Open AccessFHL 2 promotes tubular epithelial‐to‐mesenchymal transition through modulating β‐catenin signalling
Author(s) -
Cai Ting,
Sun Danqin,
Duan Ying,
Qiu Yumei,
Dai Chunsun,
Yang Junwei,
He Weichun
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13446
Subject(s) - gene knockdown , epithelial–mesenchymal transition , microbiology and biotechnology , catenin , fibronectin , chemistry , smad , phosphorylation , biology , signal transduction , cancer research , extracellular matrix , downregulation and upregulation , cell culture , gene , wnt signaling pathway , biochemistry , genetics
Abstract β‐Catenin signalling plays an important role in regulating tubular epithelial‐to‐mesenchymal transition ( EMT ), an indispensable programme for driving renal fibrosis. As an adapter protein, four and a half LIM domain protein 2 ( FHL 2) acts as a coregulator of β‐catenin in several other cell types. To determine whether FHL 2 affects β‐catenin signalling and thus is involved in tubular EMT , we examined its expression and function in the process of TGF ‐β1‐induced EMT . FHL 2 mRNA and protein were induced by TGF ‐β1 in rat tubular epithelial cells ( NRK ‐52E), an effect that intracellular Smad signalling was required. Ectopic expression of FHL 2 inhibited E‐cadherin and enhanced α‐smooth muscle actin (α‐ SMA ) and fibronectin expression, whereas knockdown of FHL 2 partially restored E‐cadherin and reduced α‐ SMA and fibronectin induction stimulated by TGF ‐β1. Overexpression of FHL 2 increased β‐catenin dephosphorylation (Ser37/Thr41), nuclear translocation and β‐catenin‐mediated transcription and up‐regulated expression of β‐catenin target, EMT ‐related genes, such as Snail, Twist, vimentin, plasminogen activator inhibitor‐1 and matrix metalloproteinase‐7. Conversely, knockdown of FHL 2 increased β‐catenin phosphorylation (Ser33/37/Thr41), decreased its nuclear translocation and inhibited β‐catenin‐mediated transcription and target genes expression. TGF ‐β1 induced a FHL 2/β‐catenin interaction in NRK ‐52E cells, especially in the nuclei. In a mouse model of obstructive nephropathy, FHL 2 mRNA and protein were induced in a time‐dependent fashion, and the extent and pattern of renal β‐catenin activation were positively correlated with FHL 2 induction. Collectively, this study suggests that FHL 2, via modulating β‐catenin signalling, may implicate in regulation of TGF ‐β1‐mediated tubular EMT and could be a potential therapeutic target for fibrotic kidney disease.