{"gene":"MSLN","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":1992,"finding":"The CAK1 antigen (mesothelin precursor) is a ~40 kDa cell-surface protein anchored via glycosylphosphatidylinositol (GPI), as demonstrated by phosphatidylinositol-phospholipase C (PI-PLC) release of the antigen from cell surfaces and SDS-PAGE immunoblotting. The K1 antibody–antigen complex remains on the cell surface and is poorly internalized, but native Pseudomonas exotoxin (which has its own cell-binding domain) can redirect the complex to intracellular compartments to cause cytotoxicity.","method":"PI-PLC treatment followed by RIA and immunoblotting; acid-wash internalization assay; immunotoxin cytotoxicity assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal biochemical methods (enzymatic release, SDS-PAGE, functional internalization assay) in a single study","pmids":["1727378"],"is_preprint":false},{"year":1996,"finding":"The MSLN gene encodes a 69 kDa precursor protein that is proteolytically processed to yield the 40 kDa GPI-anchored cell-surface protein mesothelin. The precursor is expressed on the cell surface when cDNA is transfected into COS and NIH 3T3 cells and can be released by PI-PLC treatment, confirming GPI anchorage. Mesothelin was proposed to play a role in cellular adhesion.","method":"cDNA cloning, transfection into COS/NIH 3T3 cells, PI-PLC release assay, MAb K1 immunoreactivity","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — foundational molecular cloning paper with functional validation; highly cited (619 citations)","pmids":["8552591"],"is_preprint":false},{"year":1999,"finding":"A soluble form of mesothelin (and related megakaryocyte potentiating factor, MPF) is shed from cells and detectable in sera of ovarian carcinoma patients. The shed soluble mesothelin corresponds to the membrane-associated portion of the precursor, recognized by antibody OV569 binding to the D2 domain (non-cleavable membrane-associated part), not the N-terminal D1 domain. A novel alternatively spliced member of the mesothelin/MPF family with an 82-bp insert was identified that is predicted to be constitutively soluble.","method":"Immunoadsorption, sandwich ELISA, fusion protein binding assays (D1Ig vs D2Ig), cDNA cloning of novel splice variant","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods; highly cited (263 citations)","pmids":["10500211"],"is_preprint":false},{"year":2000,"finding":"The MSLN/MPF gene spans ~8 kb on human chromosome 16, contains 15 exons encoding an 1884-bp open reading frame, and lacks a TATA box in its promoter. Transient transfection analyses localized mesothelium-specific control elements within a 1.85 kb 5' region, with minimal constitutive promoter elements in a 317-bp region and tissue-specific enhancer elements upstream of the minimal promoter acting in a position- and orientation-independent manner.","method":"Genomic cloning, transient transfection reporter assays, promoter deletion analysis","journal":"Molecular cell biology research communications : MCBRC","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional dissection of promoter elements; single lab","pmids":["10683314"],"is_preprint":false},{"year":2003,"finding":"Mesothelin binds specifically to CA125/MUC16 on ovarian carcinoma cell surfaces, mediating heterotypic cell adhesion. Anti-mesothelin antibody blocks the binding of OVCAR-3 cells (expressing CA125) to an endothelial-like cell line expressing mesothelin, demonstrating that this molecular interaction drives cell–cell adhesion relevant to tumor metastasis.","method":"Expression cloning, flow cytometry, co-immunoprecipitation, cell adhesion blocking assay with anti-mesothelin antibody","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding assays and functional cell adhesion blocking; highly cited (456 citations)","pmids":["14676194"],"is_preprint":false},{"year":2006,"finding":"Mesothelin binds MUC16 with very high affinity (apparent Kd ~5–10 nM) in a manner dependent on N-linked glycans on MUC16. Oxidation of MUC16 glycans, removal of N-linked oligosaccharides, or treatment with specific lectins (wheat germ agglutinin, erythroagglutinating phytohemagglutinin) abolishes mesothelin binding. MUC16-positive ovarian tumor cells show markedly increased adherence to mesothelin-expressing A431 cells, and MUC16 knockdown abrogates this adhesion even in the presence of patient ascites fluid.","method":"Flow cytometry binding kinetics with recombinant mesothelin-Fc, glycan oxidation/removal assays, lectin inhibition, MUC16 knockdown cell adhesion assay","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 1–2 — quantitative binding kinetics plus multiple orthogonal mechanistic experiments; highly cited (332 citations)","pmids":["17067392"],"is_preprint":false},{"year":2007,"finding":"High cancer-specific MSLN expression is driven by an 18-bp upstream enhancer element ('CanScript') containing two functional sites: an Sp1-like site and an MCAT element. The MCAT element is bound by transcription enhancer factor TEF-1 (TEAD1) both in vitro (gel retardation/EMSA) and in vivo (chromatin immunoprecipitation). TEF-1 knockdown reduces MSLN protein overexpression, and cancer specificity appears to involve a limiting cofactor of TEF-1 present only in MSLN-overexpressing cells.","method":"Promoter deletion/mutation analysis, EMSA, chromatin immunoprecipitation, TEF-1 siRNA knockdown","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 — EMSA plus ChIP plus functional knockdown with multiple orthogonal methods in one study","pmids":["17909009"],"is_preprint":false},{"year":2008,"finding":"The CA125/MUC16-binding domain on mesothelin was mapped to a 64-amino acid region (residues 296–359) at the N-terminal region of the mature cell-surface protein. Alanine substitution of tyrosine 318 (Y318A) abolishes CA125 binding entirely; substitution of tryptophan 321 (W321A) and glutamic acid 324 (E324A) partially decreases binding; mutation of histidine 354 has no effect. This domain mediates cell adhesion and is recognized by single-chain antibody SS1, which blocks mesothelin–CA125 interaction on cancer cells.","method":"Truncation and alanine-replacement mutagenesis, Western blot overlay assay, ELISA quantification, flow cytometry on cancer cells, cell adhesion inhibition assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with multiple orthogonal binding assays and functional validation; highly cited (158 citations)","pmids":["19075018"],"is_preprint":false},{"year":2008,"finding":"Mesothelin overexpression in pancreatic cancer cells significantly increases cell proliferation (~90%) and migration (~300%) in vitro and tumor volume (~4-fold) in nude mouse xenograft models. Conversely, mesothelin siRNA silencing inhibits proliferation and migration and ablates tumor progression in vivo, establishing mesothelin as a functional driver of pancreatic cancer aggressiveness.","method":"Stable overexpression and siRNA knockdown, cell proliferation assay, migration assay, nude mouse xenograft model","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal gain- and loss-of-function experiments with both in vitro and in vivo validation; highly cited (139 citations)","pmids":["18281514"],"is_preprint":false},{"year":2011,"finding":"Mesothelin confers resistance to TNF-α-induced apoptosis in pancreatic cancer cells through constitutive activation of the Akt/PI3K/NF-κB pathway, leading to upregulation of IL-6 and anti-apoptotic protein Mcl-1. MSLN overexpression elevates Bcl-XL and Mcl-1, deactivates BAD (p-Ser75), and activates Bcl-2 (p-Ser70). MSLN siRNA silencing reduces NF-κB and Akt activity and restores TNF-α sensitivity. IL-6 siRNA silencing also restores sensitivity, delineating a MSLN→Akt/NF-κB→IL-6→Mcl-1 survival axis.","method":"Stable MSLN overexpression and shRNA knockdown, NF-κB luciferase reporter, Western blot, MTT assay, TUNEL/caspase activation, IL-6 Luminex assay, IKK and PI3K inhibitors","journal":"Molecular cancer","confidence":"High","confidence_rationale":"Tier 2 — systematic gain/loss-of-function with pathway inhibitors and multiple readouts; highly cited (132 citations)","pmids":["21880146"],"is_preprint":false},{"year":2012,"finding":"Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion. In an orthotopic mouse model, MSLN-overexpressing cells preferentially localize to the tumor-invading edge and co-localize with MMP-9. MSLN knockdown reduces invasion and MMP-9 secretion. In a tissue microarray of epithelioid MPM patients (n=139, 729 cores), MSLN overexpression correlates with higher MMP-9 expression.","method":"Forced MSLN expression and shRNA knockdown in human and murine MPM cells, in vitro invasion assay, MMP secretion assay, orthotopic mouse model, tissue