Crosstalk between ERK and MRTF‐A signaling regulates TGFβ1‐induced epithelial‐mesenchymal transition

Abstract

Epithelial-mesenchymal transition (EMT) is a physiological process that is essential during embryogenesis and wound healing and also contributes to pathologies including fibrosis and cancer. EMT is characterized by marked gene expression changes, loss of cell-cell contacts, remodeling of the cytoskeleton, and acquisition of enhanced motility. In the late stages of EMT, cells can exhibit myofibroblast-like properties with enhanced expression of the mesenchymal protein marker α-smooth muscle actin and contractile activity. Transforming growth factor (TGF)-β1 is a wellknown inducer of EMT and it activates a plethora of signaling cascades including extracellular signal-regulated kinase (ERK). Previous reports have demonstrated a role for ERK signaling in the early stages of EMT, but the molecular impacts of ERK signaling on the late stages of EMT are still unknown. Here, we found that inhibition of the phosphorylation of ERK enhances focal adhesions, stress fiber formation, cell contractility, and gene expression changes associated with TGFβ1-induced EMT in mammary epithelial cells. These effects are mediated in part by the phosphorylation state and subcellular localization of myocardin-related transcription factor-A. These findings indicate that the intricate crosstalk between signaling cascades plays an important role in regulating the progression of EMT and suggests new approaches to control EMT processes.

Roles of telocytes dominated cell–cell communication in fibroproliferative acute respiratory distress syndrome

“…Important mediators include the dysregulated release of matrix metalloproteinases during the inflammatory phase of ARDS, which causes epithelial and endothelial injury and unchecked fibroproliferation 45 (Figure 4 A,B). Canonical profibrotic pathways regulated by TGF‐β are important, and there is evidence that vascular dysfunction is a key component of the switch from ARDS to fibrosis, with VEGF and cytokines such as interleukin 6 (IL‐6) and TNF‐α implicated 46,47 . It remains unclear why certain individuals could recover from such an insult, whereas in others there is a shift to unchecked cellular proliferation with the accumulation of fibroblasts and myofibroblasts and the excessive deposition of collagen alongside other components of the ECM to result in progressive pulmonary fibrosis.…”

Phenotypic Transitions the Processes Involved in Regulation of Growth and Proangiogenic Properties of Stem Cells, Cancer Stem Cells and Circulating Tumor Cells

“…It has recently been reported that inhibition of ERK phosphorylation increases focal adhesion, cell contractility and alteration in expression of genes correlated to EMT induced by TGF- β1. Subcellular localization and phosphorylation of myocardin-related transcription factor-A (MRTF-A) is a suggested mediator which indicates a crosstalk between ERK and MRTF-A signaling in EMT promotion [ 92 ]. Figure 1 demonstrates the mentioned molecular mediators which lead to EMT promotion.…”

SRF/MRTF‐A and liver cirrhosis: Pathologic associations

“…27 It has recently been shown that specific blockade of ERK inhibits EMT, including that in TGF-β-treated mammary epithelial cells, mainly by sequestering MRTF-A in cytoplasm. 28 While EMT is regulated by TGF-β, local oxidative stress enhances its fibrotic effects. 29 In the presence of reactive oxygen species, activity of the RhoA/Rac1 signaling pathway is significantly increased following activation by TGF-β.…”

“…One of the key factors exerting EMT is TGF‐β, which induces a multitude of signaling pathways, especially extracellular signal‐regulated kinase (ERK) 27 . It has recently been shown that specific blockade of ERK inhibits EMT, including that in TGF‐β‐treated mammary epithelial cells, mainly by sequestering MRTF‐A in cytoplasm 28 . While EMT is regulated by TGF‐β, local oxidative stress enhances its fibrotic effects 29 .…”