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

Lei Huang,Li Yin,Derek Liu,Donald Kufe,Dongshu Chen,Surender Kharbanda

doi:10.1158/0008-5472.can-05-2474

Lei Huang, Li Yin + Show 4 more

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https://doi.org/10.1158/0008-5472.can-05-2474

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Abstract

Dysregulation of beta-catenin is of importance to the development of diverse human malignancies. The MUC1 oncoprotein is aberrantly overexpressed by most human carcinomas and associates with beta-catenin. However, the functional significance of the MUC1-beta-catenin interaction is not known. Here, we show that MUC1 increases beta-catenin levels in the cytoplasm and nucleus of carcinoma cells. Previous studies have shown that glycogen synthase kinase 3beta (GSK3beta) phosphorylates beta-catenin and thereby targets it for proteosomal degradation. Consistent with the up-regulation of beta-catenin levels, our results show that MUC1 blocks GSK3beta-mediated phosphorylation and degradation of beta-catenin. To further define the interaction between MUC1 and beta-catenin, we identified a serine-rich motif (SRM) in the MUC1 cytoplasmic domain that binds directly to beta-catenin Armadillo repeats. Mutation of the SRM attenuated binding of MUC1 to beta-catenin and MUC1-mediated inhibition of beta-catenin degradation. Importantly, disruption of the MUC1-beta-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 GSK3beta-mediated phosphorylation and thereby degradation of beta-catenin.

Highlights

The Wnt/Wingless signaling pathway is of importance to development and tumorigenesis [1]
The abundance of h-catenin in the cytosol is regulated by glycogen synthase kinase 3h (GSK3h; ref. 2) in a complex with the adenomatous polyposis coli (APC) protein [3] and axin [4]
Densitometric scanning of the signals showed that the calculated half-lives of h-catenin in 3Y1/vector and 3Y1/MUC1 cytoplasmic domain (MUC1-CD) cells are 2 hours, respectively (Fig. 4D). These findings indicate that MUC1-CD stabilizes h-catenin by attenuating GSK3h-mediated phosphorylation of the h-catenin NH2-terminal region

Summary

Introduction

The Wnt/Wingless signaling pathway is of importance to development and tumorigenesis [1]. Wnt-1, a member of the Wnt family, regulates cytoplasmic levels of h-catenin, a component of the adherens junction of mammalian epithelial cells that, through a-catenin, links cadherin cell-surface adhesion molecules to the actin cytoskeleton. The abundance of h-catenin in the cytosol is regulated by glycogen synthase kinase 3h After priming h-catenin by casein kinase 1a– mediated phosphorylation of Ser-45 [5], GSK3h phosphorylates h-catenin on Thr-41, Ser-37, and Ser-33 and thereby targets h-catenin for recognition by h-Trcp, ubiquitination, and degradation [5, 6]. Down-regulation of GSK3h by Wnt signaling increases levels of h-catenin, promotes the formation of nuclear h-catenin complexes with the Tcf/Lef family of DNA-binding proteins, and thereby activates Wnt target genes [7, 8].

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