microarray IHC","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal loss/gain of function with both in vitro mechanistic and in vivo validation; highly cited (163 citations)","pmids":["22371455"],"is_preprint":false},{"year":2012,"finding":"Mesothelin enhances invasion of ovarian cancer cells by inducing MMP-7 expression through MAPK/ERK and JNK signaling pathways. ERK1/2-specific inhibitors, JNK-specific inhibitors, or a decoy AP-1 oligonucleotide suppress MMP-7 expression and inhibit MSLN-induced cell migration. In vivo, MAPK/ERK or JNK inhibitors decrease intratumoral MMP-7, delay tumor growth, and extend survival in mouse models.","method":"MSLN overexpression, ERK/JNK pathway inhibitors, decoy AP-1 oligonucleotide, in vitro invasion/migration assay, in vivo mouse tumor model","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 2 — pathway-specific inhibitors plus in vivo validation; highly cited (134 citations)","pmids":["21999204"],"is_preprint":false},{"year":2013,"finding":"Mesothelin binding to MUC16 on pancreatic cancer cells activates p38 MAPK signaling, leading to selective upregulation and secretion of MMP-7, thereby promoting cell motility and invasion. Depletion of MMP-7 or inhibition of p38 MAPK abolishes MSLN-mediated pancreatic cancer cell motility and invasion, placing MSLN→MUC16 interaction upstream of p38 MAPK→MMP-7 in a defined signaling pathway.","method":"Bioengineering/microfluidic motility assays, MMP-7 knockdown, p38 MAPK inhibition, invasion assay, MSLN-MUC16 co-expression system","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — epistasis established by specific inhibitors and knockdown with functional readout; highly cited (191 citations)","pmids":["23694968"],"is_preprint":false},{"year":2014,"finding":"A SNP (rs1057147) within the 3' UTR of MSLN affects a miR-611 binding site; the G allele allows miR-611 binding while the A allele does not, as demonstrated by dual-luciferase reporter assays. miR-611 transfection into mesothelin-expressing MPM cells significantly reduces endogenous MSLN protein, establishing functional post-transcriptional regulation of MSLN by miR-611 at this polymorphic site.","method":"Dual luciferase reporter assay with alternative alleles, miRNA mimic transfection, Western blot for endogenous MSLN protein","journal":"Journal of thoracic oncology","confidence":"Medium","confidence_rationale":"Tier 2 — direct functional reporter assay with endogenous validation; single lab","pmids":["25436799"],"is_preprint":false},{"year":2021,"finding":"Mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) form a signaling complex critical for fibroblast activation. Msln-/- mice are protected from cholestatic liver fibrosis (Mdr2-deficient model), bleomycin-induced lung fibrosis, and UUO-induced kidney fibrosis. Conversely, Thy1-/- mice are more susceptible to fibrosis, indicating Msln-Thy1 operate in the same pathway. Anti-MSLN immunotoxins targeting MSLN+ activated portal fibroblasts reduce collagen deposition in bile duct ligation-injured mice.","method":"Msln-/- and Thy1-/- knockout mouse models (multiple fibrosis models), anti-MSLN immunotoxin treatment, collagen deposition assay, human activated portal fibroblast studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis using multiple knockout models across multiple organ fibrosis systems, confirmed with pharmacological targeting","pmids":["34253615"],"is_preprint":false},{"year":2021,"finding":"Metformin reduces MSLN expression in ovarian cancer cells, which in turn downregulates IL-6/STAT3 signaling activity and subsequently decreases VEGF and TGFβ1 expression. Conversely, forced MSLN overexpression in ovarian cancer cells demonstrates an oncogenic function upstream of IL-6/STAT3. MSLN knockdown phenocopies metformin effects on cell growth, migration, stemness, and angiogenesis.","method":"Metformin treatment, MSLN overexpression, siRNA knockdown, IL-6/STAT3 pathway Western blot, cell growth/migration/apoptosis assays, capillary-like structure formation assay","journal":"Cell transplantation","confidence":"Medium","confidence_rationale":"Tier 3 — pathway placement established by gain/loss of function but mechanistic link between MSLN and IL-6/STAT3 not fully reconstituted; single lab","pmids":["34238029"],"is_preprint":false}],"current_model":"MSLN encodes a 69 kDa GPI-anchored glycoprotein precursor that is proteolytically processed into the 40 kDa cell-surface protein mesothelin and a shed 31 kDa megakaryocyte potentiating factor (MPF); mesothelin binds CA125/MUC16 via a defined N-terminal domain (residues 296–359, requiring Y318) in an N-glycan-dependent, high-affinity interaction (Kd ~5–10 nM) that mediates heterotypic cell adhesion relevant to peritoneal metastasis; downstream of this interaction, mesothelin activates p38 MAPK→MMP-7 (in pancreatic cancer) and MAPK/ERK and JNK→MMP-7 (in ovarian cancer) to drive invasion, while also constitutively activating Akt/PI3K/NF-κB→IL-6→Mcl-1 signaling to confer apoptosis resistance; its cancer-specific overexpression is transcriptionally driven by a TEF-1/TEAD1-bound MCAT enhancer element; and Msln forms a signaling complex with Thy1 that is required for fibroblast activation across multiple organs."},"narrative":{"teleology":[{"year":1992,"claim":"Establishing the biophysical identity of the mesothelin antigen as a GPI-anchored cell-surface protein resolved how the K1 antibody target is tethered to the membrane and why it resists internalization.","evidence":"PI-PLC enzymatic release, SDS-PAGE immunoblotting, and internalization assays on K1-reactive cells","pmids":["1727378"],"confidence":"High","gaps":["Protein sequence unknown at this stage","Physiological ligand unidentified","Normal tissue function not addressed"]},{"year":1996,"claim":"Cloning the MSLN cDNA revealed that a 69 kDa precursor is proteolytically processed to yield the 40 kDa GPI-anchored mesothelin and a released fragment (MPF), defining the gene product's molecular architecture.","evidence":"cDNA cloning and transfection into COS/NIH 3T3 cells with PI-PLC release confirmation","pmids":["8552591"],"confidence":"High","gaps":["Protease responsible for precursor cleavage unidentified","Binding partner and cellular function unknown"]},{"year":1999,"claim":"Detection of soluble mesothelin in sera of ovarian cancer patients and identification of an alternatively spliced constitutively soluble variant demonstrated that mesothelin exists in both membrane-bound and shed forms with potential biomarker utility.","evidence":"Sandwich ELISA, immunoadsorption, and domain-mapping with D1Ig/D2Ig fusion proteins on patient sera","pmids":["10500211"],"confidence":"High","gaps":["Sheddase identity unknown","Functional role of soluble mesothelin versus membrane-bound form not distinguished"]},{"year":2003,"claim":"Identification of CA125/MUC16 as mesothelin's binding partner answered the long-standing question of mesothelin's adhesion function and linked it mechanistically to ovarian cancer metastasis.","evidence":"Expression cloning, co-immunoprecipitation, flow cytometry, and antibody-blocking cell adhesion assays","pmids":["14676194"],"confidence":"High","gaps":["Binding affinity not quantified","Binding domain on mesothelin unmapped","Downstream signaling unknown"]},{"year":2006,"claim":"Quantitative binding studies established mesothelin–MUC16 interaction as high-affinity (Kd ~5–10 nM) and N-glycan-dependent, explaining why glycan-rich tumor surfaces support robust heterotypic adhesion.","evidence":"Flow cytometry binding kinetics with mesothelin-Fc, glycan oxidation/removal and lectin inhibition, MUC16 knockdown adhesion assay","pmids":["17067392"],"confidence":"High","gaps":["Structural basis of glycan requirement unresolved","Mesothelin residues mediating binding not yet mapped"]},{"year":2007,"claim":"Discovery that the TEF-1/TEAD1 transcription factor drives cancer-specific MSLN overexpression through an MCAT enhancer element explained how mesothelin expression is restricted to tumors and mesothelial tissues.","evidence":"Promoter deletion/mutation, EMSA, chromatin immunoprecipitation, and TEF-1 siRNA knockdown","pmids":["17909009"],"confidence":"High","gaps":["Identity of the cancer-specific cofactor of TEF-1 unknown","Epigenetic regulation not addressed"]},{"year":2008,"claim":"Mapping the MUC16-binding domain to residues 296–359 with critical dependence on Y318, combined with demonstration that mesothelin drives proliferation and migration in pancreatic cancer xenografts, established mesothelin as a functional oncogenic driver acting through a defined binding interface.","evidence":"Systematic truncation and alanine-scanning mutagenesis with binding assays; reciprocal overexpression and siRNA knockdown in