MUC4 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Aliases | MUC4 , ASGP, HSA276359, MUC-4, mucin 4, cell surface associated | ||||||||||||||||||||||||||||||||||||||||||||||||||
External IDs | OMIM: 158372 GeneCards: MUC4 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Mucin-4 (MUC-4) is a mucin protein that in humans is encoded by the MUC4 gene. [3] Like other mucins, MUC-4 is a high-molecular weight glycoprotein. [4]
The major constituents of mucus, the viscous secretion that covers epithelial surfaces such as those in the trachea, colon, and cervix, are highly glycosylated proteins called mucins. These glycoproteins play important roles in the protection of the epithelial cells and have been implicated in epithelial renewal and differentiation. This gene encodes an integral membrane glycoprotein found on the cell surface, although secreted isoforms may exist. At least two dozen transcript variants of this gene have been found, although for many of them the full-length transcript has not been determined or they are found only in tumor tissues. [5]
MUC-4 has been found to play various roles in the progression of cancer, particularly due to its signaling and anti-adhesive properties which contribute to tumor development and metastasis. It is also found to play roles in other diseases such as endometriosis and inflammatory bowel disease. MUC-4 belongs to the human mucin family that is membrane-anchored and can range in molecular weight from 550 to 930 kDa for the actual protein, and up to 4,650 kDa with glycosylation. [6]
MUC4 is an O-glycoprotein that can reach up to 2 micrometers outside the cell. [6] MUC4 mucin consists of a large extracellular alpha subunit that is heavily glycosylated and a beta subunit that is anchored in the cell membrane and extends into the cytosol. [7] This beta subunit is considered an oncogene, whose role in cancer is increasingly being recognized particularly due to its involvement in signalling pathways, particularly with ErbB2 (Her2). [7] This subunit serves as a ligand for ErbB2, which is suggested to cause the repression of apoptosis found in many cancer cells. [8]
The large alpha subunit that is glycosylated likely confers the anti-adhesive properties to the cell, allowing for cell–cell and cell–matrix detachment in normal as well as cancerous cells. [6] The heavy glycosylation may also serve as a reservoir for growth factors, which may become released upon degradation. [9]
The two subunits of MUC4 are transcribed from a single gene [8] made of 25 exons and with its exon/intron structure identical to that of the mouse gene. [10] Over 24 splice variants have been found for MUC4 using commercial mRNAs or total RNAs extracted from cancer cell lines. [6] [11] Some predicted forms are soluble, while others are membrane bound. However, most of these splice variants are likely artefactual. [12] Many polymorphisms are observed in the tandem repeat region of the alpha subunit, which has a variable number of repeats. [13] [14]
In normal functioning, MUC-4 is known to play anti-adhesive roles in the body, such as in lubricating the reproductive lining. [15] It is also found in the respiratory tract - particularly in the trachea and lung - and the digestive tract - in the esophagus and colon - as well as in the visual and auditory systems. [6] In these roles, MUC-4 serves to protect and lubricate the epithelium, which facilitates transport and traps foreign particles. One example of its function in the reproductive lining relates to blastocyst implantation resulting from MUC4 downregulation. [8] It is found to be overexpressed during the luteal phase of menstruation. [16] MUC-4 may also have a role in fetal morphogenic development. [6] MUC-4 is not found in the gallbladder, pancreas, or liver except in abnormal conditions such as cancer. MUC-4, however, may normally be found in bodily fluids like saliva, tears, and milk. [9] In the soluble form, MUC-4 appears to lubricate the epithelial mucosa. [8]
MUC-4 is thought to play a role in cancer progression by repressing apoptosis and consequently increasing tumor cell proliferation. [17] The molecular mechanism is thought to be through a MUC-4 complex with ERBB2 receptors, which alters downstream signaling and down regulates CDKN1B. [17] The beta subunit of MUC-4 appears to serve as a ligand that causes the phosphorylation of ErbB2, but does not activate the MAPK or AKT pathways. [18] MUC-4 may also affect HER2 signaling, and result in its stabilization. [6] [19] As a mucin, MUC-4 also alters adhesive properties of the cell. When overexpressed, the disorganization of mucins may reduce adhesion to other cells as well as the extracellular matrix, promoting cancer cell migration and metastasis.
