MUC1 Oncoprotein Functions in Activation of Fibroblast Growth Factor Receptor Signaling

Abstract

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 B-catenin and targeting of MUC1 and B-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, B-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 B-catenin and (b) delivery of MUC1 to mitochondria by HSP90. (Mol Cancer Res 2006;4(11):873 -83)

Mucin 1 enhances the tumor angiogenic response by activation of the AKT signaling pathway

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MUC1 Oncoprotein Promotes Refractoriness to Chemotherapy in Thyroid Cancer Cells

“…In addition, recent findings have revealed that diverse carcinoma cells express the MUC1-C in mitochondria or in the nucleus in association with the Wnt effector h-catenin (25)(26)(27)(28)(29). MUC1 interacts with members of the ErbB family of receptor tyrosine kinases and with the fibroblast growth factor receptor 3 (26,30,31). Stimulation of such receptors induces c-Src-dependent tyrosine phosphorylation of the MUC1-CD on a YEKV motif and thereby results in nuclear localization of MUC1 and h-catenin or heat shock protein (Hsp) 90-mediated targeting of MUC1 to mitochondria (25,31,32).…”

MUC1 Protein Induces Urokinase-type Plasminogen Activator (uPA) by Forming a Complex with NF-κB p65 Transcription Factor and Binding to the uPA Promoter, Leading to Enhanced Invasiveness of Cancer Cells

“…MUC1 engages in signal transduction through MUC1-ND-mediated ligand-binding (39,42,43) or by interacting with receptors for growth (34,40) and differentiation factors (10 -12), which contributes to the growth and survival of cancer cells. With respect to invasion and metastasis, its molecular role has not been clarified.…”