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mucin-1; MUC-1 glycoprotein; 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)

Function: 1) alpha subunit a) has cell adhesive properties b) can act both as an adhesion & an anti-adhesion protein c) may provide a protective layer on epithelial cells against bacterial & enzyme attack 2) beta subunit - contains a C-terminal domain which is involved in cell signaling, through phosphorylations & protein-protein interactions 3) modulates signaling in ERK, Src & NF-kappaB pathways 4) in activated T-cells, influences directly or indirectly the Ras/MAPK pathway 5) promotes tumor progression 6) regulates P53-mediated transcription & determines cell fate in the genotoxic stress response 7) binds, together with KLF4, the PE21 promoter element of P53 & represses P53 activity 8) proteolytic cleavage in the SEA domain occurs in the endoplasmic reticulum by an autoproteolytic mechanism 9) ectodomain shedding is mediated by ADAM17 10) dual palmitoylation on Cys in the CQC motif is required for recycling from endosomes back to the plasma membrane 11) phosphorylated on Tyr & Ser in the C-terminal region 12) phosphorylation on Tyr in the C-terminal region increases nuclear location of MUC1 & beta-catenin 13) phosphorylation by PKC delta induces binding of MUC1 to beta-catenin/CTNNB1 & thus decreases the formation of the beta-catenin/E-cadherin complex 14) Src-mediated phosphorylation inhibits interaction with GSK3B 15) Src- & EGFR-mediated phosphorylation on Tyr-1229 increases binding to beta-catenin/CTNNB1 16) GSK3beta-mediated phosphorylation on Ser-1227 decreases this interaction but restores the formation of the beta-cadherin/E-cadherin complex 17) on T-cell receptor activation, phosphorylated by LCK 18) PDGFR-mediated phosphorylation increases nuclear colocalization of MUC1CT & CTNNB1 19) the alpha subunit forms a tight, non-covalent heterodimeric complex with the proteolytically-released beta-subunit 20) interaction, via the tandem repeat region, with domain 1 of ICAM1 is implicated in cell migration & metastases 21) isoform 1 binds directly the SH2 domain of GRB2, & forms a MUC1/GRB2/SOS1 complex involved in RAS signaling 22) the cytoplasmic tail (MUC1CT) interacts with several proteins such as SRC, CTNNB1 & ERBs 23) interaction with the SH2 domain of CSK decreases interaction with GSK3B 24) interacts with CTNNB1/beta-catenin & JUP/gamma-catenin & promotes cell adhesion 25) interaction with JUP/gamma-catenin is induced by heregulin 26) binds PRKCD, ERBB2, ERBB3 & ERBB4 27) heregulin (HRG) stimulates the interaction with ERBB2 &, to a much lesser extent, the interaction with ERBB3 & ERBB4 28) interacts with P53 in response to DNA damage 29) interacts with KLF4 30) interacts with estrogen receptor alpha/ESR1, through its DNA- binding domain, & stimulates its transcription activity 31) 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 a) cell membrane cytoplasm, nucleus b) on EGF & PDGFRB stimulation, transported to the nucleus through interaction with CTNNB1, a process stimulated by phosphorylation c) 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 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 Pathology: - tumors staining positively with antibody - adenocarcinomas, high expression, associated with poor prognosis - overexpressed in > 90% of breast cancers - 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] Pharmacology: - MUC-1 vaccine in conjunction with standard neoadjuvant systemic therapy may improve distant relapse-free survival & overall survival rates in breast cancer patients

Related

CD227 (mucin-1) Ag in tissue CD227 cells in blood

Specific

Mucin 1 Rectal

General

antigen cluster-of-differentiation antigen; cluster designation antigen; CD antigen cytoskeletal protein membrane protein mucin

Properties

SIZE: entity length = 1255 aa MW = 122 kD COMPARTMENT: cytoplasm cell nucleus MOTIF: signal sequence {1-23} domain {126-965} MOTIF: PAPGSTAPPAHGVTSAPDTR {126-965} (42) Thr glycosylation site {T131} Thr glycosylation site {T139} Ser glycosylation site {S140} N-glycosylation site {N957} N-glycosylation site {N975} N-glycosylation site {N1029} SEA domain {1034-1151} MOTIF: N-glycosylation site {N1055} peptide motif {1097-1098} N-glycosylation site {N1133} transmembrane domain {1159-1181} cysteine residue {C1184} MODIFICATION: palmitate COMPARTMENT: membrane cysteine residue {C1186} MODIFICATION: palmitate COMPARTMENT: membrane Tyr phosphorylation site {Y1191} P53 interaction {1192-1228} MOTIF: peptide motif {1203-1206} Tyr phosphorylation site {Y1203} Tyr phosphorylation site {Y1209} Tyr phosphorylation site {Y1212} Tyr phosphorylation site {Y1218} GSK3B interaction {1223-1230} MOTIF: Thr phosphorylation site {T1224} Ser phosphorylation site {S1227} peptide motif {1229-1232} MOTIF: Tyr phosphorylation site {Y1229} catenin interaction {1233-1241} peptide motif {1243-1246} MOTIF: Tyr phosphorylation site {Y1243}

Database Correlations

OMIM correlations UniProt P15941 Pfam PF01390 Entrez Gene 4582 Kegg hsa:4582

References

  1. UniProt :accession P15941
  2. mucin database http://www.medkem.gu.se/mucinbiology/databases/
  3. NIEHS-SNPs http://egp.gs.washington.edu/data/muc1/
  4. Parry S et al Identification of MUC1 proteolytic cleavage sites in vivo. Biochem Biophys Res Commun. 2001 May 11;283(3):715-20 PMID: 11341784
  5. 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: 7744025
  6. 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: 9597769