MUC1
Proteins

Author: Gianpiero Pescarmona
Date: 17/09/2009

Description

DEFINITION

A short protein description with the molecular wheight, isoforms, etc...
Use, when available, the link to Wikipedia (Es Trypsin)

External links not available on Wikipedia have to be added here

DatabaseLink
WikigenesURL
GeneCardsURL
iHOPURL
OMIMURL

CHEMICAL STRUCTURE AND IMAGES

When relevant for the function

  • Primary structure
  • Secondary structure
  • Tertiary structure
  • Quaternary structure

AA % is partially similar to FOXE3
The emerging roles of forkhead box (Fox) proteins in cancer 2007

FOX function cartoon

iHOP link FOX MUC

SYNTHESIS AND TURNOVER

mRNA synthesis

Human MUC1 oncoprotein regulates p53-responsive gene transcription in the genotoxic stress response 2004
The CREB binding protein (CBP) functions as a histone acetyltransferase and coactivator of transcription. MUC1 expression was associated with an increase in CBP occupancy of the p21p53RE2, indicating that MUC1 is associated with recruitment of CBP to the p53 transcription complex

protein synthesis
post-translational modifications
degradation

CELLULAR FUNCTIONS

cellular localization,

biological function

Proteins with specific functions

1. FUNCTION: The alpha subunit has cell adhesive properties. Can act both as an adhesion and an anti-adhesion protein. May provide a protective layer on epithelial cells against bacterial and enzyme attack.
2. FUNCTION: The beta subunit contains a C-terminal domain which is involved in cell signaling, through phosphorylations and protein- protein interactions. Modulates signaling in ERK, Src and NF- kappaB pathways. In activated T-cells, influences directly or indirectly the Ras/MAPK pathway. Promotes tumor progression. Regulates P53-mediated transcription and determines cell fate in the genotoxic stress response. Binds, together with KLF4, the PE21 promoter element of P53 and represses P53 activity.
3. SUBUNIT: 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 and metastases. Isoform 1 binds directly the SH2 domain of GRB2, and forms a MUC1/GRB2/SOS1 complex involved in RAS signaling. The cytoplasmic tail (MUC1CT) interacts with several proteins such as SRC, CTNNB1 and ERBs. Interaction with the SH2 domain of CSK decreases interaction with GSK3B. Interacts with CTNNB1/beta-catenin and JUP/gamma-catenin and promotes cell adhesion. Interaction with JUP/gamma-catenin is induced by heregulin. Binds PRKCD, ERBB2, ERBB3 and ERBB4. Heregulin (HRG) stimulates the interaction with ERBB2 and, to a much lesser extent, the interaction with ERBB3 and ERBB4. Interacts with P53 in response to DNA damage. Interacts with KLF4. Interacts with estrogen receptor alpha/ESR1, through its DNA- binding domain, and stimulates its transcription activity. Binds ADAM17.
4. SUBCELLULAR LOCATION: Apical cell membrane; Single-pass type I membrane protein. Note=Exclusively located in the apical domain of the plasma membrane of highly polarized epithelial cells. After endocytosis, internalized and recycled to the cell membrane. Located to microvilli and to the tips of long filopodial protusions.
5. SUBCELLULAR LOCATION: Isoform 5: Secreted.
6. SUBCELLULAR LOCATION: Isoform 7: Secreted.
7. SUBCELLULAR LOCATION: Isoform 9: Secreted.
8. SUBCELLULAR LOCATION: Mucin-1 subunit beta: Cell membrane. Cytoplasm. Nucleus. Note=On EGF and PDGFRB stimulation, transported to the nucleus through interaction with CTNNB1, a process which is stimulated by phosphorylation. On HRG stimulation, colocalizes with JUP/gamma-catenin at the nucleus.
9. ALTERNATIVE PRODUCTS: Event=Alternative splicing; Named isoforms=10; Comment=Additional isoforms seem to exist; Name=1; Synonyms=A; IsoId=P15941-1; Sequence=Displayed; Name=2; Synonyms=B; IsoId=P15941-2; Sequence=VSP_003280; Name=3; Synonyms=C; IsoId=P15941-3; Sequence=VSP_003281; Name=4; Synonyms=D; IsoId=P15941-4; Sequence=VSP_003282; Name=5; Synonyms=SEC; IsoId=P15941-5; Sequence=VSP_003288, VSP_003289; Name=6; Synonyms=X; IsoId=P15941-6; Sequence=VSP_003283, VSP_003284; Name=7; Synonyms=Y; IsoId=P15941-7; Sequence=VSP_003285; Name=8; Synonyms=Z; IsoId=P15941-8; Sequence=VSP_003286; Name=9; Synonyms=S; IsoId=P15941-9; Sequence=VSP_003286, VSP_003287; Name=10; Synonyms=F; IsoId=P15941-10; Sequence=VSP_035046, VSP_035047;
