Regulation of Epithelial Cell Migration and Tumor Formation by β-Catenin Signaling

Cell migration requires precise control, which is altered or lost when tumor cells become invasive and metastatic. β-catenin plays a dual role in this process: as a member of adherens junctions it is essential to link cadherins to the cytoskeleton thereby allowing tight intercellular adhesion, and as a member of the Wnt-signaling pathway, β-catenin is translocated into the nucleus and serves together with the LEF1/TCF-transcription factors to drive gene expression necessary for the epithelial-to-mesenchymal transition (EMT). Activated β-catenin signaling has been implicated in the genesis of a variety of tumors. Here we demonstrate a pivotal function for β-catenin signaling in epithelial cell migration and tumorigenesis. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) induce β-catenin signaling under conditions where they stimulate cell motility. Ectopic expression of either stabilized β-catenin or a regulatable form of activated β-catenin induces cell migration in different cell types and cooperates with EGF and HGF in this process. Activation of β-catenin signaling induces expression of the new target gene osteopontin during migration. Cells expressing stabilized β-catenin also exhibit significantly increased capability to form tumors in a nude mouse xenograft model. The data suggest that a critical threshold of β-catenin signaling, activated by cooperative mechanisms, may be important during the EMT and tumorigenesis.