MUCs

Definition: Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by many epithelial tissues in vertebrates.

Although some mucins are membrane-bound due to the presence of a hydrophobic membrane-spanning domain that favors retention in the plasma membrane, most mucins are secreted onto mucosal surfaces or secreted to become a component of saliva.

See also : mucin

Pathology

Increased mucin production occurs in many adenocarcinomas, including cancer of the pancreas, lung, breast, ovary, colon, etc.

Mucins are also overexpressed in lung diseases such as asthma, bronchitis, COPD or cystic fibrosis.

Two membrane mucins, MUC1 and MUC4 have been extensively studied in relation to their pathological implication in the disease process.

Moreover, mucins are also being investigated for their potential as diagnostic markers.

In pancreas cancer : PMID: 22126377

• Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion.
• MUC1 or MUC4 expression is related to the aggressive behavior and poor outcome of human neoplasms.
• MUC2 is expressed in indolent pancreatobiliary neoplasms, but these tumors sometimes show invasive growth with MUC1 expression in invasive areas.
• MUC5AC shows de novo high expression in many types of precancerous lesions of pancreatobiliary cancers and is an effective marker for early detection of the neoplasms.
• The combination of MUC1, MUC2, MUC4 and MUC5AC expression may be useful for early detection and evaluation of the potential for malignancy of pancreatobiliary neoplasms.

Types

At least 19 human mucin genes have been distinguished by cDNA cloning: MUC1 , MUC2 , MUC3A , MUC3B , MUC4 , MUC5AC , MUC5B , MUC6 , MUC7 , MUC8 , MUC12 , MUC13 , MUC15 , MUC16 , MUC17 , MUC19 , and MUC20.

The major secreted airway mucins are MUC5AC and MUC5B , while MUC2 is secreted mostly in the intestine but also in the airway.

Protein Structure

Mature mucins are composed of two distinct regions:

 The amino- and carboxy-terminal regions which are very lightly glycosylated, but rich in cysteines. The cysteine residues participate in establishing disulfide linkages within and among mucin monomers.

 A large central region formed of multiple tandem repeats of 10 to 80 residue sequences in which up to half of the amino acids are serine or threonine. This area becomes saturated with hundreds of O-linked oligosaccharides. N-linked oligosaccharides are also found on mucins, but in less abundance than O-linked sugars.

Glycosylation and aggregation

Mucin genes encode mucin monomers that are synthesized as rod-shape apomucin cores that are post-translationally modified by exceptionally abundant glycosylation.

The dense "sugar coating" of mucins gives them considerable water-holding capacity and also makes them resistant to proteolysis, which may be important in maintaining mucosal barriers.

Mucins are secreted as massive aggregates of proteins with molecular masses of roughly 1 to 10 million Da. Within these aggregates, monomers are linked to one another mostly by non-covalent interactions, although intermolecular disulfide bonds may also play a role in this process.

Secretion

Upon stimulation, MARCKS (myristylated alanine-rich C kinase substrate) protein coordinates the secretion of mucin from mucin filled vesicles within the specialized epithelial cells.

Fusion of the vesicles to the plasma membrane causes release of the mucin, which as it exchanges Ca2+ for Na+ expands up to 600 fold. The result is a viscoelastic product of interwoven molecules which, combined with other secretions (e.g., from the airway epithelium and the submucosal glands in the respiratory system), is called mucus.