Mucin short variant S1

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 the surface of the cell.{{cite journal |vauthors=Brayman M, Thathiah A, Carson DD | title = MUC1: a multifunctional cell surface component of reproductive tissue epithelia | journal = Reprod Biol Endocrinol | volume = 2 | pages = 4 |date=January 2004 | pmid = 14711375 | doi = 10.1186/1477-7827-2-4 | pmc = 320498 | doi-access = free }}

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.{{cite journal | vauthors = Hattrup CL, Gendler SJ | title = Structure and function of the cell surface (tethered) mucins | journal = Annual Review of Physiology | volume = 70 | pages = 431–57 | date = 2008 | pmid = 17850209 | doi = 10.1146/annurev.physiol.70.113006.100659 }} 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.{{cite web | title = Entrez Gene: SEA Domain of MUC1| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4582}}

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.{{cite journal | vauthors = Ligtenberg MJ, Kruijshaar L, Buijs F, van Meijer M, Litvinov SV, Hilkens J | title = Cell-associated episialin is a complex containing two proteins derived from a common precursor | journal = The Journal of Biological Chemistry | volume = 267 | issue = 9 | pages = 6171–7 | date = March 1992 | doi = 10.1016/S0021-9258(18)42677-4 | pmid = 1556125| doi-access = free }} 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.{{cite journal |vauthors=Julian J, Carson DD | title = Formation of MUC1 metabolic complex is conserved in tumor-derived and normal epithelial cells | journal = Biochem Biophys Res Commun | volume = 293 | issue = 4 | pages = 1183–1190 |date=May 2002 | pmid = 12054500 | doi = 10.1016/S0006-291X(02)00352-2}} The cytoplasmic tail of MUC1 is 72 amino acids long and contains several phosphorylation sites.{{cite journal |vauthors=Singh PK, Hollingsworth MA | title = Cell surface-associated mucins in signal transduction | journal = Trends Cell Biol | volume = 16 | issue = 9 | pages = 467–476 |date=August 2006 | pmid = 16904320 | doi = 10.1016/j.tcb.2006.07.006}}

The protein serves a protective function by binding to pathogens{{cite journal |vauthors=Lindén SK, Sheng YH, Every AL, Miles KM, Skoog EC, Florin TH, Sutton P, McGuckin MA | title = MUC1 limits Helicobacter pylori infection both by steric hindrance and by acting as a releasable decoy | journal = PLOS Pathog. | volume = 5 | issue = 10 | pages = e1000617 |date=October 2009 | pmid = 19816567 | pmc = 2752161 | doi = 10.1371/journal.ppat.1000617 | doi-access = free }} 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 is a novel glycoform of MUC1.{{cite journal |vauthors=Tolcher AW, Ochoa L, Hammond LA, Patnaik A, Edwards T, Takimoto C, Smith L, de Bono J, Schwartz G, Mays T, Jonak ZL, Johnson R, DeWitte M, Martino H, Audette C, Maes K, Chari RV, Lambert JM, Rowinsky EK | title = Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study | journal = J. Clin. Oncol. | volume = 21 | issue = 2 | pages = 211–22 |date=January 2003 | pmid = 12525512 | doi = 10.1200/JCO.2003.05.137 }} 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.{{cite journal|last1=Vlahopoulos|first1=SA|title= Aberrant control of NF-κB in cancer permits transcriptional and phenotypic plasticity, to curtail dependence on host tissue: molecular mode|journal= Cancer Biology & Medicine|date=15 August 2017|pmid= 28884042|doi= 10.20892/j.issn.2095-3941.2017.0029|volume=14|issue=3|pages=254–270|pmc=5570602}}

MUC1 has been shown to interact with:

