Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein.

TitleHeregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein.
Publication TypeJournal Article
Year of Publication2003
AuthorsLi Y, Yu W-H, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D
JournalMol Cancer Res
Volume1
Issue10
Pagination765-75
Date Published2003 Aug
ISSN1541-7786
KeywordsActive Transport, Cell Nucleus, Antigens, Neoplasm, Breast Neoplasms, Cell Adhesion, Cell Line, Tumor, Cell Nucleolus, Cytoskeletal Proteins, Desmoplakins, Epidermal Growth Factor, Female, gamma Catenin, Humans, Mucin-1, Neoplasm Proteins, Neuregulin-1, Phosphorylation, Protein Binding, Receptor, ErbB-2
Abstract

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.

Alternate JournalMol Cancer Res
PubMed ID12939402
Grant ListCA97098 / CA / NCI NIH HHS / United States
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Massimo Loda, M.D.

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