MUC1
Encyclopedia
Mucin 1, cell surface associated (MUC1) or polymorphic epithelial mucin (PEM) is a mucin
encoded by the MUC1 gene
in humans. MUC1 is a proteoglycan
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 oligosaccharide
s 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.
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 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 sheddase
s. 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 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 domain 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 the subunits. The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosporylation sites.
Overexpression, aberrant intracellular localization, and changes in glycosylation
of this protein have been associated with carcinoma
s. eg. The CanAg tumour antigen is a novel glycoform of MUC1.
with HER2/neu
, Plakoglobin
, CTNND1
, SOS1
and Grb2
.
. 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 fibroblast
s increased 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 of MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents 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 the mitochondria prevents the activation of apoptotic mechanisms.
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 is antagonized by degradation of beta-catenin by GSK3B
. MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B. The end 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 the initiation of epithelial-mesenchymal transition
which promotes the formation of metastases.
Mucin
Mucins are a family of high molecular weight, heavily glycosylated proteins produced by epithelial tissues in most metazoans. 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...
encoded by the MUC1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
in humans. MUC1 is a proteoglycan
Proteoglycan
Proteoglycans are proteins that are heavily glycosylated. The basic proteoglycan unit consists of a "core protein" with one or more covalently attached glycosaminoglycan chain. The point of attachment is a Ser residue to which the glycosaminoglycan is joined through a tetrasaccharide bridge...
with extensive O-linked glycosylation
O-linked glycosylation
- O-N-acetylgalactosamine :O-linked glycosylation occurs at a later stage during protein processing, probably in the Golgi apparatus...
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
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
binding to oligosaccharide
Oligosaccharide
An oligosaccharide is a saccharide polymer containing a small number of component sugars, also known as simple sugars...
s 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.
Structure
MUC1 is a member of the mucin family and encodes a membrane bound, glycosylatedGlycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
phosphoprotein
Phosphoprotein
Phosphoproteins are proteins that are physically bonded to a substance containing phosphoric acid . This category of organic molecules includes Fc receptors, Ulks, Calcineurins, K chips, and urocortins....
. MUC1 has a core protein mass of 120-225 kDa which increases to 250-500 kDa with glycosylation. It extends 200-500 nm beyond the surface of the cell.
The protein is anchored to the apical surface of many epithelia
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
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 sheddase
Sheddase
Sheddases are membrane-bound enzymes that cleave extracellular portions of transmembrane proteins, releasing the soluble ectodomains from the cell surface...
s. The extracellular domain includes a 20 amino acid variable number tandem repeat (VNTR
Variable number tandem repeat
A Variable Number Tandem Repeat is a location in a genome where a short nucleotide sequence is organized as a tandem repeat. These can be found on many chromosomes, and often show variations in length between individuals. Each variant acts as an inherited allele, allowing them to be used for...
) 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 the full-length nature of only some has been determined.
MUC1 is cleaved in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
into two pieces, the cytoplasmic tail including the transmembrane domain and the extracellular domain. These domain tightly associate in a non-covalent fashion. This tight, non-covalent association is not broken by treatment with urea
Urea
Urea or carbamide is an organic compound with the chemical formula CO2. The molecule has two —NH2 groups joined by a carbonyl functional group....
, low pH, high salt or boiling. Treatment with sodium dodecyl sulfate
Sodium dodecyl sulfate
Sodium dodecyl sulfate , sodium laurilsulfate or sodium lauryl sulfate is an organic compound with the formula CH311OSO3Na). It is an anionic surfactant used in many cleaning and hygiene products...
triggers dissociation of the subunits. The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosporylation sites.
Function
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
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
of this protein have been associated with carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
s. eg. The CanAg tumour antigen is a novel glycoform of MUC1.
Interactions
MUC1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with HER2/neu
HER2/neu
HER-2 also known as proto-oncogene Neu, receptor tyrosine-protein kinase erbB-2, CD340 or p185 is an enzyme that in humans is encoded by the ERBB2 gene. Over expression of this gene is correlated with higher aggressiveness in breast cancers...
