Wnt-independent β-catenin transactivation in tumor development

Abstract

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