Mr Hyde MUC1 Promotes Tumorigenesis

MUC1 is the first described and best known member of the mucin family that currently has 20 members [18]. This family is characterized by transmembrane-associated and secreted glycoproteins, which show a dense O-glycosylation linked to serine-, threonine- and proline-rich tandem repeat domain called VNTR (variable number of tandem repeats). The VNTR domain of MUC1 is comprised of 20-120 tandemly repeated 20 amino acid segments whose sequence includes 5 potential O-glycosylation sites per repeat [19]. In its normal expression, MUC1 is found at low amounts on the apical cell surface of most glandular epithelial cells [20, 21]. There, it performs a variety of biological functions, such as lubrication and hydration of epithelia and, protection against colonization by pathogens. It is also involved in cell-cell (via E-cadherin) and cell-matrix (via integrins) interactions as a part of both adhesion and anti-adhesion mechanisms. Adhesion effects are mediated by carbohydrate structures on the extracellular repeat domain, whereas anti-adhesive effects can be mediated by the glycosylation-stabilized rigid conformation of the several hundred-nanometer long mucin molecules [22]. Its highly conserved cytoplasmic domain can be phosphorylated at seven phosphorylation sites by, among other signaling proteins, glycogen synthase kinase 30, c-src and protein kinase C5, and thus, regulate further cell signaling, such as through interaction with 0-catenin [23-26]. MUC1 furthermore associates with members of the ErbB family of receptor tyrosine kinases and FGFR3 [27].

During tumorigenesis, cells lose their polarity and MUC1 expression is found at very high levels on the entire cell surface [28, 29]. The extracellular tandem repeat region can act as a ligand for intercellular adhesion molecule (ICAM) 1, involved in metastatic intravasation [30, 31]. The O-glycosylated extended ectodomain can receive signals from selectin binding or conceivably trigger signaling events. Overexpression of MUC1 regulates binding to Wnt effector 0-catenin competitively for E-cadherin, modulates the localization of 0-catenin to the cytoplasm and subverts E-cadherin-mediated cell adhesion in epithelial cells, leading to destabilization of intercellular junctions, which benefits tumor cell migration [23]. MUC1 has been shown to bind to the signaling mediators Grb2/SOS upon phosphorylation [32] and to mediate activation of numerous receptor tyrosine kinases. Activation of the ras signaling pathway phosphorylates Raf, MEK, and ERK1/2, with the latter translocating to the nucleus and inducing transcription of genes involved in mitogenesis, differentiation, apoptosis, and quiescence [33]. Expression of high levels of MUC1 has been shown to elicit EGF-dependent activation of ERK1/2 MAPK [34]. Moreover, MUC1 can mediate resistance to apoptosis in a survival response to oxidative stress [35] by suppression of H2O2-induced accumulation of reactive oxygen species (ROS) and in response to DNA damaging agents, suggesting its important contribution to the resistance of cancer cells to genotoxic agents [36].

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