Cell surface mucins are large transmembrane glycoproteins involved in diverse functions ranging from shielding the airway epithelium against pathogenic infection to regulating cellular signaling and transcription. Although hampered by the relatively recent characterization of cell surface mucins and the difficulties inherent in working with molecules of their size, numerous studies have placed the tethered mucins in the thick of normal and diseased lung physiology. This review focuses on the three best-characterized cell surface mucins expressed in the respiratory tract: MUC1, MUC4, and MUC16.

Acetylcholine (ACh) released from the stimulated vagus nerve decreases heart rate via modulation of several types of ion channels expressed in cardiac pacemaker cells. Although the muscarinic-gated potassium channel I(KACh) has been implicated in vagally mediated heart rate regulation, questions concerning the extent of its contribution have remained unanswered. To assess the role of I(KACh) in heart rate regulation in vivo, we generated a mouse line deficient in I(KACh) by targeted disruption of the gene coding for GIRK4, one of the channel subunits. We analyzed heart rate and heart rate variability at rest and after pharmacological manipulation in unrestrained conscious mice using electrocardiogram (ECG) telemetry. We found that I(KACh) mediated approximately half of the negative chronotropic effects of vagal stimulation and adenosine on heart rate. In addition, this study indicates that I(KACh) is necessary for the fast fluctuations in heart rate responsible for beat-to-beat control of heart activity, both at rest and after vagal stimulation. Interestingly, noncholinergic systems also appear to modulate heart activity through I(KACh). Thus, I(KACh) is critical for effective heart rate regulation in mice.

MUC1 is a large (>400 kDa), heavily glycosylated transmembrane protein that is aberrantly expressed on greater than 90% of human breast carcinomas and subsequent metastases. The precise function of MUC1 overexpression in tumorigenesis is unknown, although various domains of MUC1 have been implicated in cell adhesion, cell signaling, and immunoregulation. Stimulation of the MDA-MB-468 breast cancer line as well as mouse mammary glands with epidermal growth factor results in the co-immunoprecipitation of MUC1 with a tyrosine-phosphorylated protein of ϳ180 kDa. We have generated transgenic lines overexpressing full-length (MMF), cytoplasmic tail deleted (⌬CT), or tandem repeat deleted (⌬TR)-human MUC1 under the control of the mouse mammary tumor virus promoter to further examine the role of MUC1 in signaling and tumorigenesis. Immunoprecipitation experiments revealed that fulllength transgenic MUC1 physically associates with all four erbB receptors, and co-localizes with erbB1 in the lactating gland. Furthermore, we detected a sharp increase in ERK1/2 activation in MUC1 transgenic mammary glands compared with Muc1 null and wild-type animals. These results point to a novel function of increased MUC1 expression, potentiation of erbB signaling through the activation of mitogenic MAP kinase pathways.The transmembrane mucin MUC1 (DF3, CD227, episialin, PEM) is a heavily O-glycosylated protein expressed on most secretory epithelium, including the mammary gland as well as some hematopoetic cells. MUC1 is expressed abundantly in the lactating mammary gland in addition to being overexpressed in greater than 90% of human breast carcinomas and metastases (1). In the normal mammary gland, MUC1 is expressed mainly on the apical surface of glandular epithelium and is believed to play a role in anti-adhesion and immune protection (2-4). In breast cancer, MUC1 is overexpressed, underglycosylated, and apical localization is lost (2). Mice lacking Muc1 demonstrate no overt phenotypic developmental abnormalities in the mammary gland, but when crossed with the tumorigenic MMTV 1 -mTag transgenic line (5), mammary gland tumor growth was significantly slowed. Additionally, these Muc1-null/MMTVmTag transgenics demonstrated a trend toward decreased metastasis, showing that the absence of Muc1 results in both reduced tumor growth and spread (6). MUC1 is transcribed as a large precursor gene product, which, upon translation, is cleaved in the endoplasmic reticulum, yielding two separate proteins that form a heterodimeric complex, bound together by noncovalent interactions (7). The larger of the two components (the "mucin-like" subunit) contains most of the extracellular domain, including the signal sequence, tandem repeats, as well as some degenerate repeats. The tandem repeats consist of 30 to 90 repeat sequences of 20 amino acids, rich in serine and threonine residues. Approximately 50 -90% of the mass of MUC1 is derived from O-glycosylation that occurs on these amino acids (8)). The second component of the heterodimer consists of an extr...

The last seven years have been exciting in the world of mucin biology. Molecular analyses of mucin genes and deduced protein structures have provided insight into structural features of mucins and tools with which to examine expression, secretion, and glycosylation, thereby enabling a better understanding of the role of mucins in normal physiological processes and in disease. Functional studies are in progress both in vitro using cDNAs and cell lines and in vivo utilizing mutant mice in which a particular mucin gene has been inactivated or overexpressed. These studies should help determine whether the functions of mucins are restricted to protection and lubrication, or if they are involved in the adhesion of tumor cells to other cells or tissue components or in modulation of the immune system.

Cell surface mucin glycoproteins are highly expressed by all mucosal tissues, yet their physiological role is currently unknown. We hypothesized that cell surface mucins protect mucosal cells from infection. A rapid progressive increase in gastrointestinal expression of mucin 1 (Muc1) cell surface mucin followed infection of mice with the bacterial pathogen Campylobacter jejuni. In the first week following oral infection, C. jejuni was detected in the systemic organs of the vast majority of Muc1 -/-mice but never in Muc1 +/+ mice. Although C. jejuni entered gastrointestinal epithelial cells of both Muc1 -/-and Muc1 +/+ mice, small intestinal damage as manifested by increased apoptosis and enucleated and shed villous epithelium was more common in Muc1 -/-mice. Using radiation chimeras, we determined that prevention of systemic infection in wild-type mice was due exclusively to epithelial Muc1 rather than Muc1 on hematopoietic cells. Expression of MUC1-enhanced resistance to C. jejuni cytolethal distending toxin (CDT) in vitro and CDT null C. jejuni showed lower gastric colonization in Muc1 -/-mice in vivo. We believe this is the first in vivo experimental study to demonstrate that cell surface mucins are a critical component of mucosal defence and that the study provides the foundation for exploration of their contribution to epithelial infectious and inflammatory diseases.