10. TISSUE SPECIFICITY: Expressed on the apical surface of epithelial cells, especially of airway passages, breast and uterus. Also expressed in activated and unactivated T-cells. Overexpressed in epithelial tumors, such as breast or ovarian cancer and also in non-epithelial tumor cells. Isoform 7 expressed in tumor cells only.
11. DEVELOPMENTAL STAGE: During fetal development, expressed at low levels in the colonic epithelium from 13 weeks of gestation.
12. PTM: Highly glycosylated (N- and O-linked carbohydrates and sialic acid). O-glycosylated to a varying degree on serine and threonine residues within each tandem repeat, ranging from mono- to penta- glycosylation. The average density ranges from about 50% in human milk to over 90% in T47D breast cancer cells. Further sialylation occurs during recycling. Membrane-shed glycoproteins from kidney and breast cancer cells have preferentially sialyated core 1 structures, while secreted forms from the same tissues display mainly core 2 structures. The O-glycosylated content is overlapping in both these tissues with terminal fucose and galactose, 2- and 3-linked galactose, 3- and 3,6-linked GalNAc-ol and 4-linked GlcNAc predominating. Differentially O-glycosylated in breast carcinomas with 3,4-linked GlcNAc. N-glycosylation consists of high-mannose, acidic complex-type and hybrid glycans in the secreted form MUC1/SEC, and neutral complex-type in the transmembrane form, MUC1/TM.
13. PTM: Proteolytic cleavage in the SEA domain occurs in the endoplasmic reticulum by an autoproteolytic mechanism and requires the full-length SEA domain as well as requiring a Ser, Thr or Cys residue at the P + 1 site. Cleavage at this site also occurs on isoform MUC1/X but not on isoform MUC1/Y. Ectodomain shedding is mediated by ADAM17.
14. PTM: Dual palmitoylation on cysteine residues in the CQC motif is required for recycling from endosomes back to the plasma membrane.
15. PTM: Phosphorylated on tyrosines and serine residues in the C- terminal. Phosphorylation on tyrosines in the C-terminal increases the nuclear location of MUC1 and beta-catenin. Phosphorylation by PKC delta induces binding of MUC1 to beta-catenin/CTNNB1 and thus decreases the formation of the beta-catenin/E-cadherin complex. Src-mediated phosphorylation inhibits interaction with GSK3B. Src- and 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 and CTNNB1.
16. POLYMORPHISM: The number of repeats is highly polymorphic. It varies from 21 to 125 in the northern European population. The most frequent alleles contains 41 and 85 repeats. The tandemly repeated icosapeptide underlies polymorphism at three positions: PAPGSTAP[PAQT]AHGVTSAP[DT/ES]R, DT > ES and the single replacements P -> A, P -> Q and P> T. The most frequent replacement DT > ES occurs in up to 50% of the repeats.
17. SIMILARITY: Contains 1 SEA domain.
18. CAUTION: The N-terminal sequence has been shown (PubMed:11341784) to begin at position 24 or 28.
19. CAUTION: O-glycosylation sites are annotated in first sequence repeat only. Residues at similar position are probably glycosylated in all repeats. Experimental sites were determined in a synthetic peptide glycosylated in vitro (PubMed:7744025, PubMed:9597769).
20. WEB RESOURCE: Name=Mucin database; URL="http://www.medkem.gu.se/mucinbiology/databases/";
21. WEB RESOURCE: Name=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/muc1/";
* Enzymes
* Cell signaling and Ligand transport
* Structural proteins

REGULATION

DIAGNOSTIC USE

MeSH
Comments
2009-09-21T12:26:31 - Gianpiero Pescarmona

Because AAT and SLC11A1 proteins directly or indirectly function as inhibitors of human leukocyte elastase, mutations in the AAT and SLC11A1 genes may change the balance between elastase produced by leukocytes during phagocytosis. [2008] ref

Attachments
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MUC1-500.gifgp17/09/2009
MUC1-FOXE3.gifgp18/09/2009
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