MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90.
The MUC1 heterodimeric transmembrane glycoprotein is aberrantly overexpressed by most human carcinomas. The MUC1 C-terminal subunit localizes to mitochondria and blocks stress-induced activation of the intrinsic apoptotic pathway. How MUC1 is delivered to mitochondria is not known. The present studies demonstrate that MUC1 forms intracellular complexes with HSP70 and HSP90. We show that the MUC1 cytoplasmic domain binds directly to HSP70 in vitro. By contrast, binding of MUC1 to HSP90 in vitro is induced by c-Src-mediated phosphorylation of the MUC1 cytoplasmic domain. c-Src also increases binding of MUC1 to HSP90 in cells. In concert with these results, we show that heregulin (HRG), a ligand for ErbB receptors, activates c-Src and, in turn, stimulates binding of MUC1 to HSP90. We also show that inhibitors of c-Src or HSP90 block HRG-induced targeting of MUC1 to mitochondria and integration of MUC1 into the mitochondrial outer membrane. These findings indicate that MUC1 is delivered to mitochondria by a mechanism involving activation of the ErbB receptor-->c-Src pathway and transport by the molecular chaperone HSP70/HSP90 complex.
Ren
J
J
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Bharti
A
A
Raina
D
D
Chen
W
W
Ahmad
R
R
Kufe
D
D
D000595:Amino Acid Sequence; D000818:Animals; D000941:Antigens / Q000378:metabolism / Q000502:physiology*; D000951:Antigens, Neoplasm; D002460:Cell Line; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D066246:ErbB Receptors / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D007074:Immunoglobulin G / Q000737:chemistry; D047468:Immunoprecipitation; D013058:Mass Spectrometry; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D018396:Mucin-1; D009077:Mucins / Q000378:metabolism / Q000502:physiology*; D020890:Neuregulin-1 / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism*
D000941:Antigens; D000951:Antigens, Neoplasm; D006023:Glycoproteins; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D007074:Immunoglobulin G; C060192:MUC1 protein, human; D018832:Molecular Chaperones; D018396:Mucin-1; D009077:Mucins; D020890:Neuregulin-1; D066246:ErbB Receptors; D019061:src-Family Kinases