MUC1: the polymorphic appearance of a human mucin

Abstract

Accepted on December 1, 1999; The term “mucin” has changed its meaning over the last decades prompted by the impressive progress made in the field of glycobiology. Up to the 1970s researchers exclusively used this term to refer to the major glycoprotein components in secreted mucus lining the surfaces of glandular epithelia. The best characterized species during that time, the mucins from ovine and bovine submaxillary glands, served as structural models for this subclass of glycoproteins, since they exhibited the features regarded as typical for mucins: a high carbohydrate content (exceeding 50% by weight) with a concomitant high buoyant density and a threonine/serine rich peptide core serving as a scaffold for the addition of uniform, simple and mainly acidic oligosaccharides. A dense hydrophilic coat of O-linked negatively charged glycans was a simple structural model, but in accord with the proposed function of mucins which was regarded to lie in the formation of a viscoelastic gel serving in physicochemical protection of epithelial surfaces. Two important observations, which were made during the 1980s, have changed this view and conferred the mucins increased attraction as a research topic. Using advanced methodology and sophisticated instrumentation (FABMS, 500 MHz H-NMR) several groups could demonstrate by means of structural chemistry that mucins are much more complex glycosylated than expected (Lamblin et al., 1984; Hanisch et al., 1985, 1986; Hounsell et al., 1985, 1989; Mutsaers et al., 1986). A second major point was the identification of tumor-associated epitopes on mucins as immunotargets on malignant epithelial cells and their secretions (Magnani et al., 1983; Hilkens et al., 1984; Burchell et al., 1987). In particular the latter aspect has driven tremendous efforts to characterize distinct mucin species by recombinant technology. In 1990 four groups were able to sequence the first human mucin gene on the DNA level (Gendler et al., 1990; Lan et al., 1990; Ligtenberg et al., 1990; Wreschner et al., 1990). Designated as MUC1 in accord with the Human Genome Mapping conventions, this mucin protein is identical to the polymorphic epithelial mucin (PEM), the polymorphic urinary mucin (PUM), Episialin, DF3 antigen, and several other glycoforms of MUC1 isolated from various sources. MUC1 and meanwhile a series of other human mucins (MUC2 to MUC12) have revealed to exhibit large domains of tandemly repeated peptides as a structural characteristic of the “real” mucins (Porchet et al., 1991; Bobek et al., 1993; Toribara et al., 1993; Gum et al., 1994; Meerzaman et al., 1994; Shankar et al., 1994; Van Klinken et al., 1997; Lapensee et al., 1997; Nollet et al., 1998; Williams et al., 1999). They can be discriminated in this way from mucin-like glycoproteins, like GlyCAM1 or MadCAM1, serving roles in cell adhesion (Shimizu and Shaw, 1993). The currently known MUC species can be subdivided into two groups dependent on their structural aspects and biosynthetic routes. Membrane bound mucins (MUC1, MUC3, MUC4, MUC12) exhibit hydrophobic sequences or “transmembrane domains” responsible for their anchoring in the lipid bilayer and C-terminal peptides enter the cytosol (Table I). With one exception (MUC7) the secretory mucins (MUC2, MUC5AC, MUC5B, MUC6) possess one or several von Willebrandt factor-like D domains (Table I), cystein-rich peptides, which function in the oligomerization of mucin monomers and in the packaging into secretory vesicles (Perez-Vilar and Hill, 1999). This review will focus on MUC1 by attempting to summarize the actual knowledge on the structural, biosynthetic and functional aspects accumulated over the last decade. While previous reviews have concentrated on the mucin gene (Gendler and Spicer, 1995), the processing of the protein and its function in cell adhesion (Hilkens et al., 1992) or on MUC1 immunology (Apostolopoulos and McKenzie, 1994; Finn et al., 1995), we will emphasize those aspects related to O-glycosylation of MUC1 in health and disease. In this context reference will primarily be made to structural and enzymatic work and only sporadically to evidence from immunochemical studies. Recent findings have led to a series of revisions of previous concepts on site-specific O-glycosylation of MUC1 and glycosylation-induced effects on MUC1 antigenicity. These findings and their implications will be tied into the current concepts of the field and discussed with reference to ongoing developments of tumor defense strategies on the humoral and cellular level. MUC1 exhibits a ubiquitous organ distribution (Zotter et al., 1988) including mammary gland acini and ducts, salivary gland ducts and serous acini, but not mucinous acini; squamous epithelium of the esophagus; parietal cells, canaliculi and peptic cells of the stomach; acini and ducts of the pancreas; bile ducts in the liver; enterocytes of the duodenum, but not the large intestine; respiratory and ciliated epithelium of the lungs, se