γ-Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of β-catenin

Abstract

β-Catenin and γ-catenin (plakoglobin), vertebrate homologs of Drosophila armadillo, function in cell adhesion and the Wnt signaling pathway. In colon and other cancers, mutations in the APC tumor suppressor protein or β-catenin's amino terminus stabilize β-catenin, enhancing its ability to activate transcription of Tcf/Lef target genes. Though β- and γ- catenin have analogous structures and functions and like binding to APC, evidence that γ-catenin has an important role in cancer has been lacking. We report here that APC regulates both β- and γ-catenin and γ-catenin functions as an oncogene. In contrast to β-catenin, for which only amino- terminal mutated forms transform RK3E epithelial cells, wild-type and several amino-terminal mutated forms of γ-catenin had similar transforming activity, γ-Catenin's transforming activity, like β-catenin's, was dependent on Tcf/Lef function. However, in contrast to β-catenin, γ-catenin strongly activated c-Myc expression and c-Myc function was crucial for γ-catenin transformation. Our findings suggest APC mutations alter regulation of both β- and γ-catenin, perhaps explaining why the frequency of APC mutations in colon cancer far exceeds that of β-catenin mutations. Elevated c-Myc expression in cancers with APC defects may be due to altered regulation of both β- and γ-catenin. Furthermore, the data imply β- and γ-catenin may have distinct roles in Wnt signaling and cancers via differential effects on downstream target genes.