c-erbB-3: a nuclear protein in mammary epithelial cells.
c-erbB receptors are usually located in cell membranes and are activated by extracellular binding of EGF-like growth factors. Unexpectedly, using immunofluorescence we found high levels of c-erbB-3 within the nuclei of MTSV1-7 immortalized nonmalignant human mammary epithelial cells. Nuclear localization was mediated by the COOH terminus of c-erbB-3, and a nuclear localization signal was identified by site-directed mutagenesis and by transfer of the signal to chicken pyruvate kinase. A nuclear export inhibitor caused accumulation of c-erbB-3 in the nuclei of other mammary epithelial cell lines as demonstrated by immunofluorescence and biochemical cell fractionation, suggesting that c-erbB-3 shuttles between nuclear and nonnuclear compartments in these cells. Growth of MTSV1-7 on permeable filters induced epithelial polarity and concentration of c-erbB-3 within the nucleoli. However, the c-erbB-3 ligand heregulin beta1 shifted c-erbB-3 from the nucleolus into the nucleoplasm and then into the cytoplasm. The subcellular localization of c-erbB-3 obviously depends on exogenous stimuli and on the stage of epithelial polarity and challenges the specific function of c-erbB-3 as a transmembrane receptor protein arguing for additional, as yet unidentified, roles of c-erbB-3 within the nucle(ol)us of mammary epithelial cells.
Offterdinger
Martin
M
Signaling Networks Program, Division of Oncology, Department of Internal Medicine I, University of Vienna, A-1097 Vienna, Austria.
Schöfer
Christian
C
Weipoltshammer
Klara
K
Grunt
Thomas W
TW
D018829:Adhesins, Bacterial / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D001692:Biological Transport; D001940:Breast / Q000166:cytology / Q000378:metabolism*; D002461:Cell Line, Transformed; D002466:Cell Nucleolus / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D016764:Cell Polarity; D003593:Cytoplasm / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000648:ultrastructure; D005260:Female; D006801:Humans; D020890:Neuregulin-1 / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D020893:Receptor, ErbB-3 / Q000737:chemistry / Q000378:metabolism*; D028901:alpha Karyopherins / Q000378:metabolism
D018829:Adhesins, Bacterial; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D020890:Neuregulin-1; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D028901:alpha Karyopherins; C087230:heregulin beta1; D020893:Receptor, ErbB-3