1SM3 , 2ACM
49-832: 4582 n/a ENSG00000185499 n/a P15941 Q7Z551 n/a NM_001044392 NM_001044393 NM_001204285 NM_001204286 NM_001204287 NM_001204288 NM_001204289 NM_001204290 NM_001204291 NM_001204292 NM_001204293 NM_001204294 NM_001204295 NM_001204296 NM_001204297 NM_002456 NM_182741 NM_001371720 n/a NP_001037858 NP_001191214 NP_001191215 NP_001191216 NP_001191217 NP_001191218 NP_001191219 NP_001191220 NP_001191221 NP_001191222 NP_001191223 NP_001191224 NP_001191225 NP_001191226 NP_002447 NP_001358649 NP_001191217.1 NP_001191225.1 NP_001037856.1 n/a Mucin short variant S1 , also called polymorphic epithelial mucin ( PEM ) or epithelial membrane antigen ( EMA ),
98-558: A Korean snail mucin product called COSRX have been selling online, putting users at risk. Glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan '), i.e. a glycosyl donor , is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor ) in order to form a glycoconjugate . In biology (but not always in chemistry), glycosylation usually refers to an enzyme-catalysed reaction, whereas glycation (also 'non-enzymatic glycation' and 'non-enzymatic glycosylation') may refer to
147-490: A consequence, they are also hard to treat. However, thanks to the many advances that have been made in next-generation sequencing , scientists can now understand better these disorders and have discovered new CDGs. It has been reported that mammalian glycosylation can improve the therapeutic efficacy of biotherapeutics . For example, therapeutic efficacy of recombinant human interferon gamma , expressed in HEK ;293 platform,
196-465: A decreased level, skin elasticity is reduced which is an important symptom of aging. They are also the precursors of many hormones and regulate and modify their receptor mechanisms at the DNA level. There are different enzymes to remove the glycans from the proteins or remove some part of the sugar chain. Notch signalling is a cell signalling pathway whose role is, among many others, to control
245-407: A highly hydrophilic region which prevents hydrophobic chemotherapeutic drugs from passing through. This prevents the drugs from reaching their targets which usually reside within the cell. Similarly, the glycosylation has been shown to bind to growth factors. This allows cancer cells which produce a large amount of MUC1 to concentrate growth factors near their receptors, increasing receptor activity and
294-413: A non-enzymatic reaction. Glycosylation is a form of co-translational and post-translational modification . Glycans serve a variety of structural and functional roles in membrane and secreted proteins. The majority of proteins synthesized in the rough endoplasmic reticulum undergo glycosylation. Glycosylation is also present in the cytoplasm and nucleus as the O -GlcNAc modification. Aglycosylation
343-450: A result of endogenous functionality (such as cell trafficking ). However, it is more likely that diversification is driven by evasion of pathogen infection mechanism (e.g. Helicobacter attachment to terminal saccharide residues) and that diversity within the multicellular organism is then exploited endogenously. Glycosylation can also modulate the thermodynamic and kinetic stability of the proteins. Glycosylation increases diversity in
392-465: A role in this process. 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 Ca for Na expands up to 600 fold. The result is a viscoelastic product of interwoven molecules which, combined with other secretions (e.g., from
441-492: A specific molecule (or marker) of MUC1. MUC1 is found on nearly all epithelial cells, but it is over expressed in cancer cells, and its associated glycans are shorter than those of non-tumor-associated MUC1. Because MUC1 is overexpressed (and differently glycosylated) in many cancers it has been investigated as a drug target, e.g. for the MUC1 vaccine ONT-10, which has had a phase 1 clinical study. This article incorporates text from
490-439: A wide range of secretory epithelia and their neoplastic equivalents: Using MUC1, vaccines are being tested against a type of blood cancer called multiple myeloma . The technology could in theory be applied to 90 percent of all known cancers, including prostate and breast cancer, solid and non-solid tumors. This method would activate the immune system by training T-cells to search out and destroy cells that display
539-451: 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
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#1733106152346588-463: Is a feature of engineered antibodies to bypass glycosylation. Five classes of glycans are produced: Glycosylation is the process by which a carbohydrate is covalently attached to a target macromolecule , typically proteins and lipids . This modification serves various functions. For instance, some proteins do not fold correctly unless they are glycosylated. In other cases, proteins are not stable unless they contain oligosaccharides linked at
637-408: Is a novel glycoform of MUC1. In the cell nucleus, the protein MUC1 regulates the activity of transcription factor complexes that have a documented role in tumor-induced changes of host immunity. MUC1 has been shown to interact with: The ability of chemotherapeutic drugs to access the cancer cells is inhibited by the heavy glycosylation in the extracellular domain of MUC1. The glycosylation creates