vitro and in nude mouse xenografts","pmids":["19075018","18281514"],"confidence":"High","gaps":["Crystal structure of mesothelin or mesothelin–MUC16 complex unavailable","Downstream signaling pathways from mesothelin–MUC16 interaction not yet delineated"]},{"year":2011,"claim":"Delineation of the Akt/PI3K/NF-κB→IL-6→Mcl-1 survival axis downstream of mesothelin explained how mesothelin confers apoptosis resistance in pancreatic cancer cells.","evidence":"Stable MSLN overexpression and shRNA knockdown, NF-κB reporter, PI3K/IKK inhibitors, IL-6 siRNA, caspase/TUNEL assays","pmids":["21880146"],"confidence":"High","gaps":["Proximal signaling event linking GPI-anchored mesothelin to Akt activation unknown","Whether the survival axis requires MUC16 engagement not tested"]},{"year":2012,"claim":"Identification of MAPK/ERK and JNK pathways converging on MMP-7 (ovarian cancer) and MMP-9 (mesothelioma) as mesothelin-regulated invasion effectors established the downstream proteolytic program through which mesothelin drives tumor invasion.","evidence":"ERK/JNK-specific inhibitors, AP-1 decoy oligonucleotide, gain/loss-of-function in vitro and in vivo mouse models, tissue microarray correlation","pmids":["21999204","22371455"],"confidence":"High","gaps":["Direct physical link between mesothelin and MAPK activation not identified","Relative contribution of MMP-7 vs MMP-9 across cancer types unclear"]},{"year":2013,"claim":"Placing mesothelin–MUC16 binding upstream of p38 MAPK→MMP-7 in pancreatic cancer established that intercellular adhesion through the mesothelin–MUC16 axis directly triggers a defined intracellular signaling cascade promoting motility.","evidence":"Microfluidic motility assays, MMP-7 knockdown and p38 inhibition epistasis in MSLN-MUC16 co-expression system","pmids":["23694968"],"confidence":"High","gaps":["Adaptor protein linking GPI-anchored mesothelin to p38 MAPK unknown","Whether other mesothelin ligands can trigger the same cascade not tested"]},{"year":2021,"claim":"Discovery that mesothelin forms a signaling complex with Thy1 required for fibroblast activation across liver, lung, and kidney fibrosis models expanded mesothelin's functional role beyond cancer to organ fibrosis.","evidence":"Msln−/− and Thy1−/− knockout mice in cholestatic liver, bleomycin lung, and UUO kidney fibrosis models; anti-MSLN immunotoxin treatment","pmids":["34253615"],"confidence":"High","gaps":["Molecular details of the Msln–Thy1 signaling complex (stoichiometry, intermediaries) unresolved","Whether Msln–Thy1 signals through the same MAPK/Akt axes identified in cancer unknown"]},{"year":null,"claim":"The proximal signaling mechanism by which a GPI-anchored protein lacking an intracellular domain activates Akt, MAPK, and NF-κB pathways remains unknown, and no atomic-resolution structure of mesothelin or the mesothelin–MUC16 complex is available.","evidence":"","pmids":[],"confidence":"High","gaps":["No transmembrane co-receptor or adaptor identified that transduces signal from GPI-anchored mesothelin","No crystal or cryo-EM structure of mesothelin or mesothelin–MUC16 complex","Protease(s) responsible for precursor cleavage and ectodomain shedding remain unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098631","term_label":"cell adhesion mediator activity","supporting_discovery_ids":[4,5,7,12]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[4,5,12]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,11,12]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[4,5,7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10,11]}],"complexes":[],"partners":["MUC16","THY1","TEAD1","MMP7","MMP9"],"other_free_text":[]},"mechanistic_narrative":"Mesothelin is a GPI-anchored cell-surface glycoprotein generated by proteolytic processing of a 69 kDa precursor into the 40 kDa membrane-bound mesothelin and a shed 31 kDa megakaryocyte potentiating factor (MPF) [PMID:8552591, PMID:10500211]. Mesothelin binds CA125/MUC16 with high affinity (Kd ~5–10 nM) through an N-terminal domain (residues 296–359, critically dependent on Y318) in an N-glycan-dependent manner, mediating heterotypic cell adhesion that promotes peritoneal metastasis [PMID:14676194, PMID:17067392, PMID:19075018]. Downstream of this interaction, mesothelin activates MAPK/ERK, JNK, and p38 MAPK signaling to induce MMP-7 and MMP-9 secretion driving invasion, and constitutively activates Akt/PI3K/NF-κB→IL-6→Mcl-1 signaling to confer apoptosis resistance in pancreatic and ovarian cancers [PMID:21880146, PMID:21999204, PMID:23694968]. Beyond cancer, mesothelin forms a signaling complex with Thy1 on fibroblasts that is required for fibroblast activation across liver, lung, and kidney fibrosis models [PMID:34253615]."},"prefetch_data":{"uniprot":{"accession":"Q13421","full_name":"Mesothelin","aliases":["CAK1 antigen","Pre-pro-megakaryocyte-potentiating factor"],"length_aa":630,"mass_kda":69.0,"function":"Membrane-anchored forms may play a role in cellular adhesion Megakaryocyte-potentiating factor (MPF) potentiates megakaryocyte colony formation in vitro","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q13421/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MSLN","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MSLN","total_profiled":1310},"omim":[{"mim_id":"601051","title":"MESOTHELIN; MSLN","url":"https://www.omim.org/entry/601051"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Vesicles","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":89.2},{"tissue":"fallopian tube","ntpm":261.5}],"url":"https://www.proteinatlas.org/search/MSLN"},"hgnc":{"alias_symbol":["CAK1","MPF"],"prev_symbol":[]},"alphafold":{"accession":"Q13421","domains":[{"cath_id":"-","chopping":"59-275","consensus_level":"medium","plddt":87.8198,"start":59,"end":275},{"cath_id":"-","chopping":"330-432","consensus_level":"medium","plddt":84.0996,"start":330,"end":432}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13421","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13421-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13421-F1-predicted_aligned_error_v6.png","plddt_mean":78.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MSLN","jax_strain_url":"https://www.jax.org/strain/search?query=MSLN"},"sequence":{"accession":"Q13421","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13421.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13421/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13421"}},"corpus_meta":[{"pmid":"3293802","id":"PMC_3293802","title":"The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis.","date":"1988","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/3293802","citation_count":748,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8428594","id":"PMC_8428594","title":"Phosphorylation and activation of human cdc25-C by cdc2--cyclin B and its involvement in the self-amplification of MPF at mitosis.","date":"1993","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8428594","citation_count":586,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2844417","id":"PMC_2844417","title":"cdc2 is a component of the M phase-specific histone H1 kinase: evidence for identity with MPF.","date":"1988","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/2844417","citation_count":497,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2531073","id":"PMC_2531073","title":"MPF from starfish oocytes at first meiotic metaphase is a heterodimer containing one molecule of cdc2 and one molecule of cyclin B.","date":"1989","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/2531073","citation_count":491,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8232587","id":"PMC_8232587","title":"Calmodulin-dependent protein kinase II mediates inactivation of MPF and CSF upon fertilization of Xenopus eggs.","date":"1993","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/8232587","citation_count":404,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7600950","id":"PMC_7600950","title":"Microtubule and chromatin behavior follow MAP kinase activity but not MPF activity during meiosis in mouse oocytes.","date":"1994","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7600950","citation_count":356,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"2649251","id":"PMC_2649251","title":"Purification of MPF from starfish: identification as the H1 histone kinase p34cdc2 and a possible mechanism for its periodic activation.","date":"1989","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/2649251","citation_count":338,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9670027","id":"PMC_9670027","title":"MPF localization is controlled by nuclear export.