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.
Li
Yongqing
Y
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Yu
Wei-Hsuan
WH
Ren
Jian
J
Chen
Wen
W
Huang
Lei
L
Kharbanda
Surender
S
Loda
Massimo
M
Kufe
Donald
D
D021581:Active Transport, Cell Nucleus; D000951:Antigens, Neoplasm / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D051180:Desmoplakins; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D006801:Humans; D018396:Mucin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D020890:Neuregulin-1 / Q000494:pharmacology*; D010766:Phosphorylation; D011485:Protein Binding; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D051185:gamma Catenin
D000951:Antigens, Neoplasm; D003598:Cytoskeletal Proteins; D051180:Desmoplakins; D004815:Epidermal Growth Factor; D018396:Mucin-1; D009363:Neoplasm Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D051185:gamma Catenin; C495292:JUP protein, human