(759c) Regulation of TGF?1-Induced Epithelial-Mesenchymal Transition By ERK and Mrtf-a

Epithelial-mesenchymal transition (EMT) is a physiological process that is essential during embryogenesis, wound healing, and organ development 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 alpha smooth muscle actin (αSMA) and contractile activity. Transforming growth factor (TGF)-β1 is a well-known inducer of EMT and it activates a plethora of signaling cascades including extracellular signal-regulated kinase (ERK). ERK signaling regulates cellular processes such as motility and increased ERK phosphorylation has been indicated in tumor progression. 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 ERK signaling, which blocks the phosphorylation of ERK, enhances focal adhesions, stress fiber formation, cell contractility, and gene expression changes associated with TGFβ1-induced EMT. These effects are mediated by the phosphorylation state and subcellular localization of myocardin related transcription factor (MRTF)-A. These findings suggest that crosstalk between signaling cascades plays an important role in regulating the progression of EMT and that simultaneously targeting multiple pathways may be important for controlling EMT processes such as fibrosis and cancer.