Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin.
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.
Li
Y
Y
Cancer Pharmacology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bharti
A
A
Chen
D
D
Gong
J
J
Kufe
D
D
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001665:Binding Sites; D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000201:enzymology*; D015820:Cadherins / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D010766:Phosphorylation; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015534:Trans-Activators; D014162:Transfection / Q000235:genetics; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D000951:Antigens, Neoplasm; C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D018396:Mucin-1; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051176:beta Catenin; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3