MUC4 is often overexpressed in pancreatic adenocarcinomas and has been shown to promote tumor growth and metastasis, though the mechanism by which it does so is not known. [4] MUC4 detection is emerging as a method to diagnose pancreatic cancer, especially since MUC4 is not detectably expressed in normal pancreas and increased expression of MUC-4 suggests a greater progression of the disease. [4] Scientists have recently experimented with MUC4 inhibition in pancreatic cancer using drug delivery methods such as microRNAs. [20] Such efforts have been successful at reducing EGF receptor expression, its downstream signaling, and consequently malignant behavior of the cancer cell such as migration, invasion, and cell detachment.
Bile acids have been found to stimulate carcinogenesis in pancreatic ductal adenocarcinoma cells through increased expression of MUC4. [21]
MUC4 expression in esophageal cancer often leads to increased tumor proliferation and migration. Like with prostate cancer, increased expression of MUC4 suggests greater development of esophageal cancer. Bile acids present in gastroesophageal reflux disease are thought to contribute to this over-expression of MUC4. By inhibiting MUC-4, scientists have been able to reduce cancer cell proliferation, migration, and tumor size as well as reduce protein S100A4 expression, presenting MUC-4 as a good therapeutic target for the treatment of esophageal cancer. [22]
Unlike pancreatic and esophageal cancers, MUC4 expression is suppressed in the primary tumor when compared to normal cells. [23] It, however, is found to be overexpressed in lymph node metastases. The initial reduction in MUC-4 appears to promote the transition to the primary tumor, but its subsequent increase in expression facilitate metastasis and ultimately increased malignancy [23]
MUC4 is found to be overexpressed in papillary thyroid carcinoma, and could serve as a potential marker of malignancy and prognosis. [24] MUC-4 is also found to be a very sensitive and specific marker in low-grade fibromyxoid sarcoma. [25]
MUC-4 is also relevant to several other disease conditions. Polymorphisms in the MUC4 gene have been found to play a role in the progression of endometriosis and related infertility, [15] as well as dysplastic cervical disorders. [26] MUC-4 also has important roles in inflammatory bowel disease such as Crohn's disease and is found to be overexpressed in ulcerative colitis. [27]
Mucin-16(MUC-16) also known as Ovarian cancer-related tumor marker CA125 is a protein that in humans is encoded by the MUC16 gene. MUC-16 is a member of the mucin family glycoproteins. MUC-16 has found application as a tumor marker or biomarker that may be elevated in the blood of some patients with specific types of cancers, most notably ovarian cancer, or other conditions that are benign.
Mucins are a family of high molecular weight, heavily glycosylated proteins (glycoconjugates) produced by epithelial tissues in most animals. Mucins' key characteristic is their ability to form gels; therefore they are a key component in most gel-like secretions, serving functions from lubrication to cell signalling to forming chemical barriers. They often take an inhibitory role. Some mucins are associated with controlling mineralization, including nacre formation in mollusks, calcification in echinoderms and bone formation in vertebrates. They bind to pathogens as part of the immune system. Overexpression of the mucin proteins, especially MUC1, is associated with many types of cancer.
Receptor tyrosine-protein kinase erbB-2 is a protein that normally resides in the membranes of cells and is encoded by the ERBB2 gene. ERBB is abbreviated from erythroblastic oncogene B, a gene originally isolated from the avian genome. The human protein is also frequently referred to as HER2 or CD340.
Glypicans constitute one of the two major families of heparan sulfate proteoglycans, with the other major family being syndecans. Six glypicans have been identified in mammals, and are referred to as GPC1 through GPC6. In Drosophila two glypicans have been identified, and these are referred to as dally and dally-like. One glypican has been identified in C. elegans. Glypicans seem to play a vital role in developmental morphogenesis, and have been suggested as regulators for the Wnt and Hedgehog cell signaling pathways. They have additionally been suggested as regulators for fibroblast growth factor and bone morphogenic protein signaling.
The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.
EGF-like module-containing mucin-like hormone receptor-like 2 also known as CD312 is a protein encoded by the ADGRE2 gene. EMR2 is a member of the adhesion GPCR family. Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.
Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the MUC1 gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and several other organs. Mucins protect the body from infection by pathogen binding to oligosaccharides in the extracellular domain, preventing the pathogen from reaching the cell surface. Overexpression of MUC1 is often associated with colon, breast, ovarian, lung and pancreatic cancers. Joyce Taylor-Papadimitriou identified and characterised the antigen during her work with breast and ovarian tumors.
