ERK Phosphorylates P120-catenin To Promote TGFβ-induced EMT And Tumors Metastasis

Cell junctions are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals.Cell junctions are especially abundant in epithelial tissues,which are critical to maintain the epithelial barrier and transport functions.Cell junctions help hold animal cells together,reduce the external stress on cells,and maintain certain tissue morphology,therefore playing an important role in coordination of the functions of various tissues in the organism.The epithelial-mesenchymal transition(EMT)is a process by which epithelial cells lose their cell polarity and cell-cell adhesion,and gain migratory and invasive properties to become mesenchymal cells.In this process,epithelial cells will gradually dissociate cell-cell connections including tight juntions(TJs)and adherens junctions(AJs),eventually transformed to loose and spindle-shaped cells.p120-catenin is an important protein in the adherens junction complex for binding and stabilizeing E-caherin,therefore is required for the existence of adherens junctions complex.Our previous study showed that E3 ubiquitin ligase Smurfl can monoubiquitinate p120-catenin,leading to the dissociation of p120-catenin from the adherens junctons complex and subsequent adherens junctions dissocitation.In this study,we demonstrate that in response to TGFβ treatment,activated ERK1/2 phosphorylates p120-catenin at Thr900,thereby promoting binding of p120-catenin to Smurfl and subsequent monoubiquitination of p120-catenin.The monoubiquitination of p120-catenin is required for its dissociation from AJ complex,which is critical for AJ dissociation.Inhibition of AJ dissociation also impeded TJ dissociation and cytoskeleton rearrangement,indicating that epithelial cells go through a stepwise procedure to dissolve the cell-cell junctions during EMT.Therefore,our study identifies an underlying molecular mechanism for AJ dissociation in TGFβ-induced EMT,providing a new insight to fully understand the regulation of epithelial cell plasticity during EMT.