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

• 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
    • 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

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

Pharmacology

• MUC-1 vaccine in conjunction with standard neoadjuvant systemic therapy may improve distant relapse-free survival & overall survival rates in breast cancer patients

More general terms

• CD antigen
• mucin
• cytoskeletal protein
• membrane protein
• antigen

Database

• UniProt: http://www.uniprot.org/uniprot/P15941.html
• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4582
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:4582
• OMIM: https://mirror.omim.org/entry/113720
• OMIM: https://mirror.omim.org/entry/158340