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MUC1 Oncoprotein Blocks Glycogen Synthase Kinase 3ß–Mediated Phosphorylation and Degradation of ß-Catenin

Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Donald Kufe, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-3141; Fax: 617-632-2934; E-mail: donald_kufe{at}dfci.harvard.edu.

Dysregulation of ß-catenin is of importance to the development of diverse human malignancies. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and associates with ß-catenin. However, the functional significance of the MUC1-ß-catenin interaction is not known. Here, we show that MUC1 increases ß-catenin levels in the cytoplasm and nucleus of carcinoma cells. Previous studies have shown that glycogen synthase kinase 3ß (GSK3ß) phosphorylates ß-catenin and thereby targets it for proteosomal degradation. Consistent with the up-regulation of ß-catenin levels, our results show that MUC1 blocks GSK3ß-mediated phosphorylation and degradation of ß-catenin. To further define the interaction between MUC1 and ß-catenin, we identified a serine-rich motif (SRM) in the MUC1 cytoplasmic domain that binds directly to ß-catenin Armadillo repeats. Mutation of the SRM attenuated binding of MUC1 to ß-catenin and MUC1-mediated inhibition of ß-catenin degradation. Importantly, disruption of the MUC1-ß-catenin interaction with the SRM mutant also attenuated MUC1-induced anchorage-dependent and -independent growth and delayed MUC1-mediated tumorigenicity. These findings indicate that MUC1 promotes transformation, at least in part, by blocking GSK3ß-mediated phosphorylation and thereby degradation of ß-catenin.

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