Molecular signaling in the regulation of mucins (original) (raw)
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Structure and function of epithelial mucins
Biopolymers and Cell, 1998
Mucins are the structural components of the epithelial mucose that protects the respiratory, gastrointestinal and reproductive tracts from the hostile environments, including microorganisms, toxim and abrasives. Mucins constitute a group of high molecular weight (> 200 kDa), polydisperse and highly glycosylated proteins which are present on the surface of most epithelial tissues. Our understanding of the structure and function of mucins has advanced significantly in the last decade. This progress was mainly associated with the isolation of the cDNA clones, encoding a family of epithelial mucins. To date, this family includes eight mucin genes (MUCJ-MUC8) and more await to be discovered. Based on sequence analysis and studies of subcellular localisation, epithelial mucins could be divided into two classes: membrane-associated (MUC1) and secretory (MUC2-8). This review is focused on our current knowledge of the structure of products of mucin genes and their function in normal tissues and in disease. The regulation of the expression of mucin genes, posttranslational modifications and alterations in secretion and processing will also be discussed.
Expression of conserved mucin domains by epithelial tissues in various mammalian species
Research in Veterinary Science, 2009
Mucins are related to infectious and non-infectious diseases in Veterinary and Human Medicine. MUC1 mucin is a transmembrane glycoprotein expressed on the apical surface of human epithelia while MUC5AC is the predominant secreted mucin expressed in human gastric epithelium and goblet cells of lung and eyes. MUC5AC C-terminus cysteine rich regions and the cytoplasmic tail of MUC1 domains are conserved among several mammalian species. Objective: to compare the expression of MUC1 and MUC5AC mucins in mammalian epithelia. CT33 anti-MUC1 cytoplasmic tail (MUC1CT) polyclonal antibody and 45M1 anti-MUC5AC monoclonal antibody were employed. By immunohistochemistry, MUC1CT was expressed in most tissues while MUC5AC was restricted to gastric surface epithelium and goblet cells from trachea and lung. By western blot, MUC1CT showed a band at approximately 35 kDa in most tissues; MUC5AC revealed bands at >180 kDa in stomach and lung secretions from rat, cat, pig and cow. When rat MUC5AC was immunoprecipitated, a band at about 180 kDa was obtained.
Mucin gene structure and expression: protection vs. adhesion
The American journal of physiology, 1995
The cloning of mucin cDNAs brought about by the application of molecular biology and molecular analyses constitutes a major step in understanding mucin structure and function. Here two classes of mucins are described: epithelium-associated and endothelium/leukocyte-associated mucins, which have thus far been described separately in the literature. The epithelial mucins are generally believed to play a role in cytoprotection. The endothelial and leukocyte class of mucins are adhesion molecules involved in lymphocyte homing and lymphocyte activation or are part of the adhesion cascade that plays a role in the initiation of inflammation. Mucins in general contain many threonine and serine residues, which are extensively O-glycosylated. Due to this profound glycosylation, mucins have a filamentous conformation. By virtue of their extended filamentous, and often negatively charged, structure, mucins can act as a barrier protecting the cell. However, when an opposing cell has specific rec...
Mucins make up a large part of the mucus covering of the lumenal surfaces of epithelial organs that serve as selective physical barriers between the extra cellular milieu and the plasma membrane and cell interior. Mucins are subdi vided into secretory and membrane-associated forms. Secretory mucins constitute the viscous mucus of the tracheobronchial, gastrointestinal, and reproductive tracts and typically form extremely large oligomers through link age of protein monomers via disulfide bonds. These proteins are secreted from the cell and remain at the apical surface of the epithelial cells in the form of a mucus gel. The membrane-associated mucins, however, have a hydrophobic membrane-spanning domain and have not been observed to form oligomeric complexes, Mucin-like glycoproteins have also been found in nonepithelial tissues that are not barrier tissues. They serve as ligands for selectins and are involved in lymphocyte trafficking (130). These molecules fall under the broad definition of mucin, a protein containing, as greater than 50% of its mass, a-linked oligosaccharides. Ultimately, it may be necessary to refine the defi nition of a mucin or to expand the proposed functions, mainly protection and lubrication, to cover a much wider range of possibilities. The nonepithelial mucins are not discussed in any detail in this review.
