Autoregulation of E-cadherin expression by cadherin-cadherin interactions: the roles of β-catenin signaling, slug and MAPK

ranscriptional repression of E-cadherin , characteristic of epithelial to mesenchymal transition, is often found also during tumor cell invasion. At metastases, migratory fibroblasts sometimes revert to an epithelial phenotype, by a process involving regulation of the E-cadherin– -catenin complex. We investigated the molecular basis of this regulation, using human colon cancer cells with aberrantly activated -catenin signaling. Sparse cultures mimicked invasive tumor cells, displaying low levels of E-cadherin due to transcriptional repression of E-cadherin by Slug. Slug was induced by -catenin signaling and, T independently, by ERK. Dense cultures resembled a differentiated epithelium with high levels of E-cadherin and -catenin in adherens junctions. In such cells, -catenin signaling, ErbB-1/2 levels, and ERK activation were reduced and Slug was undetectable. Disruption of E-cadherin– mediated contacts resulted in nuclear localization and signaling by -catenin, induction of Slug and inhibition of E-cadherin transcription, without changes in ErbB-1/2 and ERK activation. This autoregulation of E-cadherin by cell–cell adhesion involving Slug, -catenin and ERK could be important in tumorigenesis.