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9670027","citation_count":291,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9660921","id":"PMC_9660921","title":"PKA and MPF-activated polo-like kinase regulate anaphase-promoting complex activity and mitosis progression.","date":"1998","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/9660921","citation_count":280,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"1714387","id":"PMC_1714387","title":"Xenopus M phase MAP kinase: isolation of its cDNA and activation by MPF.","date":"1991","source":"The EMBO 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Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/12546658","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7541376","id":"PMC_7541376","title":"Brefeldin A provokes indirect activation of cdc2 kinase (MPF) in Xenopus oocytes, resulting in meiotic cell division.","date":"1995","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/7541376","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"7962177","id":"PMC_7962177","title":"Progesterone but not ras requires MPF for in vivo activation of MAPK and S6 KII: MAPK is an essential conexion point of both signaling pathways.","date":"1994","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7962177","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"3539598","id":"PMC_3539598","title":"Partial purification of the maturation-promoting factor MPF from unfertilized eggs of Xenopus laevis.","date":"1986","source":"European journal of biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3539598","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31287381","id":"PMC_31287381","title":"Mutagenicity assessment of food contact material migrates with the Ames MPF assay.","date":"2019","source":"Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment","url":"https://pubmed.ncbi.nlm.nih.gov/31287381","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28234231","id":"PMC_28234231","title":"The effect of conspecific ampulla oviductal epithelial cells during in vitro maturation on oocyte developmental competence and maturation-promoting factor (MPF) activity in sheep.","date":"2016","source":"Theriogenology","url":"https://pubmed.ncbi.nlm.nih.gov/28234231","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8180003","id":"PMC_8180003","title":"Kinetics of MPF and histone H1 kinase activity differ during the G2- to M-phase transition in mouse oocytes.","date":"1993","source":"The International journal of developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/8180003","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32296183","id":"PMC_32296183","title":"A reference map of the human binary protein interactome.","date":"2020","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/32296183","citation_count":849,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human 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America","url":"https://pubmed.ncbi.nlm.nih.gov/8552591","citation_count":619,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25378643","id":"PMC_25378643","title":"Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity.","date":"2014","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25378643","citation_count":472,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14676194","id":"PMC_14676194","title":"Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14676194","citation_count":456,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome 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reports","url":"https://pubmed.ncbi.nlm.nih.gov/27342126","citation_count":306,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10500211","id":"PMC_10500211","title":"Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10500211","citation_count":263,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34325726","id":"PMC_34325726","title":"IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin.","date":"2021","source":"Journal of hematology & oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34325726","citation_count":248,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16428485","id":"PMC_16428485","title":"Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer.","date":"2006","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/16428485","citation_count":226,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24824231","id":"PMC_24824231","title":"Discovery of mesothelin and exploiting it as a target for immunotherapy.","date":"2014","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/24824231","citation_count":213,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21988832","id":"PMC_21988832","title":"Toward an understanding of the protein interaction network of the human liver.","date":"2011","source":"Molecular systems biology","url":"https://pubmed.ncbi.nlm.nih.gov/21988832","citation_count":207,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23694968","id":"PMC_23694968","title":"Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation.","date":"2013","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/23694968","citation_count":191,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22412141","id":"PMC_22412141","title":"Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis.","date":"2012","source":"Journal of clinical oncology : official journal of the American Society of Clinical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22412141","citation_count":166,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22371455","id":"PMC_22371455","title":"Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients.","date":"2012","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/22371455","citation_count":163,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19075018","id":"PMC_19075018","title":"A binding domain on mesothelin for CA125/MUC16.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19075018","citation_count":158,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24334761","id":"PMC_24334761","title":"Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma.","date":"2013","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/24334761","citation_count":152,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33373818","id":"PMC_33373818","title":"The exosomes derived from CAR-T cell efficiently target mesothelin and reduce triple-negative breast cancer growth.","date":"2020","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33373818","citation_count":143,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18281514","id":"PMC_18281514","title":"Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer.","date":"2008","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/18281514","citation_count":139,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"29117863","id":"PMC_29117863","title":"RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination.","date":"2017","source":"BMC biology","url":"https://pubmed.ncbi.nlm.nih.gov/29117863","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15897581","id":"PMC_15897581","title":"Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients.","date":"2005","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/15897581","citation_count":134,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21999204","id":"PMC_21999204","title":"Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways.","date":"2012","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/21999204","citation_count":134,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"19293794","id":"PMC_19293794","title":"High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma.","date":"2009","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/19293794","citation_count":132,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21880146","id":"PMC_21880146","title":"Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression.","date":"2011","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21880146","citation_count":132,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46514,"output_tokens":2361,"usd":0.087479},"stage2":{"model":"claude-opus-4-6","input_tokens":5260,"output_tokens":3565,"usd":0.173137},"total_usd":0.568959,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":60817,"output_tokens":6093,"usd":0.136923},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8446,"output_tokens":2882,"usd":0.17142}},"stage1_raw":"Looking at the corpus, I need to identify papers about the human gene MSLN (Mesothelin). The vast majority of papers in this corpus are about MPF (Maturation-Promoting Factor), which is CDK1/cyclin B — completely unrelated to MSLN. I need to carefully filter for papers actually about MSLN/Mesothelin.