MUC13, a Novel Human Cell Surface Mucin Expressed by Epithelial and Hemopoietic Cells
Journal of Biological Chemistry, 2001
Transmembrane mucins are glycoproteins involved in barrier function in epithelial tissues. To identify novel transmembrane mucin genes, we performed a tblastn search of the GenBank EST data bases with a serine/ threonine-rich search string, and a rodent gene expressed in bone marrow was identified. We determined the cDNA sequence of the human orthologue of this gene, MUC13, which localizes to chromosome band 3q13.3 and generates 3.2-kilobase pair transcripts encoding a 512-amino acid protein comprised of an N-terminal mucin repeat domain, three epidermal growth factor-like sequences, a SEA module, a transmembrane domain, and a cytoplasmic tail (GenBank accession no. AF286113). MUC13 mRNA is expressed most highly in the large intestine and trachea, and at moderate levels in the kidney, small intestine, appendix, and stomach. In situ hybridization in murine tissues revealed expression in intestinal epithelial and lymphoid cells. Immunohistochemistry demonstrated the human MUC13 protein on the apical membrane of both columnar and goblet cells in the gastrointestinal tract, as well as within goblet cell thecae, indicative of secretion in addition to presence on the cell surface. MUC13 is cleaved, and the -subunit containing the cytoplasmic tail undergoes homodimerization. Including MUC13, there are at least five cell surface mucins expressed in the gastrointestinal tract.
MARCKS Regulation of Mucin Secretion by Airway Epithelium in Vitro
American Journal of Respiratory Cell and Molecular Biology, 2008
We have reported previously that myristoylated alanine-rich C kinase substrate (MARCKS) is a key regulatory molecule controlling mucin secretion by airway epithelial cells in vitro and in vivo. The results of those studies supported a mechanism whereby MARCKS, upon phosphorylation by protein kinase C (PKC), translocates from plasma membrane to cytoplasm, where its binding to membranes of intracellular mucin granules is a key component of the secretory pathway. It remains unknown how MARCKS is targeted to and/or preferentially attaches to mucin granule membranes. We hypothesized that the chaperone cysteine string protein (CSP) may play an important role in this process. CSP was shown to associate with membranes of intracellular mucin granules in well-differentiated normal human bronchial epithelial (NHBE) cells in vitro, as determined by ultrastructural immunohistochemistry and Western blotting of isolated granule membranes. CSP in these cells complexed with MARCKS, as shown by co-immunoprecipitation. Given reported associations between CSP and a second chaperone, heat shock protein 70 (HSP70), a role for HSP70 in the MARCKS-dependent secretory mechanism also was investigated. HSP70 appeared to form a trimeric complex with MARCKS and CSP associated with mucin granule membranes within airway epithelial cells. Transfection of the HBE1 human bronchial epithelial cell line with siRNAs targeting sequences of MARCKS, CSP, or HSP70 resulted, in each case, in significant knockdown of expression of these proteins and subsequent attenuation of mucin secretion. The results provide the first evidence that CSP and HSP70, and their interactions with MARCKS, are involved in mucin secretion.
Glycoconjugate Journal, 2015
Mucins are major glycoprotein components of the mucus that coats the surfaces of cells lining the respiratory, digestive, gastrointestinal and urogenital tracts. They function to protect epithelial cells from infection, dehydration and physical or chemical injury, as well as to aid the passage of materials through a tract i.e., lubrication. They are also implicated in the pathogenesis of benign and malignant diseases of secretory epithelial cells. In Human there are two types of mucins, membrane-bound and secreted that are originated from mucous producing goblet cells localized in the epithelial cell layer or in mucous producing glands and encoded by MUC gene. Mucins belong to a heterogeneous family of high molecular weight proteins composed of a long peptidic chain with a large number of tandem repeats that form the so-called mucin domain. The molecular weight is generally high, ranging between 0.2 and 10 million Dalton and all mucins contain one or more domains which are highly glycosylated. The size and number of repeats vary between mucins and the genetic polymorphism represents number of repeats (VNTR polymorphisms), which means the size of individual mucins can differ substantially between individuals which can be used as markers. In human it is only MUC1 and MUC7 that have mucin domains with less than 40 % serine and threonine which in turn could reduce number of PTS domains. Mucins can be considered as powerful two-edged sword, as its normal function protects from unwanted substances and organisms at an arm's length while, malfunction of mucus may be an important factor in human diseases. In this review we have unearthed the current status of different mucin proteins in understanding its role and function in various noncommunicable diseases in human with special reference to its organ specific locations. The findings described in this review may be of direct relevance to the major research area in biomedicine with reference to mucin and mucin associated diseases.