MSLN encodes a 71-kDa precursor that is cleaved by a furin-like convertase into a secreted N-terminal fragment, megakaryocyte-potentiating factor (MPF), and mature mesothelin, a ~40-kDa glycosylphosphatidylinositol (GPI)-anchored glycoprotein displayed on the outer surface of the plasma membrane. Mesothelin is expressed by mesothelial cells lining the pleural, peritoneal and pericardial cavities and is highly overexpressed in mesothelioma, ovarian, pancreatic and other carcinomas. Its superhelical N-terminal region binds the mucin CA125/MUC16, mediating heterotypic cell adhesion that is thought to promote peritoneal implantation of ovarian cancer. Soluble mesothelin and MPF released into serum are tumour biomarkers, and cell-surface mesothelin is a major target of antibody, immunotoxin and CAR-T therapies.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005515 protein binding | IPI PMID:14676194 Binding of ovarian cancer antigen CA125/MUC16 to mesothelin ... | MODIFY | Summary: Mesothelin binds the mucin CA125/MUC16; expression cloning, flow cytometry and immunoprecipitation. Reason: The interaction is specific and mediates heterotypic cell adhesion; cell adhesion molecule binding conveys this function better than bare protein binding. 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. PMID:14676194 By flow cytometric analysis and immunoprecipitation, we demonstrate that CA125 binds to mesothelin in a specific manner. |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Secreted/extracellular localization (ARBA, UniProt Secreted keyword for MPF and isoform 5). Reason: The N-terminal megakaryocyte-potentiating factor (MPF) fragment is secreted after furin cleavage and soluble mesothelin (SMRP) circulates in patient serum, so an extracellular pool is real; the mature mesothelin chain itself is GPI-anchored at the cell surface. Supporting Evidence: file:human/MSLN/MSLN-uniprot.txt SUBCELLULAR LOCATION: [Megakaryocyte-potentiating factor]: Secreted. PMID:16857795 MPF is secreted by several mesothelioma cell lines and is frequently elevated in the blood of patients with mesothelioma |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-8940388 | KEEP AS NON CORE | Summary: Reactome places GPLD1-released mesothelin in the extracellular region. Reason: Valid shed pool after GPI-anchor hydrolysis; secondary to the cell-surface form. Supporting Evidence: Reactome:R-HSA-8940388 Some proteins function at the cell's surface, attached to the plasma membrane via GPI (glycosylphosphatidylinositol) anchors |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | MARK AS OVER ANNOTATED | Summary: Reactome FAM20C substrate reaction places MSLN in the ER lumen. Reason: Mesothelin passes through the ER lumen during biosynthesis, as all secretory-pathway proteins do, but this is a transit compartment and not where it functions; no MSLN-specific evidence for an ER-resident pool. Supporting Evidence: Reactome:R-HSA-8952289 FAM20C is an extracellular kinase that can phosphorylate a broad range of secreted protein. PMID:8552591 When the cDNA was transfected into COS and NIH 3T3 cells, the antigen was found on the cell surface and could be released by treatment with phosphatidylinositol-specific phospholipase C. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt subcellular location lists Golgi apparatus. Reason: The precursor is processed by a furin-like convertase, which acts in the late secretory pathway, so a Golgi pool is plausible; it is transit, not the functional site. Supporting Evidence: file:human/MSLN/MSLN-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. Golgi apparatus. file:human/MSLN/MSLN-uniprot.txt Proteolytically cleaved by a furin-like convertase to generate megakaryocyte-potentiating factor (MPF), and the cleaved form of mesothelin. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence localizes MSLN to the plasma membrane. Reason: Consistent with GPI-anchored surface expression shown by PI-PLC release. Supporting Evidence: PMID:8552591 When the cDNA was transfected into COS and NIH 3T3 cells, the antigen was found on the cell surface and could be released by treatment with phosphatidylinositol-specific phospholipase C. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt Cell membrane; GPI-anchor mapping. Reason: Correct. Supporting Evidence: file:human/MSLN/MSLN-uniprot.txt SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor. Golgi apparatus. PMID:8552591 When the cDNA was transfected into COS and NIH 3T3 cells, the antigen was found on the cell surface and could be released by treatment with phosphatidylinositol-specific phospholipase C. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8940388 | ACCEPT | Summary: Reactome GPI-anchored MSLN at plasma membrane as GPLD1 substrate. Reason: Correct. Supporting Evidence: Reactome:R-HSA-8940388 Some proteins function at the cell's surface, attached to the plasma membrane via GPI (glycosylphosphatidylinositol) anchors PMID:8552591 When the cDNA was transfected into COS and NIH 3T3 cells, the antigen was found on the cell surface and could be released by treatment with phosphatidylinositol-specific phospholipase C. |
