Interaction of Glycogen Synthase Kinase 3β with the DF3/MUC1 Carcinoma-Associated Antigen and β-Catenin

Abstract

The DF3/MUC1 mucin-like glycoprotein is highly overexpressed in human carcinomas. Recent studies have demonstrated that the cytoplasmic domain of MUC1 interacts with β-catenin. Here we show that MUC1 associates with glycogen synthase kinase 3β (GSK3β). GSK3β binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3β decreases binding of MUC1 to β-catenin in vitro and in vivo. GSK3β-mediated phosphorylation of MUC1 had no apparent effect on β-catenin levels or the transcriptional coactivation function of β-catenin. The results, however, demonstrate that MUC1 expression decreases binding of β-catenin to the E-cadherin cell adhesion molecule. Negative regulation of the β-catenin–MUC1 interaction by GSK3β is associated with restoration of the complex between β-catenin and E-cadherin. These findings indicate that GSK3β decreases the interaction of MUC1 with β-catenin and that overexpression of MUC1 in the absence of GSK3β activity inhibits formation of the E-cadherin–β-catenin complex.