\n\nRelevant MSLN papers I can identify:\n- PMID:1727378 - Characterization of CAK1 antigen (mesothelin precursor recognized by K1 antibody)\n- PMID:1351045 - CAK1 expression in squamous-cell carcinomas\n- PMID:17909009 - MSLN promoter/enhancer characterization\n- PMID:10683314 - Structure of Mesothelin/MPF gene and promoter\n- PMID:34253615 - Msln role in fibroblast activation/fibrosis\n- PMID:34238029 - Metformin/MSLN/IL-6/STAT3 signaling\n- PMID:24465798 - MSLN silencing effects in mesothelioma\n- PMID:25436799 - miR-611 binding site polymorphism in MSLN\n\nNote: PMID:10683314 uses \"MPF\" to mean \"Megakaryocyte Potentiating Factor\" — the mesothelin precursor protein, not the cell cycle MPF. This is the MSLN gene product.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"The CAK1 antigen (mesothelin precursor, now known as MSLN gene product) is a ~40 kDa GPI-anchored cell-surface protein expressed on mesothelial cells and ovarian tumor cells. It is released from the cell surface by phosphatidylinositol-phospholipase C, is poorly internalized upon antibody binding alone, but can be internalized when antibody is coupled to native Pseudomonas exotoxin (via domain I-mediated internalization), demonstrating GPI anchorage and defining internalization behavior relevant to immunotoxin targeting.\",\n      \"method\": \"Immunofluorescence microscopy, PI-PLC cleavage assay, SDS-PAGE/immunoblot, acid-wash internalization assay, immunotoxin cytotoxicity assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal biochemical methods in a single study with rigorous controls establishing GPI anchor, molecular weight, and internalization mechanism\",\n      \"pmids\": [\"1727378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The MSLN gene encodes both mesothelin and megakaryocyte potentiating factor (MPF) from a single 1884-bp open reading frame across 15 exons on human chromosome 16. The 1.85-kb region at the 5' end lacks a TATA box and canonical SP1 sites; mesothelium-specific control elements reside within this region, with a minimal constitutive promoter in a 317-bp segment and tissue-specific enhancer elements upstream that act in a position- and orientation-independent manner.\",\n      \"method\": \"Genomic cloning, transient transfection reporter assays, deletion analysis\",\n      \"journal\": \"Molecular cell biology research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional dissection of promoter by deletion/transfection in a single study\",\n      \"pmids\": [\"10683314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Cancer-specific overexpression of MSLN is driven by an 18-bp upstream enhancer element called CanScript, which contains two functionally distinct sites: an Sp1-like site and an MCAT element. The MCAT element is bound by transcription enhancer factor TEF-1 (TEAD1) both in vitro (gel retardation) and in vivo (chromatin immunoprecipitation). TEF-1 knockdown reduces MSLN protein overexpression, and a limiting TEF-1 cofactor appears to confer cancer specificity.\",\n      \"method\": \"Mutational analysis of CanScript, gel retardation (EMSA), chromatin immunoprecipitation (ChIP), siRNA knockdown, reporter assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (EMSA, ChIP, KD, mutagenesis) in a single study with strong mechanistic follow-up\",\n      \"pmids\": [\"17909009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MSLN silencing by siRNA in MSLN-overexpressing malignant pleural mesothelioma cell lines reduces proliferation rate, invasive capacity, and sphere formation, and sensitizes cells to cisplatin-induced apoptosis, establishing a functional role for MSLN in supporting mesothelioma cell malignancy.\",\n      \"method\": \"siRNA knockdown, proliferation assay, invasion assay, sphere formation assay, apoptosis assay combined with cisplatin\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with multiple defined cellular phenotype readouts in a single lab study\",\n      \"pmids\": [\"24465798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A common SNP (rs1057147) in the 3' UTR of MSLN disrupts a binding site for miR-611; the G allele supports miR-611 binding whereas the A allele does not. Dual-luciferase reporter assays confirmed allele-dependent regulation, and transfection of miR-611 mimic into MPM cells significantly reduced endogenous MSLN protein, identifying miR-611 as a post-transcriptional regulator of MSLN expression.\",\n      \"method\": \"Dual luciferase reporter assay with allele-specific constructs, miRNA mimic transfection, western blot for endogenous MSLN protein\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional reporter assay plus endogenous protein knockdown validation in a single study\",\n      \"pmids\": [\"25436799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Msln-knockout mice are protected from cholestatic liver fibrosis (Mdr2-deficient model), bleomycin-induced lung fibrosis, and UUO-induced kidney fibrosis, while Thy1-knockout mice show increased susceptibility to fibrosis, indicating that a Msln-Thy1 signaling complex is required for fibroblast activation across multiple organs. Targeting MSLN+ activated portal fibroblasts with anti-MSLN immunotoxins reduced collagen deposition in bile-duct-ligation-injured mice.\",\n      \"method\": \"Knockout mouse models (Msln-/-, Thy1-/-), multiple fibrosis models (BDL, bleomycin, UUO), anti-MSLN immunotoxin treatment, collagen deposition quantification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function replicated across three distinct fibrosis models with defined cellular and molecular phenotype, plus functional immunotoxin rescue experiment\",\n      \"pmids\": [\"34253615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In ovarian cancer cells, MSLN sustains IL-6/STAT3 signaling; metformin treatment reduces MSLN expression and consequently downregulates IL-6/STAT3 activity, VEGF, and TGFβ1, leading to reduced proliferation, migration, stemness, and angiogenic capacity. Overexpression of MSLN confers oncogenic properties to ovarian cancer cells.\",\n      \"method\": \"siRNA knockdown and overexpression of MSLN, western blot for STAT3 signaling components, cell growth/migration/apoptosis assays, metformin pharmacological intervention\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD and OE with pathway readout, single lab, moderate mechanistic depth placing MSLN upstream of IL-6/STAT3\",\n      \"pmids\": [\"34238029\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSLN encodes a GPI-anchored cell-surface glycoprotein (mesothelin) whose cancer-specific overexpression is driven by a TEF-1/TEAD1-bound MCAT enhancer element (CanScript) within an otherwise weak promoter; its expression is post-transcriptionally regulated by miR-611; at the cellular level, MSLN promotes fibroblast activation through a Msln-Thy1 signaling complex and sustains oncogenic IL-6/STAT3 signaling in cancer cells, while the mature protein's GPI anchorage and poor spontaneous internalization define its behavior as an immunotherapy target.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n\nThe corpus is dominated by papers about MPF (Maturation-Promoting Factor = CDK1/cyclin B complex) — these are clearly about a completely different molecular entity. \"MPF\" in those papers stands for \"Maturation-Promoting Factor,\" not MSLN.\n\nPapers about MSLN (Mesothelin):\n- PMID:1727378 — KEEP (CAK1 antigen = mesothelin precursor, characterized by K1 antibody)\n- PMID:1351045 — KEEP (CAK1 antigen expression, K1 antibody)\n- PMID:8552591 — KEEP (molecular cloning of mesothelin)\n- PMID:14676194 — KEEP (mesothelin binds CA125/MUC16)\n- PMID:17067392 — KEEP (mesothelin-MUC16 binding kinetics, N-glycan dependence)\n- PMID:19075018 — KEEP (binding domain on mesothelin for CA125)\n- PMID:23694968 — KEEP (MSLN-MUC16 interaction, MMP-7, p38 MAPK)\n- PMID:21999204 — KEEP (MSLN enhances invasion via MMP-7, ERK/JNK)\n- PMID:21880146 — KEEP (MSLN confers resistance via Akt/PI3K/NF-κB/IL-6/Mcl-1)\n- PMID:18281514 — KEEP (MSLN promotes proliferation/migration in pancreatic cancer)\n- PMID:22371455 — KEEP (MSLN overexpression promotes invasion, MMP-9)\n- PMID:17909009 — KEEP (MSLN transcriptional regulation, TEF-1/TEAD1)\n- PMID:10683314 — KEEP (MSLN/MPF gene structure, promoter characterization)\n- PMID:34253615 — KEEP (Msln-Thy1 signaling complex in fibroblast activation)\n- PMID:25436799 — KEEP (miR-611 binding site SNP affects MSLN levels)\n- PMID:24465798 — KEEP (MSLN silencing anti-malignant effects)\n- PMID:34238029 — KEEP (MSLN mediates IL-6/STAT3 in ovarian cancer)\n- PMID:10500211 — KEEP (soluble mesothelin/MPF family)\n- PMID:15217923 — KEEP (mesothelin review, GPI anchor, processing)\n- PMID:24824231 — KEEP (mesothelin discovery review)\n- PMID:16428485 — KEEP (mesothelin shed into serum)\n- PMID:28514442 — KEEP (BioPlex