MUC16 (CA125) is a giant (about 22,000 residues) membrane-associated mucin, a single-pass type I transmembrane glycoprotein with an enormous, heavily O- and N-glycosylated extracellular region composed of a Ser/Thr-rich N-terminal domain and tens of SEA-domain-containing tandem repeats, a single transmembrane helix and a short polybasic cytoplasmic tail. It is expressed at the apical surfaces of ocular surface, respiratory, and reproductive tract epithelia and mesothelium, where it forms part of the glycocalyx, providing a disadhesive, lubricating barrier against particles and pathogens; its cytoplasmic tail binds ezrin/radixin/moesin proteins linking it to the actin cytoskeleton. The ectodomain is shed into body fluids and is measured as the serum ovarian cancer marker CA125. MUC16 binds mesothelin, mediating heterotypic adhesion that may favour peritoneal spread of ovarian cancer.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:14676194 Binding of ovarian cancer antigen CA125/MUC16 to mesothelin ... | MODIFY | Summary: CA125/MUC16 binds mesothelin, shown by expression cloning, flow cytometry and immunoprecipitation. Reason: Bare protein binding is uninformative; the specific MUC16-mesothelin interaction mediates heterotypic cell adhesion, so cell adhesion molecule binding is the informative replacement. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:14676194 Binding of CA125 to membrane-bound mesothelin mediates heterotypic cell adhesion as anti-mesothelin antibody blocks binding of OVCAR-3 cells expressing CA125 to an endothelial-like cell line expressing mesothelin. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt Secreted/extracellular space location mapped to extracellular region. Reason: The CA125 ectodomain is proteolytically shed and circulates (the basis of the CA125 serum assay), so an extracellular pool is real; the intact molecule is a type I transmembrane mucin at the apical cell surface. Supporting Evidence: file:human/MUC16/MUC16-uniprot.txt Phosphorylation of the intracellular C-terminal domain may induce proteolytic cleavage and the liberation of the extracellular domain into the extracellular space. file:human/MUC16/MUC16-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Secreted, extracellular space. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1964501 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-1964501 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-1964505 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-1964505 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-5096532 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-5096532 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-5096537 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-5096537 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-5694487 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-5694487 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-6785524 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-6785524 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-6786012 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-6786012 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-913675 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-913675 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. Reactome:R-HSA-913675 This reaction takes place in the Golgi apparatus |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914005 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-914005 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914006 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-914006 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914008 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-914008 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914010 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-914010 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914012 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-914012 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914017 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-914017 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-914018 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-914018 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-977071 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-977071 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-981497 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-981497 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-981809 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-981809 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005796 Golgi lumen | TAS Reactome:R-HSA-981814 | KEEP AS NON CORE | Summary: Reactome mucin O-glycosylation reaction places the MUC16 ectodomain as substrate in the Golgi lumen. Reason: MUC16 is heavily O-glycosylated, and mucin-type O-glycan initiation and elongation occur in the Golgi, where the ectodomain of a type I membrane protein faces the lumen. This is a biosynthetic transit location rather than the site of MUC16 function (the apical cell surface). Supporting Evidence: Reactome:R-HSA-981814 file:human/MUC16/MUC16-uniprot.txt PTM: Heavily O-glycosylated; expresses both type 1 and type 2 core glycans. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt Cell membrane; single-pass type I mapped to plasma membrane. Reason: MUC16 is a single-pass type I transmembrane mucin; this UniProt subcellular-location (Cell membrane) row asserts plasma membrane at the resolution its evidence supports. The apical sub-localization is recorded separately on the NEW apical plasma membrane row (GO:0016324). Supporting Evidence: file:human/MUC16/MUC16-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Secreted, extracellular space. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8858500 | ACCEPT | Summary: Reactome CLEC10A recognition of Tn-glycosylated mucins at the plasma membrane. Reason: Plasma membrane location of MUC16 is correct, independently supported. Supporting Evidence: Reactome:R-HSA-8858500 file:human/MUC16/MUC16-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein. Secreted, extracellular space. |
| GO:0007155 cell adhesion | NAS PMID:14676194 Binding of ovarian cancer antigen CA125/MUC16 to mesothelin ... | MODIFY | Summary: Binding of CA125 to mesothelin mediates heterotypic adhesion of ovarian cancer cells. Reason: Correct but general; the evidence is specifically heterotypic cell-cell adhesion between CA125-expressing and mesothelin-expressing cells. Proposed replacements: heterotypic cell-cell adhesion Supporting Evidence: PMID:14676194 Binding of CA125 to membrane-bound mesothelin mediates heterotypic cell adhesion as anti-mesothelin antibody blocks binding of OVCAR-3 cells expressing CA125 to an endothelial-like cell line expressing mesothelin. |
| GO:0009897 external side of plasma membrane | IDA PMID:12766047 MUC16 mucin is expressed by the human ocular surface epithel... | ACCEPT | Summary: MUC16 carries the H185 epitope on the apical surface of corneal and conjunctival epithelia. Reason: The large O-glycosylated ectodomain projects from the external face of the plasma membrane, forming the glycocalyx. Supporting Evidence: PMID:12766047 H185 antibody has been shown to recognize a carbohydrate epitope on a membrane-associated mucin in the apical surfaces of the corneal and conjunctival epithelia. PMID:12766047 MUC16 mRNA and protein localized to the apical cell layers of the cornea and to the suprabasal region of the conjunctival epithelium. |
| GO:0031982 vesicle | HDA PMID:19190083 Characterization of exosome-like vesicles released from huma... | MODIFY | Summary: MUC16 detected in exosome-like vesicles secreted by tracheobronchial epithelial cells. Reason: Correct but general; the vesicles characterized are exosome-like extracellular vesicles, so extracellular exosome (already carried) is more specific. Proposed replacements: extracellular exosome Supporting Evidence: PMID:19190083 The epithelial mucins MUC1, MUC4, and MUC16 also contributed to the vesicles |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: MUC16 identified in parotid saliva exosome proteome. Reason: High-throughput proteomic detection; a minor vesicle-associated pool of a cell-surface mucin. Supporting Evidence: PMID:19199708 we catalogued 491 proteins in the exosome fraction of human parotid saliva |
| GO:0016324 apical plasma membrane | IDA PMID:17898272 Functions of MUC16 in corneal epithelial cells. | NEW | Summary: MUC16 localizes to the tips of microplicae on the apical surface of ocular surface epithelia. Reason: Immunolocalization shows MUC16 at the apical surface (microplicae tips) of corneal and conjunctival epithelia; apical plasma membrane is more precise than plasma membrane for this polarized mucin. Supporting Evidence: PMID:17898272 The membrane-associated mucin MUC16, a heavily O-glycosylated transmembrane protein, is expressed by the ocular surface epithelia and localized on the tips of the surface microplicae. PMID:12766047 H185 antibody has been shown to recognize a carbohydrate epitope on a membrane-associated mucin in the apical surfaces of the corneal and conjunctival epithelia. |
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Download this section (compressed HTML)Q: What protease(s) cleave MUC16 to release the CA125 ectodomain, and is shedding regulated by phosphorylation of its cytoplasmic tail?
Q: Does MUC16 binding to galectin-3 or siglecs contribute to its barrier or immunomodulatory functions in vivo?
Experiment: Map the MUC16 cleavage site by mass spectrometry of shed CA125 from ocular and ovarian cells, and test cleavage-resistant mutants for barrier function (rose bengal exclusion, bacterial adherence) in MUC16-knockout corneal epithelial cells.
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