Title | Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein. |
Publication Type | Journal Article |
Year of Publication | 2003 |
Authors | Li Y, Yu W-H, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D |
Journal | Mol Cancer Res |
Volume | 1 |
Issue | 10 |
Pagination | 765-75 |
Date Published | 2003 Aug |
ISSN | 1541-7786 |
Keywords | Active 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 Journal | Mol Cancer Res |
PubMed ID | 12939402 |
Grant List | CA97098 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.