FHL2 promotes tubular epithelial‐to‐mesenchymal transition through modulating β‐catenin signalling

Abstract

Abstractβ‐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 (FHL2) acts as a coregulator of β‐catenin in several other cell types. To determine whether FHL2 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. FHL2 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 FHL2 inhibited E‐cadherin and enhanced α‐smooth muscle actin (α‐SMA) and fibronectin expression, whereas knockdown of FHL2 partially restored E‐cadherin and reduced α‐SMA and fibronectin induction stimulated by TGF‐β1. Overexpression of FHL2 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 FHL2 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 FHL2/β‐catenin interaction in NRK‐52E cells, especially in the nuclei. In a mouse model of obstructive nephropathy, FHL2 mRNA and protein were induced in a time‐dependent fashion, and the extent and pattern of renal β‐catenin activation were positively correlated with FHL2 induction. Collectively, this study suggests that FHL2, 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.

C3a and suPAR drive versican V1 expression in tubular cells of focal segmental glomerulosclerosis

“…β-Catenin signaling plays an important role in regulating fibrogenic activation. Cai et al reported that overexpression of the adapter protein FHL2 increased β-catenin dephosphorylation, nuclear translocation, and β-catenin-mediated transcription of snail and vimentin (34). AKT can activate β-catenin/TCF transcriptional activity by the indirect stabilization of β-catenin through GSK-3β inhibition and by the direct phosphorylation of β-catenin (35).…”

Farnesoid X receptor antagonizes Wnt/β-catenin signaling in colorectal tumorigenesis

“…Moreover, blockage of Wnt signaling by XAV-939 attenuated the tumor-suppressive effect of FXR knockdown on colon cancer cells. Activation of Wnt/β-catenin signaling is a strong inducer of EMT, as evidenced by the identification of β-catenin-regulated genes, such as fibronectin 48 , slug 15 , MMP-7 49 , and VEGF 50 . These genes, directly or indirectly involved in EMT, code for direct effectors of CRC progression.…”

Deficiency of Fhl2 leads to delayed neuronal cell migration and premature astrocyte differentiation

“…Rather, Fhl2 plays an important role as an essential regulator of stem cell behavior during stress and or inflammation, and in wound-repair processes. In hematopoietic stem cells under regenerative stress (Hou et al, 2014), mesenchymal stem cells during skin wound healing Park et al, 2008), during epithelial-mesenchymal transition (Zhang et al, 2010;Cai et al, 2018), chronic inflammatory arthritis (Wixler et al, 2015) or liver regeneration (Dahan et al, 2013), Fhl2-deficient stem cells show diverse phenotypes. These include reduced self-renewal capacity and migration deficiency, and Fhl2-deficient tissue revealed delayed wound healing, or abnormal inflammatory signal processing and matrix organization during repair (this study; Wixler et al, 2007;Park et al, 2008;Leite Dantas et al, 2004).…”