interactome - includes MSLN interactions)\n- PMID:32296183 — KEEP (HuRI interactome)\n- PMID:33961781 — KEEP (BioPlex 3.0)\n- PMID:22939629 — KEEP (human protein complexes)\n- PMID:21988832 — KEEP (human liver interactome)\n- PMID:24167356 — KEEP (MSLN gene products MPF and mesothelin as biomarkers)\n- PMID:31064781 — KEEP (MSLN-TTC, mechanistic mode of action study)\n- PMID:25378643 — KEEP (MSLN-CAR T, CD4-dependent immunity)\n\nPapers about MPF (Maturation-Promoting Factor/CDK1 complex): PMID:3293802, 8428594, 2844417, 2531073, 8232587, 7600950, 2649251, 9670027, 9660921, 1714387, 1846321, 2834064, 9601104, 2538367, 1824935, 1830371, 8994825, 2145153, 10602278, 1727378(already KEEP), 9774652, 9135146, 10629030, 11739722, 15870265, 12215532, 11976990, 23222840, 23333317, 10683314(already KEEP), 8625296, 12546658, etc. — EXCLUDE (these are about CDK1/cyclin B MPF, not MSLN)\n\nPMID:10683314 — this is about the Mesothelin/MPF gene (where MPF = Megakaryocyte Potentiating Factor, a product of the MSLN locus) — KEEP\n\nPMID:24167356 — MPF here = Megakaryocyte Potentiating Factor, product of MSLN gene — KEEP\n\nPMID:31287381 — Ames MPF assay (mutagenicity test) — EXCLUDE (different MPF entirely)\n\nPMID:27935965 — CAK1 in Candida albicans — EXCLUDE (fungal CAK1, alias collision)\nPMID:8208556 — human CAK1 = CDK-activating kinase — EXCLUDE (alias collision; this is CDK7, not MSLN)\nPMID:9774652, 9135146, 10629030, 11739722, 15870265, 12215532 — CAK1 = yeast CDK-activating kinase — EXCLUDE\n\nNow extracting discoveries from KEEP papers:\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1992,\n      \"finding\": \"The CAK1 antigen (mesothelin precursor) is a ~40 kDa cell-surface protein anchored via glycosylphosphatidylinositol (GPI), as demonstrated by phosphatidylinositol-phospholipase C (PI-PLC) release of the antigen from cell surfaces and SDS-PAGE immunoblotting. The K1 antibody–antigen complex remains on the cell surface and is poorly internalized, but native Pseudomonas exotoxin (which has its own cell-binding domain) can redirect the complex to intracellular compartments to cause cytotoxicity.\",\n      \"method\": \"PI-PLC treatment followed by RIA and immunoblotting; acid-wash internalization assay; immunotoxin cytotoxicity assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal biochemical methods (enzymatic release, SDS-PAGE, functional internalization assay) in a single study\",\n      \"pmids\": [\"1727378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The MSLN gene encodes a 69 kDa precursor protein that is proteolytically processed to yield the 40 kDa GPI-anchored cell-surface protein mesothelin. The precursor is expressed on the cell surface when cDNA is transfected into COS and NIH 3T3 cells and can be released by PI-PLC treatment, confirming GPI anchorage. Mesothelin was proposed to play a role in cellular adhesion.\",\n      \"method\": \"cDNA cloning, transfection into COS/NIH 3T3 cells, PI-PLC release assay, MAb K1 immunoreactivity\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — foundational molecular cloning paper with functional validation; highly cited (619 citations)\",\n      \"pmids\": [\"8552591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"A soluble form of mesothelin (and related megakaryocyte potentiating factor, MPF) is shed from cells and detectable in sera of ovarian carcinoma patients. The shed soluble mesothelin corresponds to the membrane-associated portion of the precursor, recognized by antibody OV569 binding to the D2 domain (non-cleavable membrane-associated part), not the N-terminal D1 domain. A novel alternatively spliced member of the mesothelin/MPF family with an 82-bp insert was identified that is predicted to be constitutively soluble.\",\n      \"method\": \"Immunoadsorption, sandwich ELISA, fusion protein binding assays (D1Ig vs D2Ig), cDNA cloning of novel splice variant\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; highly cited (263 citations)\",\n      \"pmids\": [\"10500211\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The MSLN/MPF gene spans ~8 kb on human chromosome 16, contains 15 exons encoding an 1884-bp open reading frame, and lacks a TATA box in its promoter. Transient transfection analyses localized mesothelium-specific control elements within a 1.85 kb 5' region, with minimal constitutive promoter elements in a 317-bp region and tissue-specific enhancer elements upstream of the minimal promoter acting in a position- and orientation-independent manner.\",\n      \"method\": \"Genomic cloning, transient transfection reporter assays, promoter deletion analysis\",\n      \"journal\": \"Molecular cell biology research communications : MCBRC\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional dissection of promoter elements; single lab\",\n      \"pmids\": [\"10683314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mesothelin binds specifically to CA125/MUC16 on ovarian carcinoma cell surfaces, mediating heterotypic cell adhesion. Anti-mesothelin antibody blocks the binding of OVCAR-3 cells (expressing CA125) to an endothelial-like cell line expressing mesothelin, demonstrating that this molecular interaction drives cell–cell adhesion relevant to tumor metastasis.\",\n      \"method\": \"Expression cloning, flow cytometry, co-immunoprecipitation, cell adhesion blocking assay with anti-mesothelin antibody\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding assays and functional cell adhesion blocking; highly cited (456 citations)\",\n      \"pmids\": [\"14676194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mesothelin binds MUC16 with very high affinity (apparent Kd ~5–10 nM) in a manner dependent on N-linked glycans on MUC16. Oxidation of MUC16 glycans, removal of N-linked oligosaccharides, or treatment with specific lectins (wheat germ agglutinin, erythroagglutinating phytohemagglutinin) abolishes mesothelin binding. MUC16-positive ovarian tumor cells show markedly increased adherence to mesothelin-expressing A431 cells, and MUC16 knockdown abrogates this adhesion even in the presence of patient ascites fluid.\",\n      \"method\": \"Flow cytometry binding kinetics with recombinant mesothelin-Fc, glycan oxidation/removal assays, lectin inhibition, MUC16 knockdown cell adhesion assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — quantitative binding kinetics plus multiple orthogonal mechanistic experiments; highly cited (332 citations)\",\n      \"pmids\": [\"17067392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"High cancer-specific MSLN expression is driven by an 18-bp upstream enhancer element ('CanScript') containing two functional sites: an Sp1-like site and an MCAT element. The MCAT element is bound by transcription enhancer factor TEF-1 (TEAD1) both in vitro (gel retardation/EMSA) and in vivo (chromatin immunoprecipitation). TEF-1 knockdown reduces MSLN protein overexpression, and cancer specificity appears to involve a limiting cofactor of TEF-1 present only in MSLN-overexpressing cells.\",\n      \"method\": \"Promoter deletion/mutation analysis, EMSA, chromatin immunoprecipitation, TEF-1 siRNA knockdown\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — EMSA plus ChIP plus functional knockdown with multiple orthogonal methods in one study\",\n      \"pmids\": [\"17909009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The CA125/MUC16-binding domain on mesothelin was mapped to a 64-amino acid region (residues 296–359) at the N-terminal region of the mature cell-surface protein. Alanine substitution of tyrosine 318 (Y318A) abolishes CA125 binding entirely; substitution of tryptophan 321 (W321A) and glutamic acid 324 (E324A) partially decreases binding; mutation of histidine 354 has no effect. This domain mediates cell adhesion and is recognized by single-chain antibody SS1, which blocks mesothelin–CA125 interaction on cancer cells.\",\n      \"method\": \"Truncation and alanine-replacement mutagenesis, Western blot overlay assay, ELISA quantification, flow cytometry on cancer cells, cell adhesion inhibition assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with multiple orthogonal binding assays and functional validation; highly cited (158 citations)\",\n      \"pmids\": [\"19075018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mesothelin overexpression in pancreatic cancer cells significantly increases cell proliferation (~90%) and migration (~300%) in vitro and tumor volume (~4-fold) in nude mouse xenograft models. Conversely, mesothelin siRNA silencing inhibits proliferation and migration and ablates tumor progression in vivo, establishing mesothelin as a functional driver of pancreatic cancer aggressiveness.