Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin
1Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
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 beta-catenin. Here we show that MUC1 associates with glycogen synthase kinase 3beta (GSK3beta). GSK3beta binds directly to an STDRSPYE site in MUC1 and phosphorylates the serine adjacent to proline. Phosphorylation of MUC1 by GSK3beta decreases binding of MUC1 to beta-catenin in vitro and in vivo. GSK3beta-mediated phosphorylation of MUC1 had no apparent effect on beta-catenin levels or the transcriptional coactivation function of beta-catenin. The results, however, demonstrate that MUC1 expression decreases binding of beta-catenin to the E-cadherin cell adhesion molecule. Negative regulation of the beta-catenin-MUC1 interaction by GSK3beta is associated with restoration of the complex between beta-catenin and E-cadherin. These findings indicate that GSK3beta decreases the interaction of MUC1 with beta-catenin and that overexpression of MUC1 in the absence of GSK3beta activity inhibits formation of the E-cadherin-beta-catenin complex.
Related Concept Videos
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
Receptor Downregulation in MVBs
The EGFR can initiate signaling pathways that lead to cell proliferation, migration, and differentiation. Overexpression of EGFR stimulates cells to proliferate. Excessive EGFR activation may...
MAPK Signaling Cascades
PI3K/mTOR/AKT Signaling Pathway
TGF - β Signaling Pathway
Catenins
Catenins in Cell Junctions
Catenins bind to cell adhesion molecules such as cadherins and link them to different cytoskeletal proteins depending on the type of cell junction. At the adherens...