• CTNND1,{{cite journal |vauthors=Li Y, Kufe D | title = The Human DF3/MUC1 carcinoma-associated antigen signals nuclear localization of the catenin p120(ctn) | journal = Biochem. Biophys. Res. Commun. | volume = 281 | issue = 2 | pages = 440–3 |date=February 2001 | pmid = 11181067 | doi = 10.1006/bbrc.2001.4383 }}
• ERBB2,{{cite journal |vauthors=Li Y, Yu WH, Ren J, Chen W, Huang L, Kharbanda S, Loda M, Kufe D | title = Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein | journal = Mol. Cancer Res. | volume = 1 | issue = 10 | pages = 765–75 |date=August 2003 | pmid = 12939402 }}{{cite journal |vauthors=Schroeder JA, Thompson MC, Gardner MM, Gendler SJ | title = Transgenic MUC1 interacts with epidermal growth factor receptor and correlates with mitogen-activated protein kinase activation in the mouse mammary gland | journal = J. Biol. Chem. | volume = 276 | issue = 16 | pages = 13057–64 |date=April 2001 | pmid = 11278868 | doi = 10.1074/jbc.M011248200 | doi-access = free }}
• GRB2,{{cite journal |vauthors=Pandey P, Kharbanda S, Kufe D | title = Association of the DF3/MUC1 breast cancer antigen with Grb2 and the Sos/Ras exchange protein | journal = Cancer Res | volume = 55 | issue = 18 | pages = 4000–4003 |date=September 1995 | pmid = 7664271}}
• JUP, and
• SOS1.

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.

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.{{cite journal |vauthors=Wei X, Xu H, Kufe D | title = Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response | journal = Cancer Cell | volume = 7 | issue = 2 | pages = 167–178 |date=February 2005 | pmid = 15710329 | doi = 10.1016/j.ccr.2005.01.008| doi-access = free }}

Overexpression of MUC1 in fibroblasts 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 MUC1 in cancer. The presence of free Bcl-2 and Bcl-xL prevents the release of cytochrome c from mitochondria, thereby preventing apoptosis.{{cite journal |vauthors=Raina D, Kharbanda S, Kufe D | title = The MUC1 oncoprotein activates the anti-apoptotic phosphoinositide 3-kinase/Akt and Bcl-xL pathways in rat 3Y1 fibroblasts | journal = J Biol Chem | volume = 279 | issue = 20 | pages = 20607–20612 |date=May 2004 | pmid = 14999001 | doi = 10.1074/jbc.M310538200| doi-access = free }} 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.{{cite journal |vauthors=Ren J, Bharti A, Raina D, Chen W, Ahmad R, Kufe D | title = MUC1 oncoprotein is targeted to mitochondria by heregulin-induced activation of c-Src and the molecular chaperone HSP90 | journal = Oncogene | volume = 25 | issue = 1 | pages = 20–31 |date=January 2006 | pmid = 16158055 | doi = 10.1038/sj.onc.1209012 | doi-access = free }}

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.{{cite journal |vauthors=Yamamoto M, Bharti A, Li Y, Kufe D | title = Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion | journal = J. Biol. Chem. | volume = 272 | issue = 19 | pages = 12492–4 |date=May 1997 | pmid = 9139698 | doi = 10.1074/jbc.272.19.12492| doi-access = free }} 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,{{cite journal |vauthors=Li Y, Chen W, Ren J, Yu WH, Li Q, Yoshida K, Kufe D | title = DF3/MUC1 signaling in multiple myeloma cells is regulated by interleukin-7 | journal = Cancer Biol. Ther. | volume = 2 | issue = 2 | pages = 187–93 | year = 2003 | pmid = 12750561 | doi = 10.4161/cbt.2.2.282| doi-access = free }} Src through mediation of EGFR,{{cite journal |vauthors=Li Y, Kuwahara H, Ren J, Wen G, Kufe D | title = The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin | journal = J. Biol. Chem. | volume = 276 | issue = 9 | pages = 6061–4 |date=March 2001 | pmid = 11152665 | doi = 10.1074/jbc.C000754200 | doi-access = free }}{{cite journal |vauthors=Li Y, Ren J, Yu W, Li Q, Kuwahara H, Yin L, Carraway KL, Kufe D | title = The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin | journal = J. Biol. Chem. | volume = 276 | issue = 38 | pages = 35239–42 |date=September 2001 | pmid = 11483589 | doi = 10.1074/jbc.C100359200 | doi-access = free }} and PRKCD.{{cite journal |vauthors=Ren J, Li Y, Kufe D | title = Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling | journal = J. Biol. Chem. | volume = 277 | issue = 20 | pages = 17616–22 |date=May 2002 | pmid = 11877440 | doi = 10.1074/jbc.M200436200 | doi-access = free }} This interaction is antagonized by degradation of beta-catenin by GSK3B. MUC1 blocks the phosphorylation-dependent degradation of beta-catenin by GSK3B.{{cite journal |vauthors=Li Y, Bharti A, Chen D, Gong J, Kufe D | title = Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin | journal = Mol. Cell. Biol. | volume = 18 | issue = 12 | pages = 7216–24 |date=December 1998 | pmid = 9819408 | pmc = 109303 | doi = 10.1128/mcb.18.12.7216}}{{cite journal |vauthors=Huang L, Chen D, Liu D, Yin L, Kharbanda S, Kufe D | title = MUC1 oncoprotein blocks glycogen synthase kinase 3beta-mediated phosphorylation and degradation of beta-catenin | journal = Cancer Res | volume = 65 | issue = 22 | pages = 10413–10422 |date=November 2005 | pmid = 16288032 | doi = 10.1158/0008-5472.CAN-05-2474| doi-access = free }} 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 the initiation of epithelial-mesenchymal transition which promotes the formation of metastases.{{cite journal |vauthors=Schroeder JA, Adriance MC, Thompson MC, Camenisch TD, Gendler SJ | title = MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion | journal = Oncogene | volume = 22 | issue = 9 | pages = 1324–32 |date=March 2003 | pmid = 12618757 | doi = 10.1038/sj.onc.1206291 | doi-access = free }}{{cite journal |vauthors=Roy LD, Sahraei M, Subramani DB, Besmer D, Nath S, Tinder TL, Bajaj E, Shanmugam K, Lee YY, Hwang SI, Gendler SJ, Mukherjee P | title = MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition | journal = Oncogene | volume = 30 | issue = 12 | pages = 1449–1459 |date=March 2011 | pmid = 21102519 | doi = 10.1038/onc.2010.526 | pmc = 3063863}}

