Wnt-Independent ?-catenin Transactivation in Tumor Developement

AbstractAccumulation of beta-catenin, which leads to enhanced TCF/LEF-1 driven transcription and thereby contributes to tumor development, can result from mutation of beta-catenin itself, inactivation of the adenomatous polyposis coli (APC) protein, or Wnt pathway inhibition of the GSK-3b kinase that together with APC promotes beta-catenin degradation. Nevertheless, emerging evidence shows that the activation of beta-catenin can occur independently of Wnt signaling to GSK-3b. In response to EGF, tumor cells overexpressing EGF receptor display GSK-3b-independent activation of beta-catenin, which may result from a combination of effects—EGF-stimulated, caveolin-1-dependent internalization of E-cadherin, resulting in release of b-catenin from cell-cell contacts, and EGF-induced downregulation of caveolin-1, relieving the inhibition of signaling molecules sequestered by caveolin-1 at caveolae.