, Plakoglobin
Plakoglobin
Junction plakoglobin, also known as gamma-catenin or JUP, is a protein that in humans is encoded by the JUP gene.- Function :...
, CTNND1
CTNND1
Catenin delta-1 is a protein that in humans is encoded by the CTNND1 gene.-Interactions:CTNND1 has been shown to interact with Beta-catenin, FYN, Collagen, type XVII, alpha 1, PTPN6, YES1, PTPRJ, VE-cadherin, MUC1, CDH1, CDH2, PTPRM, Cortactin, Nephrin, ZBTB33 and PSEN1.-Further reading:...
, SOS1
SOS1
Son of sevenless homolog 1 is a protein that in humans is encoded by the SOS1 gene.Recent studies also show that mutations in Sos1 can cause Noonan syndrome and hereditary gingival fibromatosis type 1. Noonan syndrome has also been shown to be caused by mutations in KRAS and PTPN11 genes...
and Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
.
Role in Cancer
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 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 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.Preventing Cell Death
MUC1 cytoplasmic tail has been shown to bind to p53P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
. This interaction is increased by genotoxic stress. MUC1 and p53 were found to be associated with the p53 response element of the p21
P21
p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
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 fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
s increased the phosphorylation of Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
. Phosphorylation of Akt results in phosphorylation of Bcl-2-associated death promoter
Bcl-2-associated death promoter
The Bcl-2-associated death promoter protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family...
. This results in dissociation of Bcl-2-associated death promoter with Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
and Bcl-xL
Bcl-xL
B-cell lymphoma-extra large is a transmembrane molecule in the mitochondria. It is involved in the signal transduction pathway of the FAS-L. It is one of several anti-apoptotic proteins which are members of the Bcl-2 family of proteins. It has been implicated in the survival of cancer cells. Other...
. Activation was shown to be dependent on the upstream activation of PI3K. Additionally, MUC1 was shown to increase expression of Bcl-xL. Overexpression of of MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents the release of cytochrome c
Cytochrome c
The Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
from mitochondria, thereby preventing apoptosis.
MUC1 cytoplasmic tail is shuttled to the mitochondria through interaction with hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
. This interaction is induced through phosphorylation of the MUC1 cytoplasmic tail by Src (gene)
Src (gene)
Proto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
. 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 the mitochondria prevents the activation of apoptotic mechanisms.
Promoting Tumor Invasion
MUC1 cytoplasmic tail was shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Beta-catenin
Beta-catenin
Beta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
. 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
LYN
Tyrosine-protein kinase Lyn is a protein that in humans is encoded in humans by the LYN gene.Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells, in neural tissues liver, and adipose tissue. In various hematopoietic cells, Lyn has emerged...
through mediation of interleukin 7
Interleukin 7
IL-7 a hematopoietic growth factor secreted by stromal cells in the red marrow and thymus. It is also produced by keratinocytes, dendritic cells, hepatocytes, neurons, and epithelial cells but is not produced by lymphocytes.- Genetics :...
, Src through mediation of EGFR, and PRKCD
PRKCD
Protein kinase C delta type is an enzyme that in humans is encoded by the PRKCD gene.- Function :Protein kinase C is a family of serine- and threonine-specific protein kinases that can be activated by calcium and the second messenger diacylglycerol...
. This interaction is antagonized by degradation of beta-catenin by GSK3B
GSK3B
Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene.- Function :Glycogen synthase kinase-3 is a proline-directed serine-threonine kinase that was initially identified as a phosphorylating and inactivating glycogen synthase. Two isoforms,...
. MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B. The end result is that increased expression of MUC1 in cancer increases stabilized beta-catenin. This promotes the expression of vimentin
Vimentin
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
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 the initiation of epithelial-mesenchymal transition
Epithelial-mesenchymal transition
Epithelial-mesenchymal transition or transformation is a hypothesized program of development of biological cells characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell mobility...
which promotes the formation of metastases.