Structure, evolution, and biology of the MUC4 mucin

Abstract

Mucins are high-molecular-weight glycoproteins and are implicated in diverse biological functions. MUC4, a member of transmembrane mucin family, is expressed in airway epithelial cells and body fluids like saliva, tear film, ear fluid, and breast milk. In addition to its normal expression, an aberrant expression of MUC4 has been reported in a variety of carcinomas. Among various potential domains of MUC4, epidermal growth factor (EGF) -like domains are hypothesized to interact with and activate the ErbB2 receptors, suggesting an intramembrane-growth factor function for MUC4. The heavily glycosylated tandem repeat domain provides the structural rigidity to the extended extracellular region. MUC4, by virtue of its extended structure, serves as a barrier for some cell-cell and cell-extracellular matrix interactions and as a potential reservoir for certain growth factors. An intricate relationship between MUC4 and growth factor signaling is also reflected in the transcriptional regulation of MUC4. The MUC4 promoter has binding sites for different transcription factors, which are responsible for the regulation of its expression in different tissues. The interferon-gamma, retinoic acid, and transforming growth factor-beta signaling pathways regulate MUC4 expression in a partially interdependent manner. Taken together, all of these features of MUC4 strongly support its role as a potential candidate for diagnostic and therapeutic applications in cancer and other diseases.

Pancreatic lymphoepithelial cysts express CEA and can contain mucous cells: potential pitfalls in the preoperative diagnosis

“…As MUC1 and MUC4 are expressed in the normal stratified epithelium, 32,35 pancreatic squamous metaplasia 36 and in squamoid cysts of the pancreas, 37 the presence of MUC1 and MUC4 in our study suggests that lymphoepithelial cysts may originate from the pancreatic duct with squamous metaplasia and cystic formation, or alternatively, from epithelial remnants in peripancreatic lymph nodes. 2 The scattered mucous cells could represent remnant ductal epithelial cells.…”

“…31 MUC4 is absent or minimally expressed in the normal pancreas. 32 Interestingly, mucins are differentially expressed in mucinous cysts of the pancreas; MUC5AC is consistently expressed in the epithelial lining of pancreatic mucinous cysts; MUC2 is expressed in intestinal-type epithelial lining; and both MUC1 and MUC6 are expressed in pancreaticobiliary and oncocytic epithelial lining. 33,34 The mucin expression profile of lymphoepithelial cysts has not been described previously in the literature.…”

Inflammation modulates the expression of the intestinal mucins MUC2 and MUC4 in gastric tumors

“…MUC4 is a membrane-bound mucin that has been involved in tumor growth and metastasis through several mechanisms related to its cytoplasmic tail, which has been implicated in cell signaling events (reviewed in Chaturvedi et al, 2008). The transcriptional induction of MUC4 by STAT3 agrees with the fact that no differences in MUC4/STAT3 detection were found in the two groups of tumors, suggesting that the initial acute inflammation should trigger the activation of the gp130/STAT3 signaling pathway, and this activation may promote the apparition of chronic inflammatory cells.…”

Pipeline to Identify Hydroxyproline-Rich Glycoproteins

“…Glycosylation of Hyp is a widespread phenomenon in plants but is absent in animals. Plant HRGPs have been considered functionally equivalent to mammalian proteoglycans such as mucins that are rich in Pro, Thr, and Ser, heavily glycosylated, and found in the extracellular matrix (Chaturvedi et al, 2008). Importantly, however, O-linked glycosylation of mucins occurs through Ser and Thr residues rather than Hyp residues, which are rarely, if ever, glycosylated in animals.…”