Oncogenic function of the MUC1 receptor subunit in gene regulation

Abstract

The mucin 1 (MUC1) oncoprotein is overexpressed by diverse human cancers; however, it has remained largely unclear how MUC1 contributes to tumorigenesis. In this issue of Oncogene and in concert with published work, Behrens et al. report that the MUC1 receptor subunit activates genes involved in invasion, angiogenesis and metastasis.

Figure 1. Localization of the MUC1 subunits in normal epithelial cells and carcinoma cells

The MUC1 heterodimer consisting of the MUC1-N mucin subunit and the MUC1-C transmembrane subunit are positioned at the apical membrane of polarized epithelial cells. With loss of polarity associated with the epithelial stress response or transformation, MUC1 is repositioned over the entire cell membrane and interacts with receptor tyrosine kinases (RTKs). In addition, with overexpression of MUC1 in carcinoma cells, MUC1-C accumulates in the cytoplasm and is targeted to the nucleus where it regulates the expression of genes associated with tumorigenesis, angiogenesis and ECM remodeling. Reproduced and modified with permission from reference (Kufe, 2009).

Figure 2. Activation of the MUC1-C subunit in carcinoma cells

(a) The MUC1-C subunit forms complexes with EGFR that are mediated at least in part by galectin-3 (GAL3). The MUC1-C cytoplasmic domain is phosphorylated by EGFR on the YEKV motif. Localization of MUC1-C to the cytoplasm is associated with its oligomerization and transport to the nucleus by an importin-β-mediated mechanism. The association of MUC1-C with certain transcription factors (TFs) promotes the expression of genes involved in proliferation, survival, angiogenesis and ECM remodeling. MUC1-C is also transported to the mitochondrial outer membrane in a complex with HSP70 and HSP90. (b) Amino acid sequence of the MUC1-C cytoplasmic domain which contains documented and potential phosphorylation sites (highlighted in orange with the known kinases indicated). The CQC motif is necessary for MUC1-C oligomerization and targeting to the nucleus and mitochondria. Also highlighted are the p53 and β-catenin binding sites. Reproduced and modified with permission from reference (Kufe, 2009).