\",\n      \"method\": \"Stable overexpression and siRNA knockdown, cell proliferation assay, migration assay, nude mouse xenograft model\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal gain- and loss-of-function experiments with both in vitro and in vivo validation; highly cited (139 citations)\",\n      \"pmids\": [\"18281514\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Mesothelin confers resistance to TNF-α-induced apoptosis in pancreatic cancer cells through constitutive activation of the Akt/PI3K/NF-κB pathway, leading to upregulation of IL-6 and anti-apoptotic protein Mcl-1. MSLN overexpression elevates Bcl-XL and Mcl-1, deactivates BAD (p-Ser75), and activates Bcl-2 (p-Ser70). MSLN siRNA silencing reduces NF-κB and Akt activity and restores TNF-α sensitivity. IL-6 siRNA silencing also restores sensitivity, delineating a MSLN→Akt/NF-κB→IL-6→Mcl-1 survival axis.\",\n      \"method\": \"Stable MSLN overexpression and shRNA knockdown, NF-κB luciferase reporter, Western blot, MTT assay, TUNEL/caspase activation, IL-6 Luminex assay, IKK and PI3K inhibitors\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic gain/loss-of-function with pathway inhibitors and multiple readouts; highly cited (132 citations)\",\n      \"pmids\": [\"21880146\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion. In an orthotopic mouse model, MSLN-overexpressing cells preferentially localize to the tumor-invading edge and co-localize with MMP-9. MSLN knockdown reduces invasion and MMP-9 secretion. In a tissue microarray of epithelioid MPM patients (n=139, 729 cores), MSLN overexpression correlates with higher MMP-9 expression.\",\n      \"method\": \"Forced MSLN expression and shRNA knockdown in human and murine MPM cells, in vitro invasion assay, MMP secretion assay, orthotopic mouse model, tissue microarray IHC\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal loss/gain of function with both in vitro mechanistic and in vivo validation; highly cited (163 citations)\",\n      \"pmids\": [\"22371455\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Mesothelin enhances invasion of ovarian cancer cells by inducing MMP-7 expression through MAPK/ERK and JNK signaling pathways. ERK1/2-specific inhibitors, JNK-specific inhibitors, or a decoy AP-1 oligonucleotide suppress MMP-7 expression and inhibit MSLN-induced cell migration. In vivo, MAPK/ERK or JNK inhibitors decrease intratumoral MMP-7, delay tumor growth, and extend survival in mouse models.\",\n      \"method\": \"MSLN overexpression, ERK/JNK pathway inhibitors, decoy AP-1 oligonucleotide, in vitro invasion/migration assay, in vivo mouse tumor model\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pathway-specific inhibitors plus in vivo validation; highly cited (134 citations)\",\n      \"pmids\": [\"21999204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Mesothelin binding to MUC16 on pancreatic cancer cells activates p38 MAPK signaling, leading to selective upregulation and secretion of MMP-7, thereby promoting cell motility and invasion. Depletion of MMP-7 or inhibition of p38 MAPK abolishes MSLN-mediated pancreatic cancer cell motility and invasion, placing MSLN→MUC16 interaction upstream of p38 MAPK→MMP-7 in a defined signaling pathway.\",\n      \"method\": \"Bioengineering/microfluidic motility assays, MMP-7 knockdown, p38 MAPK inhibition, invasion assay, MSLN-MUC16 co-expression system\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis established by specific inhibitors and knockdown with functional readout; highly cited (191 citations)\",\n      \"pmids\": [\"23694968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A SNP (rs1057147) within the 3' UTR of MSLN affects a miR-611 binding site; the G allele allows miR-611 binding while the A allele does not, as demonstrated by dual-luciferase reporter assays. miR-611 transfection into mesothelin-expressing MPM cells significantly reduces endogenous MSLN protein, establishing functional post-transcriptional regulation of MSLN by miR-611 at this polymorphic site.\",\n      \"method\": \"Dual luciferase reporter assay with alternative alleles, miRNA mimic transfection, Western blot for endogenous MSLN protein\",\n      \"journal\": \"Journal of thoracic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct functional reporter assay with endogenous validation; single lab\",\n      \"pmids\": [\"25436799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) form a signaling complex critical for fibroblast activation. Msln-/- mice are protected from cholestatic liver fibrosis (Mdr2-deficient model), bleomycin-induced lung fibrosis, and UUO-induced kidney fibrosis. Conversely, Thy1-/- mice are more susceptible to fibrosis, indicating Msln-Thy1 operate in the same pathway. Anti-MSLN immunotoxins targeting MSLN+ activated portal fibroblasts reduce collagen deposition in bile duct ligation-injured mice.\",\n      \"method\": \"Msln-/- and Thy1-/- knockout mouse models (multiple fibrosis models), anti-MSLN immunotoxin treatment, collagen deposition assay, human activated portal fibroblast studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis using multiple knockout models across multiple organ fibrosis systems, confirmed with pharmacological targeting\",\n      \"pmids\": [\"34253615\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Metformin reduces MSLN expression in ovarian cancer cells, which in turn downregulates IL-6/STAT3 signaling activity and subsequently decreases VEGF and TGFβ1 expression. Conversely, forced MSLN overexpression in ovarian cancer cells demonstrates an oncogenic function upstream of IL-6/STAT3. MSLN knockdown phenocopies metformin effects on cell growth, migration, stemness, and angiogenesis.\",\n      \"method\": \"Metformin treatment, MSLN overexpression, siRNA knockdown, IL-6/STAT3 pathway Western blot, cell growth/migration/apoptosis assays, capillary-like structure formation assay\",\n      \"journal\": \"Cell transplantation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — pathway placement established by gain/loss of function but mechanistic link between MSLN and IL-6/STAT3 not fully reconstituted; single lab\",\n      \"pmids\": [\"34238029\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MSLN encodes a 69 kDa GPI-anchored glycoprotein precursor that is proteolytically processed into the 40 kDa cell-surface protein mesothelin and a shed 31 kDa megakaryocyte potentiating factor (MPF); mesothelin binds CA125/MUC16 via a defined N-terminal domain (residues 296–359, requiring Y318) in an N-glycan-dependent, high-affinity interaction (Kd ~5–10 nM) that mediates heterotypic cell adhesion relevant to peritoneal metastasis; downstream of this interaction, mesothelin activates p38 MAPK→MMP-7 (in pancreatic cancer) and MAPK/ERK and JNK→MMP-7 (in ovarian cancer) to drive invasion, while also constitutively activating Akt/PI3K/NF-κB→IL-6→Mcl-1 signaling to confer apoptosis resistance; its cancer-specific overexpression is transcriptionally driven by a TEF-1/TEAD1-bound MCAT enhancer element; and Msln forms a signaling complex with Thy1 that is required for fibroblast activation across multiple organs.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MSLN encodes mesothelin, a GPI-anchored cell-surface glycoprotein expressed on mesothelial cells that functions in fibroblast activation and oncogenic signaling. The mature protein is released by PI-PLC and is poorly internalized spontaneously but can be internalized via toxin-coupled antibodies, properties central to its behavior as an immunotherapy target [PMID:1727378]. Cancer-specific overexpression is driven by a TEF-1/TEAD1-bound MCAT enhancer element (CanScript) in the MSLN promoter and is post-transcriptionally modulated by miR-611 [PMID:17909009, PMID:25436799]. Functionally, MSLN promotes fibroblast activation through a Msln–Thy1 signaling complex required for organ fibrosis in vivo and sustains IL-6/STAT3 signaling to support proliferation, invasion, and stemness in cancer cells [PMID:34253615, PMID:34238029].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"The fundamental biochemical identity of the MSLN gene product was established as a ~40 kDa GPI-anchored surface glycoprotein that resists spontaneous internalization but can be internalized via toxin-coupled antibody, defining the cell-biological constraints for subsequent immunotoxin targeting strategies.\",\n      \"evidence\": \"PI-PLC cleavage, acid-wash internalization assay, and immunotoxin cytotoxicity in mesothelial and ovarian cancer cells\",\n      \"pmids\": [\"1727378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No endogenous ligand or signaling function identified at this stage\",\n        \"Mechanism of internalization via domain I of Pseudomonas exotoxin not resolved at the molecular level\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genomic structure and transcriptional regulation of MSLN were mapped, revealing a TATA-less promoter with a minimal constitutive core and upstream tissue-specific enhancer elements, raising the question of how cancer cells achieve overexpression.