Transforming growth factor β-induced epithelial to mesenchymal transition requires the Ste20-like kinase SLK independently of its catalytic activity

Abstract

Invasion can be stimulated in vitro using the soluble ligand transforming growth factor-β (TGFβ) to induce a process called epithelial-to-mesenchymal transition (EMT) characterized by cell-cell junction breakdown and an invasive phenotype. We have previously demonstrated a role for Ste20-like kinase SLK cell migration and invasion. Here we show that SLK depletion in NMuMG mammary epithelial cells significantly impairs their TGFβ-induced migration and invasion. Immunofluorescence studies show that a fraction of SLK localizes to E-cadherin-positive adherens junction and that SLK impairs the breakdown of cell-cell contacts. We find that SLK-depleted cultures express significantly lower levels of vimentin protein as well as Snai1 and E-cadherin mRNA levels following TGF-β treatment. Surprisingly, our data show that SLK depletion does not affect the activation and nuclear translocation of Smad3. Furthermore, we show that expression of a dominant negative kinase does not impair tight junction breakdown and rescues Snai1 mRNA expression levels. Together these data suggest that SLK plays a novel role in TGFβ-induced EMT, independent of Smads, in a kinase activity-independent manner.

Degradation of splicing factor SRSF3 contributes to progressive liver disease

“…More importantly if SRSF3 were lost in liver disease, we would expect to observe altered splicing of SRSF3 target genes. Indeed, this is the case, as we observed alterations in splicing of the fibronectin 1 gene FN1, the insulin receptor gene INSR, and 2 genes involved in cytoskeletal rearrangements and epithelial-to-mesenchymal transition -the STE20-like kinase gene SLK (37) and the myosin 1B gene MYO1B (38) -in RNA from NAFLD and NASH subjects. Alternative splicing of exon 11 of the INSR gene gives rise to 2 protein isoforms designated IR-A and IR-B (8,(39)(40)(41)(42)(43) and the ratio of these isoforms is altered in many cancers including breast, lung, colon, and liver, to increase expression of IR-A that is a high-affinity receptor for IGF2 (44,45).…”

Total flavone of Abelmoschus manihot suppresses epithelial-mesenchymal transition via interfering transforming growth factor-β1 signaling in Crohn’s disease intestinal fibrosis

“…EMT refers to the transformation of epithelial cells with polar cells to the interstitial cells under a specific physiological and pathological condition. The most important features of EMT are the loss of epithelial cell phenotype and the acquisition of interstitial properties, as reflected in the down-regulation of E-cadherin and ZO-1, resulting in loss of adhesion between cells or between cells and matrix, over-expression of N-cadherin and vimentin, leading to the acquisition of migration and invasion, and over-expression of EMT transcription factors[ 31 , 32 ]. Moreover, EMT plays a key role in tissue formation, organ fibrosis and so on.…”

SNAI1 interacts with HDAC1 to control TGF‑β2‑induced epithelial‑mesenchymal transition in human lens epithelial cells

“…TGF-β2 could induce EMT in HLEcs (26). The signaling pathways that are activated in response to TGF-β2 and lead to EMT have primarily been conducted in vitro using NMuMG, MdcK and HacaT cell lines (27)(28)(29)(30). In the present study, EMT in HLEB-3 cells was activated when cells were incubated with TGF-β2, providing new insight for further exploring the potential functional relationship between SNAI1 and HdAc1 in the pathogenesis of PcO and its underlying mechanisms.…”