| GO:0007155 cell adhesion | NAS PMID:8552591 Molecular cloning of mesothelin, a differentiation antigen p... | MODIFY | Summary: Cloning paper proposes a role in cell adhesion. Reason: Correct in essence; subsequent work showed membrane mesothelin mediates heterotypic adhesion of CA125-expressing cells, so the specific term is heterotypic cell-cell adhesion. Proposed replacements: heterotypic cell-cell adhesion Supporting Evidence: PMID:8552591 Mesothelin may play a role in cellular adhesion. 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:0007160 cell-matrix adhesion | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Cell-matrix adhesion inherited from the mesothelin family node seeded by mouse Msln. Reason: Human evidence supports cell-cell adhesion via CA125 rather than adhesion to matrix; the PAINT node is grounded on a mouse annotation that was not re-examined, so the term is retained as non-core rather than removed. Supporting Evidence: PMID:8552591 Mesothelin may play a role in cellular adhesion. |
| GO:0009986 cell surface | IBA GO_REF:0000033 | ACCEPT | Summary: Cell surface inherited at the mesothelin family node. Reason: Mesothelin is a GPI-anchored cell-surface antigen recognized by antibodies on intact cells. Supporting Evidence: PMID:8552591 When the cDNA was transfected into COS and NIH 3T3 cells, the antigen was found on the cell surface and could be released by treatment with phosphatidylinositol-specific phospholipase C. PMID:14676194 Mesothelin is a glycosylphosphatidylinositol-linked cell surface molecule expressed in the mesothelial lining of the body cavities and in many tumor cells. |
| GO:0016020 membrane | NAS PMID:8552591 Molecular cloning of mesothelin, a differentiation antigen p... | MODIFY | Summary: Generic membrane from cloning paper. Reason: Correct but general; the same PI-PLC release evidence shows the mature GPI-anchored protein on the outer leaflet, so the specific supported term is external side of plasma membrane (GO:0009897, part_of plasma membrane), the term the adjacent NEW row adds on this same evidence. Proposed replacements: external side of plasma membrane Supporting Evidence: PMID:8552591 When the cDNA was transfected into COS and NIH 3T3 cells, the antigen was found on the cell surface and could be released by treatment with phosphatidylinositol-specific phospholipase C. |
| GO:0009897 external side of plasma membrane | IDA PMID:8552591 Molecular cloning of mesothelin, a differentiation antigen p... | NEW | Summary: GPI-anchored mesothelin is displayed on the outer leaflet and released by PI-PLC. Reason: PI-PLC release of the surface antigen demonstrates GPI anchorage in the outer leaflet, placing the entire mature mesothelin polypeptide on the external face of the plasma membrane, accessible to antibodies and CA125. Supporting Evidence: PMID:8552591 When the cDNA was transfected into COS and NIH 3T3 cells, the antigen was found on the cell surface and could be released by treatment with phosphatidylinositol-specific phospholipase C. PMID:14676194 Mesothelin is a glycosylphosphatidylinositol-linked cell surface molecule expressed in the mesothelial lining of the body cavities and in many tumor cells. |
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Download this section (compressed HTML)Q: Does mesothelin have a physiological function in mesothelium beyond CA125-mediated adhesion, given that Msln-deficient mice show no overt phenotype?
Q: What is the receptor and in vivo relevance of megakaryocyte-potentiating factor activity?
Experiment: Map the CA125-binding surface of mesothelin by mutagenesis of the N-terminal region (around the MORAb-009 epitope) and test heterotypic adhesion of MUC16-expressing ovarian cancer cells to mesothelin-expressing cells.
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