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 a wide range of secretory epithelia and their neoplastic equivalents:{{cite web|url=http://www.pathologyoutlines.com/topic/stainsema.html|title=Stains - Epithelial membrane antigen (EMA)|author=Nat Pernick|website=PathologyOutlines}} Topic Completed: 1 May 2012. Revised: 18 September 2019

• It is a marker of various types of cancer (see below).
• In micropapillary carcinoma of the breast and bladder, MUC1 stains the stroma-facing surface of cell clusters of micropapillary units.
• It can distinguish systemic anaplastic large cell lymphoma (MUC1 positive) from cutaneous anaplastic large cell lymphoma (usually MUC1 negative).
• Although other antibodies, such as cytokeratins, are more commonly used for the identification of metastatic carcinoma deposits, EMA can be used to distinguish mesothelioma, in which it is restricted to the cell membranes and associated micovilli, from adenocarcinoma, in which it is diffusely spread through the cytoplasm.{{cite book |author1=Cooper K |author2=Leong AS-Y |author3=Leong JW-M | title = Manual of diagnostic antibodies for immunohistology | publisher = Greenwich Medical Media | location = London | year = 2003 | pages = 205–206 | isbn = 978-1-84110-100-2 }}

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;Diseases with positive MUC1 staining:

• Adenocarcinomas

:*Breast cancer

:*Colorectal cancer

:*Pancreatic cancer

• Carcinoid tumor, chordoma
• Choriocarcinoma
• Desmoplastic small-round-cell tumor
• Epithelioid sarcoma
• Follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, reticulum cell sarcoma
• Lung: Type II cell lesions (hyperplasia, dysplasia)
• Lymphomas

:*Anaplastic large-cell lymphoma

:*Diffuse large B-cell lymphoma (variable expression)

:*Plasmablastic lymphoma

:*Primary effusion lymphoma

• Meningioma
• Mesotheliomas (epithelioid)
• Myeloma
• Paget's disease of the breast
• Perineurioma
• Plasmacytomas
• Renal cell carcinoma
• Synovial sarcoma (epithelial areas)
• Thymic carcinoma (often)

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;Negative staining:

• Myoepithelial cells
• Adrenocortical carcinoma

:Hepatocellular carcinoma

:Germ cell tumors (except choriocarcinoma)

• Acquired cystic kidney disease-associated renal cell carcinoma
• Leiomyosarcoma (usually)
• Liposarcoma
• Melanoma
• Neuroblastoma
• Paraganglioma
• Solitary fibrous tumor

;Normal tissues with positive staining:

• Apical surface of almost all glandular and ductal epithelial cells:

:*Breast, including Toker cells

:*Distal convoluted tubule of kidney

:*Type II cells of pulmonary alveoli

:*Pancreas

:*Salivary glands

:*eccrine and apocrine glands of the skin

• Several white blood cells:

:*Activated T cells

:*Some B cells

:*Monocytes

• Follicular dendritic cells
• Perineurial cells

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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 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.{{cite journal |vauthors=Gaidzik N, Westerlind U, Kunz H | title = The development of synthetic antitumour vaccines from mucin glycopeptide antigens | journal = Chem Soc Rev | volume = 42 | issue = 10 | pages = 4421–42 |date=May 2013 | pmid = 23440054 | doi = 10.1039/c3cs35470a }}

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.{{cite journal|vauthors = Nemunaitis J, Bedell C, Klucher K, Vo A, Whiting S|title = Phase 1 dose escalation of ONT-10, a therapeutic MUC1 vaccine, in patients with advanced cancer|journal=Journal for Immunotherapy of Cancer|volume = 1|issue = Suppl 1|year = 2013|pages = P240|issn = 2051-1426|doi = 10.1186/2051-1426-1-S1-P240|pmc = 3990302 | doi-access=free }}

• Cluster of differentiation
• List of histologic stains that aid in diagnosis of cutaneous conditions
• Mucin-1

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• {{Cite book |vauthors=Peterson JA, Scallan CD, Ceriani RL, Hamosh M |volume=501 |pages= 179–87 |year= 2002 |pmid= 11787681 |doi= 10.1007/978-1-4615-1371-1_23|series=Advances in Experimental Medicine and Biology |isbn=978-1-4613-5521-2 |title=Bioactive Components of Human Milk |chapter=Structural and Functional Aspects of Three Major Glycoproteins of the Human Milk Fat Globule Membrane }}
• {{Cite journal |vauthors=Hu XF, Yang E, Li J, Xing PX |title=MUC1 cytoplasmic tail: a potential therapeutic target for ovarian carcinoma |journal=Expert Rev Anticancer Ther |volume=6 |issue= 8 |pages= 1261–71 |year= 2006 |pmid= 16925492 |doi= 10.1586/14737140.6.8.1261 |s2cid=36159399 }}
• {{Cite journal |vauthors=Leroy X, Buisine MP, Leteurtre E, etal |title=[MUC1 (EMA): A key molecule of carcinogenesis?] |journal=Annales de Pathologie |volume=26 |issue= 4 |pages= 257–66 |year= 2007 |pmid= 17128152 |doi=10.1016/S0242-6498(06)70718-0 }}
• {{Cite journal |vauthors=Li Y, Cozzi PJ |title=MUC1 is a promising therapeutic target for prostate cancer therapy |journal=Current Cancer Drug Targets |volume=7 |issue= 3 |pages= 259–71 |year= 2007 |pmid= 17504123 |doi=10.2174/156800907780618338 }}
• {{cite journal | vauthors = Mahanta S, Fessler SP, Park J, Bamdad C | title = A minimal fragment of MUC1 mediates growth of cancer cells | journal = PLOS ONE | volume = 3 | issue = 4 | pages = e2054 | date = April 2008 | pmid = 18446242 | pmc = 2329594 | doi = 10.1371/journal.pone.0002054 | bibcode = 2008PLoSO...3.2054M | doi-access = free }}
• {{cite journal | vauthors = Hikita ST, Kosik KS, Clegg DO, Bamdad C | title = MUC1* mediates the growth of human pluripotent stem cells | journal = PLOS ONE | volume = 3 | issue = 10 | pages = e3312 | date = October 2008 | pmid = 18833326 | pmc = 2553196 | doi = 10.1371/journal.pone.0003312 | bibcode = 2008PLoSO...3.3312H | doi-access = free }}
• {{Cite journal |vauthors=Fessler SP, Wotkowicz MT, Mahanta S, Bamdad C |title=MUC1* is a determinant of trastuzumab (Herceptin) resistance in breast cancer cells |journal=Breast Cancer Res Treat |volume= 118|issue= 1|pages= 113–24|year=2009 |pmid=19415485 |doi=10.1007/s10549-009-0412-3 |s2cid=25176184 }}
• {{cite journal |vauthors=Zhan XX, Zhao B, Diao C, Cao Y, Cheng RC |title=Expression of MUC1 and CD176 (Thomsen-Friedenreich antigen) in papillary thyroid carcinomas |journal=Endocr. Pathol. |volume=26 |issue=1 |pages=21–6 |year=2015 |pmid=25614211 |doi=10.1007/s12022-015-9356-9 |s2cid=37471701 }}

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• {{MeshName|MUC1+protein,+human}}

{{PDB Gallery|geneid=4582}}

{{Clusters of differentiation}}

{{Mucoproteins}}

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Category:Clusters of differentiation

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Category:Human proteins