686-504: Is a special form of glycosylation that features the formation of a GPI anchor . In this kind of glycosylation a protein is attached to a lipid anchor, via a glycan chain. (See also prenylation .) Glycosylation can also be effected using the tools of synthetic organic chemistry . Unlike the biochemical processes, synthetic glycochemistry relies heavily on protecting groups (e.g. the 4,6- O -benzylidene) in order to achieve desired regioselectivity. The other challenge of chemical glycosylation
735-399: Is a spontaneous reaction and a type of post-translational modification of proteins meaning it alters their structure and biological activity. It is the covalent attachment between the carbonil group of a reducing sugar (mainly glucose and fructose) and the amino acid side chain of the protein. In this process the intervention of an enzyme is not needed. It takes place across and close to
784-416: Is added to the first tryptophan residue in the sequence W–X–X–W (W indicates tryptophan; X is any amino acid). A C-C bond is formed between the first carbon of the alpha-mannose and the second carbon of the tryptophan. However, not all the sequences that have this pattern are mannosylated. It has been established that, in fact, only two thirds are and that there is a clear preference for
833-458: Is another group of proteins that undergo C -mannosylation, type I cytokine receptors . C -mannosylation is unusual because the sugar is linked to a carbon rather than a reactive atom such as nitrogen or oxygen . In 2011, the first crystal structure of a protein containing this type of glycosylation was determined—that of human complement component 8. Currently it is established that 18% of human proteins , secreted and transmembrane undergo
882-511: Is antagonized by degradation of beta-catenin by GSK3B . MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B. The result is that increased expression of MUC1 in cancer increases stabilized beta-catenin. This promotes the expression of vimentin and CDH2 . These proteins are associated with a mesenchymal phenotype, characterized by increased motility and invasiveness. In cancer cells, increased expression of MUC1 promotes cancer cell invasion through beta-catenin, resulting in
931-420: Is still incomplete and ongoing. Known-related groups include: Mucins have been found to have important functions in defense against bacterial and fungal infections. MUC5B, the predominant mucin in the mouth and female genital tract, has been shown to significantly reduce attachment and biofilm formation of Streptococcus mutans , a bacterium with the potential to form cavities. Unusually, MUC5B does not kill
980-402: Is the stereoselectivity that each glycosidic linkage has two stereo-outcomes, α/β or cis / trans . Generally, the α- or cis -glycoside is more challenging to synthesis. New methods have been developed based on solvent participation or the formation of bicyclic sulfonium ions as chiral-auxiliary groups. The non-enzymatic glycosylation is also known as glycation or non-enzymatic glycation. It
1029-501: The Golgi apparatus . The Notch proteins go through these organelles in their maturation process and can be subject to different types of glycosylation: N-linked glycosylation and O-linked glycosylation (more specifically: O-linked glucose and O-linked fucose). All of the Notch proteins are modified by an O-fucose, because they share a common trait: O-fucosylation consensus sequences . One of
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#17331061523461078-492: The HUGO symbol MUC 1 through 22. Of these mucins, the following classes have been defined by localization: The major secreted airway mucins are MUC5AC and MUC5B , while MUC2 is secreted mostly in the intestine but also in the airway. MUC7 is the major salivary protein. Mature mammalian mucins are composed of two distinct regions: The functional classification does not correspond to an exact evolutionary relationship, which
1127-861: The United States National Library of Medicine , which is in the public domain . Mucin Mucins ( / ˈ m juː s ɪ n / ) 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
1176-509: The airway epithelium and the submucosal glands in the respiratory system ), is called mucus . Increased mucin production occurs in many adenocarcinomas , including cancers of the pancreas, lung, breast, ovary, colon and other tissues. Mucins are also overexpressed in lung diseases such as asthma , bronchitis , chronic obstructive pulmonary disease (COPD) or cystic fibrosis . Two membrane mucins, MUC1 and MUC4 have been extensively studied in relation to their pathological implication in
1225-460: The amide nitrogen of certain asparagine residues. The influence of glycosylation on the folding and stability of glycoprotein is twofold. Firstly, the highly soluble glycans may have a direct physicochemical stabilisation effect. Secondly, N -linked glycans mediate a critical quality control check point in glycoprotein folding in the endoplasmic reticulum. Glycosylation also plays a role in cell-to-cell adhesion (a mechanism employed by cells of
1274-422: The cell differentiation process in equivalent precursor cells . This means it is crucial in embryonic development, to the point that it has been tested on mice that the removal of glycans in Notch proteins can result in embryonic death or malformations of vital organs like the heart. Some of the specific modulators that control this process are glycosyltransferases located in the endoplasmic reticulum and
1323-880: The eye surface epithelia, goblet cells and associated glands, even though most of them are expressed at very low levels. They maintain wetness, lubricate the blink, stabilize the tear film, and create a physical barrier to the outside world. Mucin genes encode mucin monomers that are synthesized as rod-shaped 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
