Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein.
The DF3/MUC1 transmembrane oncoprotein is aberrantly overexpressed in most human breast carcinomas and interacts with the Wnt effector gamma-catenin. Here, we demonstrate that MUC1 associates constitutively with ErbB2 in human breast cancer cells and that treatment with heregulin/neuregulin-1 (HRG) increases the formation of MUC1-ErbB2 complexes. The importance of the MUC1-ErbB2 ... interaction is supported by the demonstration that HRG induces binding of MUC1 and gamma-catenin and targeting of the MUC1-gamma-catenin complex to the nucleolus. Significantly, nucleolar localization of gamma-catenin in response to HRG is dependent on MUC1 expression. Moreover, mutation of a RRK motif in the MUC1 cytoplasmic domain abrogates HRG-induced nucleolar localization of MUC1 and gamma-catenin. In concert with these results, we show nucleolar localization of MUC1 and gamma-catenin in human breast carcinomas but not in normal mammary ductal epithelium. These findings demonstrate that MUC1 functions in cross talk between ErbB2 and Wnt pathways by acting as a shuttle for HRG-induced nucleolar targeting of gamma-catenin.
Mesh Terms:
Active Transport, Cell Nucleus, Antigens, Neoplasm, Breast Neoplasms, Cell Adhesion, Cell Line, Tumor, Cell Nucleolus, Cytoskeletal Proteins, Desmoplakins, Epidermal Growth Factor, Female, Humans, Mucin-1, Neoplasm Proteins, Neuregulin-1, Phosphorylation, Protein Binding, Receptor, erbB-2, gamma Catenin
Active Transport, Cell Nucleus, Antigens, Neoplasm, Breast Neoplasms, Cell Adhesion, Cell Line, Tumor, Cell Nucleolus, Cytoskeletal Proteins, Desmoplakins, Epidermal Growth Factor, Female, Humans, Mucin-1, Neoplasm Proteins, Neuregulin-1, Phosphorylation, Protein Binding, Receptor, erbB-2, gamma Catenin
Mol. Cancer Res.
Date: Aug. 01, 2003
PubMed ID: 12939402
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