mucin-1; MUC-1; polymorphic epithelial mucin; PEM; PEMT; episialin; tumor-associated mucin; carcinoma-associated mucin; tumor-associated epithelial membrane antigen; EMA; H23AG; Peanut-reactive urinary mucin; PUM; breast carcinoma-associated antigen DF3; CD227; contains: MUC1-alpha; MUC1-NT; MUC1-beta; MUC1-CT (MUC1, PUM)
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Function
- alpha subunit
- has cell adhesive properties
- can act both as an adhesion & an anti-adhesion protein
- may provide a protective layer on epithelial cells against bacterial & enzyme attack
- beta subunit
- contains a C-terminal domain which is involved in cell signaling, through phosphorylations & protein-protein interactions
- modulates signaling in ERK, Src & NF-kappaB pathways
- in activated T-cells, influences directly or indirectly the Ras/MAPK pathway
- promotes tumor progression
- regulates P53-mediated transcription & determines cell fate in the genotoxic stress response
- binds, together with KLF4, the PE21 promoter element of P53 & represses P53 activity
- proteolytic cleavage in the SEA domain occurs in the endoplasmic reticulum by an autoproteolytic mechanism
- ectodomain shedding is mediated by ADAM17
- dual palmitoylation on Cys in the CQC motif is required for recycling from endosomes back to the plasma membrane
- phosphorylated on Tyr & Ser in the C-terminal region
- phosphorylation on Tyr in the C-terminal region increases nuclear location of MUC1 & beta-catenin
- phosphorylation by PKC delta induces binding of MUC1 to beta-catenin/CTNNB1 & thus decreases the formation of the beta-catenin/E-cadherin complex
- Src-mediated phosphorylation inhibits interaction with GSK3B
- Src- & EGFR-mediated phosphorylation on Tyr-1229 increases binding to beta-catenin/CTNNB1
- GSK3beta-mediated phosphorylation on Ser-1227 decreases this interaction but restores the formation of the beta-cadherin/E-cadherin complex
- on T-cell receptor activation, phosphorylated by LCK
- PDGFR-mediated phosphorylation increases nuclear colocalization of MUC1CT & CTNNB1
- the alpha subunit forms a tight, non-covalent heterodimeric complex with the proteolytically-released beta-subunit
- interaction, via the tandem repeat region, with domain 1 of ICAM1 is implicated in cell migration & metastases
- isoform 1 binds directly the SH2 domain of GRB2, & forms a MUC1/GRB2/SOS1 complex involved in RAS signaling
- the cytoplasmic tail (MUC1CT) interacts with several proteins such as SRC, CTNNB1 & ERBs
- interaction with the SH2 domain of CSK decreases interaction with GSK3B
- interacts with CTNNB1/beta-catenin & JUP/gamma-catenin & promotes cell adhesion
- interaction with JUP/gamma-catenin is induced by heregulin
- binds PRKCD, ERBB2, ERBB3 & ERBB4
- heregulin (HRG) stimulates the interaction with ERBB2 &, to a much lesser extent, the interaction with ERBB3 & ERBB4
- interacts with P53 in response to DNA damage
- interacts with KLF4
- interacts with estrogen receptor alpha/ESR1, through its DNA- binding domain, & stimulates its transcription activity
- binds ADAM17
Structure
- highly glycosylated (N- & O-linked carbohydrates & sialic acid)
- O-glycosylated to a varying degree on Ser & Thr within each tandem repeat, ranging from mono- to penta-glycosylation
- average density ranges from about 50% in human milk to > 90% in T47D breast cancer cells
- further sialylation occurs during recycling
- membrane-shed glycoproteins from kidney & breast cancer cells have preferentially sialyated core 1 structures, while secreted forms from the same tissues display mainly core 2 structures
- O-glycosylated content is overlapping in both these tissues with terminal fucose & galactose, 2- & 3-linked galactose, 3- & 3,6-linked galNAc-ol & 4-linked GlcNAc predominating
- differentially O-glycosylated in breast carcinomas with 3,4-linked GlcNAc
- N-glycosylation consists of high-mannose, acidic complex-type & hybrid glycans in the secreted form MUC1/SEC, & neutral complex-type in the transmembrane form, MUC1/TM
- contains 1 SEA domain
Compartment
- apical cell membrane; single-pass type 1 membrane protein
- exclusively located in the apical domain of the plasma membrane of highly polarized epithelial cells
- after endocytosis, internalized & recycled to the cell membrane
- located to microvilli & to the tips of long filopodial protusions
- isoforms 5,7,9: secreted
- mucin-1 subunit beta
- cell membrane cytoplasm, nucleus
- on EGF & PDGFRB stimulation, transported to the nucleus through interaction with CTNNB1, a process stimulated by phosphorylation
- on HRG stimulation, colocalizes with JUP/gamma-catenin in the nucleus
Alternative splicing
named isoforms=10 additional isoforms seem to exist
Expression
- expressed on the apical surface of epithelial cells, especially of airway passages, breast & uterus
- some hematopoietic cells: T cells (resting & activated), monocytes, some B cells
- follicular dendritic cells
- perineural cells
- overexpressed in epithelial tumors, such as breast cancer or ovarian cancer & also in non-epithelial tumor cells
- isoform 7 expressed in tumor cells only
- during fetal development, expressed at low levels in colonic epithelium from 13 weeks of gestation
Pathology
- tumors staining positively with antibody
- adenocarcinomas, high expression, associated with poor prognosis
- Paget's disease, nearly all cases
- anaplastic large cell lymphoma
- epithelioid sarcoma
- meningioma
- mesotheliomas (some)
- myeloma/plasmacytoma
- Germ cell tumors, hepatocellular & adrenal carcinomas stain negatively with antibody
- defects associated with medullary cystic kidney disease[1]
Polymorphism
- the number of repeats is highly polymorphic
- varies from 21 to 125 in the northern European population
- the most frequent alleles contains 41 & 85 repeats
- the tandemly repeated icosapeptide underlies polymorphism at three positions: PAPGSTAP[PAQT]AHGVTSAP[DT/ES]R, DT -> ES & the single replacements P -> A, P -> Q & P-> T
- the most frequent replacement DT > ES occurs in up to 50% of the repeats
More general terms
References
- ↑ 1.0 1.1 UniProt http://www.uniprot.org/uniprot/P15941.html
- ↑ mucin database http://www.medkem.gu.se/mucinbiology/databases/
- ↑ NIEHS-SNPs http://egp.gs.washington.edu/data/muc1/
- ↑ Parry S et al Identification of MUC1 proteolytic cleavage sites in vivo. Biochem Biophys Res Commun. 2001 May 11;283(3):715-20 PMID: https://www.ncbi.nlm.nih.gov/pubmed/11341784
- ↑ Stadie TR et al Studies on the order and site specificity of GalNAc transfer to MUC1 tandem repeats by UDP-GalNAc: polypeptide N-acetylgalactosaminyltransferase from milk or mammary carcinoma cells. Eur J Biochem. 1995 Apr 1;229(1):140-7. PMID: https://www.ncbi.nlm.nih.gov/pubmed/7744025
- ↑ Hanisch FG et al Localization of O-glycosylation sites of MUC1 tandem repeats by QTOF ESI mass spectrometry. J Mass Spectrom. 1998 Apr;33(4):358-62. PMID: https://www.ncbi.nlm.nih.gov/pubmed/9597769