MUC1: a multifunctional cell surface component of reproductive tissue epithelia

Abstract

MUC1 is a large, transmembrane mucin glycoprotein expressed at the apical surface of a variety of reproductive tract epithelia. Functions attributed to MUC1 include those generally associated with mucins such as lubrication and hydration of cell surfaces as well as protection from microorganisms and degradative enzymes. In addition, MUC1 is an effective inhibitor of both cell-cell and cell-extracellular matrix interactions in both normal and malignant contexts. Moreover, a series of recent studies has shown that the highly conserved cytoplasmic tail of MUC1 interacts specifically with a series of important signal transducing molecules including beta-catenin, Grb2 and erbB family members. MUC1 expression in normal epithelia can be quite dynamic, varying in response to steroid hormone or cytokine influences. Following malignant transformation, MUC1 often becomes highly overexpressed, loses its apical restriction, and displays aberrant glycosylation and altered mRNA splice variants. Regulation of MUC1 expression can occur at the transcriptional level. In addition, post-translational regulation of cell surface expression occurs via the activity of cell surface proteases or "sheddases" that release soluble forms of the large ectodomains. This review will briefly summarize studies of MUC1 expression and function in reproductive tissues with particular emphasis on the uterus. In addition, current knowledge of the mechanisms of MUC1 gene regulation, metabolic processing and potential signal transducing functions will be presented.

Figure 1

Protein structure and normal expression pattern of MUC1. Schematic diagram of the size and structure of the full-length MUC1 protein relative to the plasma membrane. The horizontal bar indicates the distance that most cell surface proteins extend into the pericellular space. The three major domains of MUC1 are indicated to the left: (1) an N-terminal, extracellular domain (ECTO); (2) a single, membrane spanning domain (TM); and (3) a C-terminal cytoplasmic domain (CT). A list of epithelial and non-epithelial human tissues that normally express MUC1 is indicated to the right.

Figure 2

Model of mucins and other cell surface glycoproteins/proteoglycans. The figure schematically portrays structures of four size classes of mucins as well as consensus structures for syndecans and integrins. All extracellular portions of these molecules are roughly drawn to scale. Blue squiggles represent O-linked oligosaccharides while red squiggles represent glycosaminoglycans. Integrins, syndecans and most other all surface receptors do not extend beyond 50 nm from the cell surface; however, with the exception of MUC13, mucins extend much farther due to the extende3d structures contributed by the praline-rich heavily O-glycosylated tandem repeat domains. MUC1 and MUC4 are the largest transmembrane mucins, extending >200 nm from the cell surface. The ectodomain structures of MUC16 and MUC17 are considerably shorter than those of MUC1 and MUC4, but still much larger than other surface glycoproteins. Soluble mucins, such as MUC2, 5AC, 5B and 19 are even larger, reading 500–100 nm in length.

Figure 3

The MUC1 proximal promoter. The 1.4 kb human MUC1 proximal promoter is sufficient for driving proper tissue-specific expression in a transgenic mouse model. Cis elements that have been shown to be important for MUC1 regulation include the two Sp1 sites, the κB site, a STAT binding element, and E-MUC1 (E box). The location of several potential progesterone response elements (PRE) also are shown.