Regulation of MLK3 by LATS

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Abstract Mixed lineage kinase 3 and 4 are mitogen-activated protein kinases (MAPKs) that regulate MAPK signaling pathways, and mediate transmission of signals from cell surface receptors to the nucleus. MLK3 and MLK4 have important functions in invasion and migration of ovarian and breast cancer cells. Epithelial mesenchymal transition (EMT) is the process by which epithelial cells lose cell polarity and adhesion properties and acquire the migratory and invasive characteristics of mesenchymal cells. Aberrant activation of EMT can contribute to cell transformation and cancer progression. Understanding how EMT is regulated is important for development of new cancer treatments. Due to their functions in cellular transformation, we hypothesized that MLK3 and MLK4 could be important regulators of the EMT process in ovarian cancer cells. Our preliminary findings using siRNA knockdown of MLK3 and MLK4 in SKOV3 ovarian cancer cells indicate that loss of MLK3 or MLK4 affects the levels of EMT markers, E- cadherin and vimentin. We propose that MLK3 and MLK4 are important modulators of EMT, and when aberrantly regulated in ovarian cancer cells, promote EMT progression, invasion and tumorigenesis. In the current study, we will investigate the mechanisms by which MLK3 and MLK4 regulate the expression of key EMT markers, and control ovarian cancer spheroid formation and invasion.