MUC1 oncoprotein functions in activation of fibroblast growth factor receptor signaling.
Activation of the fibroblast growth factor (FGF) receptor 3 (FGFR3) has been linked to the development of human cancers by mechanisms that are not well understood. The MUC1 oncoprotein is aberrantly overexpressed by certain hematologic malignancies and most human carcinomas. The present studies show that MUC1 associates with FGFR3. Stimulation of cells with FGF1 increased the interaction between MUC1 and FGFR3. FGF1 stimulation also induced c-Src-dependent tyrosine phosphorylation of the MUC1 cytoplasmic domain on a YEKV motif. FGF1-induced tyrosine phosphorylation of MUC1 was associated with increased binding of MUC1 to beta-catenin and targeting of MUC1 and beta-catenin to the nucleus. FGF1 also induced binding of MUC1 to the heat shock protein 90 (HSP90) chaperone by a mechanism dependent on phosphorylation of the YEKV motif. Notably, beta-catenin and HSP90 compete for binding to the MUC1 cytoplasmic domain, indicating that MUC1 forms mutually exclusive complexes with these proteins. The results also show that inhibition of HSP90 with geldanamycin or 17-(allylamino)-17-demethoxygeldanamycin attenuates FGF1-induced binding of MUC1 to HSP90 and targeting of MUC1 to the mitochondrial outer membrane. These findings indicate that FGF1 induces phosphorylation of MUC1 on YEKV and thereby activates two distinct pathways: (a) nuclear localization of MUC1 and beta-catenin and (b) delivery of MUC1 to mitochondria by HSP90.
Ren
Jian
J
Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Raina
Deepak
D
Chen
Wen
W
Li
Guilan
G
Huang
Lei
L
Kufe
Donald
D
D000595:Amino Acid Sequence; D016227:Benzoquinones / Q000494:pharmacology; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D003600:Cytosol / Q000737:chemistry / Q000378:metabolism; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000032:analysis / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism; D019061:src-Family Kinases
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018396:Mucin-1; D009363:Neoplasm Proteins; D051176:beta Catenin; D016220:Fibroblast Growth Factor 1; C112765:tanespimycin; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human