Receptor tyrosine-protein kinase erbB-3, also known as HER3, is a membrane bound protein that in humans is encoded by the ERBB3 gene.
Mucin-5AC(MUC-5AC) is a protein that in humans is encoded by the MUC5AC gene.
Heparanase, also known as HPSE, is an enzyme that acts both at the cell-surface and within the extracellular matrix to degrade polymeric heparan sulfate molecules into shorter chain length oligosaccharides.
Signet ring cell carcinoma (SRCC) is a rare form of highly malignant adenocarcinoma that produces mucin. It is an epithelial malignancy characterized by the histologic appearance of signet ring cells.
Laminin subunit gamma-2 is a protein that in humans is encoded by the LAMC2 gene.
RhoC is a small signaling G protein, and is a member of the Rac subfamily of the family Rho family of GTPases. It is encoded by the gene RHOC.
Anterior gradient protein 2 homolog (AGR-2), also known as secreted cement gland protein XAG-2 homolog, is a protein that in humans is encoded by the AGR2 gene. Anterior gradient homolog 2 was originally discovered in Xenopus laevis. In Xenopus AGR2 plays a role in cement gland differentiation, but in human cancer cell lines high levels of AGR2 correlate with downregulation of the p53 response, cell migration, and cell transformation. However, there have been other observations that AGR2 can repress growth and proliferation.
Reversion-inducing-cysteine-rich protein with kazal motifs, also known as RECK, is a human gene, thought to be a metastasis suppressor.
60S ribosomal protein L19 is a protein that in humans is encoded by the RPL19 gene.
Matrix metalloproteinase-24 is an enzyme that in humans is encoded by the MMP24 gene.
Melanoma inhibitory activity protein 3 (MIA3), also known as transport and Golgi organization protein 1 (TANGO1), is a protein that in humans is encoded by the MIA3 gene on chromosome 1. It is ubiquitously expressed in many tissues and cell types. MIA3 localizes to the endoplasmic reticulum (ER) exit site, where it binds bulky cargo molecules such as collagens and creates mega transport carriers for the export of cargoes from the ER. This function suggests that it plays a role in assembly of extracellular matrix (ECM) and bone formation. MIA3 has been demonstrated to contribute to both tumor suppression and progression. The MIA3 gene also contains one of 27 loci associated with increased risk of coronary artery disease.. A TANGO1 like protein called TALI is expressed in liver and intestine and shown to be required for the export of bulky very Low density lipoproteins (VLDL) and chylomicrons. TANGO1 and TALI assemble into rings around COPII coats and this function is necessary for export of bulky cargoes. The discovery of TANGO1 and understanding its function has revealed that cargo export from the ER is not be vesicles but involves transient tunnels between the ER exit site and the next compartment of the secretory pathway. Biallelic Mutations in TANGO1 cause syndrome disease and complete loss of TANGO1 leads of defects in bone mineralization. These findings highlight the significance of TANGO1 in building and ER exit site, controlling the quantities and quality of cargo exported, which is necessary for life.
Mucin-1(MUC-1) is a heterodimer transmembrane protein of the mucin family encoded in humans by the MUC1 gene. It is cleaved into two chains: mucin-1 subunit alpha and mucin-1 subunit beta. These subunits differ in size due to proteolytic cleavage of the translated precursor protein in the endoplasmic reticulum. The larger subunit of MUC-1 is characterized by numerous O-glycosylated bonds and a terminal sialic acid, creating a net negative charge on MUC-1. The smaller subunit contains a juxtamembrane region of the extracellular area, a transmembrane domain, and the cytoplasmic tail. The extracellular domain of MUC-1 is composed of 20 identical amino acid tandem repeats (TR). Each tandem repeat contains two serine and three threonine amino acid residues, providing five sites for potential O-glycosylation. MUC-1 protein is estimated to weigh 120 to 225 kDA.
hPG80 refers to the extracellular and oncogenic version of progastrin. This name first appeared in a scientific publication in January 2020. Until that date, scientific publications only mention 'progastrin', without necessarily explicitly specifying whether it is intracellular or extracellular in the tumor pathological setting.