGF‐β‐induced HK‐2 cells are regarded as classical experimental animal and cell models respectively.…”

“…Renal interstitial fibrosis is an inevitable outcome of all causes of progressive chronic kidney disease (CKD). EMT (Pang et al, 2016), chronic inflammation (Xiao et al, 2017), oxidative stress (Qin et al, 2016), and autophagy (Kawaoka et al, 2016) are reported to be key mechanisms in the pathogenesis and progression of renal interstitial fibrosis. To study renal fibrosis in vivo and in vitro, UUO and To preliminarily explore which aspects of LncRNA 74.1 exactly exerted its functional role, the markers of inflammation (IL-6, TNF-α, MCP-1), EMT (α-SMA, E-cadherin, and vimentin), oxidative stress resistance (NQO1, HO-1) and autophagy (Atg5, Atg7, and becilin 1) were all detected in LncRNA 74.1 gain-of-function HK-2 cells with or without TGF-β treatment.…”