1372-559: The immune system ) via sugar-binding proteins called lectins , which recognize specific carbohydrate moieties. Glycosylation is an important parameter in the optimization of many glycoprotein-based drugs such as monoclonal antibodies . Glycosylation also underpins the ABO blood group system. It is the presence or absence of glycosyltransferases which dictates which blood group antigens are presented and hence what antibody specificities are exhibited. This immunological role may well have driven
1421-456: The proteome , because almost every aspect of glycosylation can be modified, including: There are various mechanisms for glycosylation, although most share several common features: N -linked glycosylation is a very prevalent form of glycosylation and is important for the folding of many eukaryotic glycoproteins and for cell–cell and cell– extracellular matrix attachment. The N -linked glycosylation process occurs in eukaryotes in
1470-469: The bacteria but rather maintains it in the planktonic (non-biofilm) phase, thus maintaining a diverse and healthy oral microbiome. Similar effects of MUC5B and other mucins have been demonstrated with other pathogens, such as Candida albicans , Helicobacter pylori , and even HIV . In the mouth, mucins can also recruit anti-microbial proteins such as statherins and histatine 1 , which further reduces risk of infection. Eleven mucins are expressed by
1519-454: The brownish color and the aromas and flavors of some foods. It is demonstrated that cooking at high temperature results in various food products having high levels of AGEs. Having elevated levels of AGEs in the body has a direct impact on the development of many diseases. It has a direct implication in diabetes mellitus type 2 that can lead to many complications such as: cataracts , renal failure , heart damage... And, if they are present at
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1568-639: The disease process. Mucins are under investigation as possible diagnostic markers for malignancies and other disease processes in which they are most commonly over- or mis-expressed. Abnormal deposits of mucin are responsible for the non-pitting facial edema seen in untreated hypothyroidism . This edema is seen in the pretibial area as well. Beyond the better-studied vertebrate mucins, other animals also express (not necessarily related) proteins with similar properties. These include: Use of skincare products containing snail secretions of mucin have resulted in pain, swelling, and oozing. Counterfeit versions of
1617-506: The diversification of glycan heterogeneity and creates a barrier to zoonotic transmission of viruses. In addition, glycosylation is often used by viruses to shield the underlying viral protein from immune recognition. A significant example is the dense glycan shield of the envelope spike of the human immunodeficiency virus . Overall, glycosylation needs to be understood by the likely evolutionary selection pressures that have shaped it. In one model, diversification can be considered purely as
1666-439: The full-length nature of only some has been determined. MUC1 is cleaved in the endoplasmic reticulum into two pieces, the cytoplasmic tail including the transmembrane domain and the extracellular domain. These domains tightly associate in a non-covalent fashion. This tight, non-covalent association is not broken by treatment with urea , low pH, high salt or boiling. Treatment with sodium dodecyl sulfate triggers dissociation of
1715-656: The growth of cancer cells. MUC1 also prevents the interaction of immune cells with receptors on the cancer cell surface through steric hindrance. This inhibits an anti-tumor immune response. MUC1 cytoplasmic tail has been shown to bind to p53 . This interaction is increased by genotoxic stress. MUC1 and p53 were found to be associated with the p53 response element of the p21 gene promoter. This results in activation of p21 which results in cell cycle arrest. Association of MUC1 with p53 in cancer results in inhibition of p53-mediated apoptosis and promotion of p53-mediated cell cycle arrest. Overexpression of MUC1 in fibroblasts increased
1764-443: The immune system. Overexpression of the mucin proteins, especially MUC1 , is associated with many types of cancer. 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 as principal components of mucus by mucous membranes or are secreted to become a component of saliva . Human mucins include genes with
1813-606: The initiation of epithelial-mesenchymal transition which promotes the formation of metastases. CA 27.29 (aka BR 27.29) and CA 15-3 measure different epitopes of the same protein antigen product of the MUC1 gene seen in breast cancer. CA 27.29 has enhanced sensitivity and specificity compared to CA 15-3 and is elevated in 30% of patients with low-stage disease and 60 to 70% of patients with advanced-stage breast cancer. CA 27.29 levels over 100 U/mL and CA 15-3 levels over 25 U/mL are rare in benign conditions and suggest malignancy. Using immunohistochemistry , MUC1 can be identified in
1862-619: The literature. Fucose and GlcNAc have been found only in Dictyostelium discoideum , mannose in Leishmania mexicana , and xylose in Trypanosoma cruzi . Mannose has recently been reported in a vertebrate, the mouse, Mus musculus , on the cell-surface laminin receptor alpha dystroglycan . It has been suggested this rare finding may be linked to the fact that alpha dystroglycan is highly conserved from lower vertebrates to mammals. A mannose sugar
