The PDZ domains of zonula occludens-1 induce an epithelial to mesenchymal transition of Madin-Darby canine kidney I cells - Evidence for a role of beta-catenin/Tcf/Lef signaling

The integrity of cell-cell contacts such as adherens junctions (AJ) and tig ht junctions (TJ) is essential for the function of epithelia, During carcin ogenesis, the increased motility and invasiveness of tumor cells reflect th e loss of characteristic epithelial features, including cell adhesion. Whil e beta-catenin, a component of AJ, plays a well characterized dual role in cell adhesion and signal transduction leading to epithelial cell transforma tion, little is known about possible roles of tight junction components in signaling processes. Here we show that mutants of the TJ protein zonula occ ludens protein-1 (ZO-1), which encode the PDZ domains (ZO-1 PDZ) but no lon ger localize at the plasma membrane, induce a dramatic epithelial to mesenc hymal transition (EMT) of Madin-Darby canine kidney I (MDCKI) cells. The ob served EMT of these MDCK-PDZ cells is characterized by a repression of epit helial marker genes, a restricted differentiation potential and a significa ntly induced tumorigenicity, Intriguingly, the beta-catenin signaling path way is activated in the cells expressing the ZO-1 PDZ protein. Ectopic expr ession of the adenomatous polyposis coli tumor suppressor gene, known to do wn-regulate activated beta-catenin signaling, reverts the transformed fibro blastoid phenotype of MDCK-PDZ cells. Thus, cytoplasmic localization of the ZO-1 PDZ domains induces an EMT in MDCKI cells, most likely by modulating beta-catenin signaling.