1911-529: The lumen of the endoplasmic reticulum and widely in archaea , but very rarely in bacteria . In addition to their function in protein folding and cellular attachment, the N -linked glycans of a protein can modulate a protein's function, in some cases acting as an on/off switch. O -linked glycosylation is a form of glycosylation that occurs in eukaryotes in the Golgi apparatus , but also occurs in archaea and bacteria . Xylose , fucose , mannose , and GlcNAc phosphoserine glycans have been reported in
1960-526: The mitochondria prevents the activation of apoptotic mechanisms. MUC1 cytoplasmic tail was shown to interact with Beta-catenin . A SXXXXXSSL motif was identified in MUC1 that is conserved with other beta-catenin binding partners. This interaction was shown to be dependent on cell adhesion. Studies have demonstrated that MUC1 is phosphorylated on a YEKV motif. Phosphorylation of this site has been demonstrated by LYN through mediation of interleukin 7 , Src through mediation of EGFR, and PRKCD . This interaction
2009-674: The modulators that intervene in this process is the Fringe, a glycosyltransferase that modifies the O-fucose to activate or deactivate parts of the signalling, acting as a positive or negative regulator, respectively. There are three types of glycosylation disorders sorted by the type of alterations that are made to the glycosylation process: congenital alterations, acquired alterations and non-enzymatic acquired alterations. All these diseases are difficult to diagnose because they do not only affect one organ, they affect many of them and in different ways. As
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2058-494: 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. MUC1 is a member of the mucin family and encodes a membrane bound, glycosylated phosphoprotein . MUC1 has a core protein mass of 120-225 kDa which increases to 250-500 kDa with glycosylation. It extends 200-500 nm beyond
2107-428: The phosphorylation of Akt . Phosphorylation of Akt results in phosphorylation of Bcl-2-associated death promoter . This results in dissociation of Bcl-2-associated death promoter with Bcl-2 and Bcl-xL . Activation was shown to be dependent on the upstream activation of PI3K . Additionally, MUC1 was shown to increase expression of Bcl-xL. Overexpression of MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents
2156-422: The process of C-mannosylation. Numerous studies have shown that this process plays an important role in the secretion of Trombospondin type 1 containing proteins which are retained in the endoplasmic reticulum if they do not undergo C-mannosylation This explains why a type of cytokine receptors , erythropoietin receptor remained in the endoplasmic reticulum if it lacked C-mannosylation sites. Glypiation
2205-476: The release of cytochrome c from mitochondria, thereby preventing apoptosis. MUC1 cytoplasmic tail is shuttled to the mitochondria through interaction with hsp90 . This interaction is induced through phosphorylation of the MUC1 cytoplasmic tail by Src (gene) . Src is activated by the EGF receptor family ligand Neuregulin . The cytoplasmic tail is then inserted into the mitochondrial outer membrane. Localization of MUC1 to
2254-485: The second amino acid to be one of the polar ones (Ser, Ala , Gly and Thr) in order for mannosylation to occur. Recently there has been a breakthrough in the technique of predicting whether or not the sequence will have a mannosylation site that provides an accuracy of 93% opposed to the 67% accuracy if we just consider the WXXW motif. Thrombospondins are one of the proteins most commonly modified in this way. However, there
2303-400: The subunits. The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosphorylation sites. The protein serves a protective function by binding to pathogens and also functions in a cell signaling capacity. Overexpression, aberrant intracellular localization, and changes in glycosylation of this protein have been associated with carcinomas . e.g. The CanAg tumour antigen
2352-692: The surface of the cell. The protein is anchored to the apical surface of many epithelia by a transmembrane domain. Beyond the transmembrane domain is a SEA domain that contains a cleavage site for release of the large extracellular domain. The release of mucins is performed by sheddases . The extracellular domain includes a 20 amino acid variable number tandem repeat ( VNTR ) domain, with the number of repeats varying from 20 to 120 in different individuals. These repeats are rich in serine, threonine and proline residues which permits heavy o-glycosylation. Multiple alternatively spliced transcript variants that encode different isoforms of this gene have been reported, but
2401-692: The water channels and the protruding tubules. At first, the reaction forms temporary molecules which later undergo different reactions ( Amadori rearrangements , Schiff base reactions, Maillard reactions , crosslinkings ...) and form permanent residues known as Advanced Glycation end-products (AGEs). AGEs accumulate in long-lived extracellular proteins such as collagen which is the most glycated and structurally abundant protein, especially in humans. Also, some studies have shown lysine may trigger spontaneous non-enzymatic glycosylation. AGEs are responsible for many things. These molecules play an important role especially in nutrition, they are responsible for
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