\",\n      \"evidence\": \"Genomic cloning and deletion/reporter assays in transfected cells\",\n      \"pmids\": [\"10683314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of transcription factors driving tissue-specific versus cancer-specific expression not resolved\",\n        \"Enhancer activity tested only in transient transfection; chromatin context not assessed\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The mechanism of cancer-specific MSLN overexpression was pinpointed to the CanScript enhancer, where TEF-1/TEAD1 binds an MCAT motif; a limiting TEF-1 cofactor was proposed to confer cancer specificity, resolving the transcriptional basis for tumor-restricted expression.\",\n      \"evidence\": \"EMSA, ChIP, siRNA knockdown of TEF-1, and mutational reporter assays in cancer cell lines\",\n      \"pmids\": [\"17909009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The identity of the limiting TEF-1 cofactor conferring cancer specificity was not determined\",\n        \"Whether CanScript activity is conserved across all MSLN-overexpressing tumor types was not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two advances defined MSLN's functional oncogenic role and post-transcriptional regulation: siRNA silencing in mesothelioma cells demonstrated that MSLN promotes proliferation, invasion, sphere formation, and cisplatin resistance, while an allele-specific miR-611 binding site in the 3' UTR was shown to regulate MSLN protein levels.\",\n      \"evidence\": \"siRNA knockdown with proliferation/invasion/apoptosis assays in MPM cells; dual-luciferase allele-specific reporter assays and miR-611 mimic transfection\",\n      \"pmids\": [\"24465798\", \"25436799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway mediating MSLN's pro-survival effects in mesothelioma was not identified\",\n        \"In vivo relevance of miR-611-mediated MSLN regulation not tested\",\n        \"Whether the rs1057147 SNP affects clinical MSLN expression levels in patient tumors was not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two studies established MSLN's signaling mechanisms in distinct contexts: in fibrosis, Msln-knockout mice across three organ injury models proved that a Msln–Thy1 complex is required for fibroblast activation; in ovarian cancer, MSLN was placed upstream of IL-6/STAT3 signaling to sustain proliferation, migration, and stemness.\",\n      \"evidence\": \"Msln−/− and Thy1−/− mice in BDL, bleomycin, and UUO fibrosis models with anti-MSLN immunotoxin rescue; MSLN siRNA/overexpression with STAT3 pathway western blots in ovarian cancer cells\",\n      \"pmids\": [\"34253615\", \"34238029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical mechanism by which the Msln–Thy1 interaction activates fibroblasts is unknown\",\n        \"Whether IL-6/STAT3 signaling is a direct or indirect consequence of MSLN activity is unresolved\",\n        \"Structural basis for Msln–Thy1 interaction has not been determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct enzymatic or signaling activity of the mature mesothelin protein remains undefined: no catalytic function, receptor kinase coupling mechanism, or high-resolution structure has been reported, and the identity of the cancer-specific TEF-1 cofactor driving CanScript-dependent overexpression is still unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No intrinsic enzymatic or catalytic activity has been assigned to mesothelin\",\n        \"Structural model of the mature GPI-anchored protein is lacking\",\n        \"The TEF-1 cofactor conferring cancer-specific CanScript activation has not been identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [5, 6]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"THY1\",\n      \"TEAD1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\nWait, I made an error in the pathway field - I used a GO term instead of a Reactome term. Let me correct that.\n\n```json\n{\n  \"mechanistic_narrative\": \"MSLN encodes mesothelin, a GPI-anchored cell-surface glycoprotein expressed on mesothelial cells that functions in fibroblast activation and oncogenic signaling. The mature protein is released by PI-PLC and is poorly internalized spontaneously but can be internalized via toxin-coupled antibodies, properties central to its behavior as an immunotherapy target [PMID:1727378]. Cancer-specific overexpression is driven by a TEF-1/TEAD1-bound MCAT enhancer element (CanScript) in the MSLN promoter and is post-transcriptionally modulated by miR-611 [PMID:17909009, PMID:25436799]. Functionally, MSLN promotes fibroblast activation through a Msln–Thy1 signaling complex required for organ fibrosis in vivo and sustains IL-6/STAT3 signaling to support proliferation, invasion, and stemness in cancer cells [PMID:34253615, PMID:34238029].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"The fundamental biochemical identity of the MSLN gene product was established as a ~40 kDa GPI-anchored surface glycoprotein that resists spontaneous internalization but can be internalized via toxin-coupled antibody, defining the cell-biological constraints for subsequent immunotoxin targeting strategies.\",\n      \"evidence\": \"PI-PLC cleavage, acid-wash internalization assay, and immunotoxin cytotoxicity in mesothelial and ovarian cancer cells\",\n      \"pmids\": [\"1727378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No endogenous ligand or signaling function identified at this stage\",\n        \"Mechanism of internalization via domain I of Pseudomonas exotoxin not resolved at the molecular level\"\n      ]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Genomic structure and transcriptional regulation of MSLN were mapped, revealing a TATA-less promoter with a minimal constitutive core and upstream tissue-specific enhancer elements, raising the question of how cancer cells achieve overexpression.\",\n      \"evidence\": \"Genomic cloning and deletion/reporter assays in transfected cells\",\n      \"pmids\": [\"10683314\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of transcription factors driving tissue-specific versus cancer-specific expression not resolved\",\n        \"Enhancer activity tested only in transient transfection; chromatin context not assessed\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"The mechanism of cancer-specific MSLN overexpression was pinpointed to the CanScript enhancer, where TEF-1/TEAD1 binds an MCAT motif; a limiting TEF-1 cofactor was proposed to confer cancer specificity, resolving the transcriptional basis for tumor-restricted expression.\",\n      \"evidence\": \"EMSA, ChIP, siRNA knockdown of TEF-1, and mutational reporter assays in cancer cell lines\",\n      \"pmids\": [\"17909009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The identity of the limiting TEF-1 cofactor conferring cancer specificity was not determined\",\n        \"Whether CanScript activity is conserved across all MSLN-overexpressing tumor types was not tested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two advances defined MSLN's functional oncogenic role and post-transcriptional regulation: siRNA silencing in mesothelioma cells demonstrated that MSLN promotes proliferation, invasion, sphere formation, and cisplatin resistance, while an allele-specific miR-611 binding site in the 3' UTR was shown to regulate MSLN protein levels.\",\n      \"evidence\": \"siRNA knockdown with proliferation/invasion/apoptosis assays in MPM cells; dual-luciferase allele-specific reporter assays and miR-611 mimic transfection\",\n      \"pmids\": [\"24465798\", \"25436799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway mediating MSLN's pro-survival effects in mesothelioma was not identified\",\n        \"In vivo relevance of miR-611-mediated MSLN regulation not tested\",\n        \"Whether the rs1057147 SNP affects clinical MSLN expression levels in patient tumors was not established\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Two studies established MSLN's signaling mechanisms in distinct contexts: in fibrosis, Msln-knockout mice across three organ injury models proved that a Msln–Thy1 complex is required for fibroblast activation; in ovarian cancer, MSLN was placed upstream of IL-6/STAT3 signaling to sustain proliferation, migration, and stemness.\",\n      \"evidence\": \"Msln−/− and Thy1−/− mice in BDL, bleomycin, and UUO fibrosis models with anti-MSLN immunotoxin rescue; MSLN siRNA/overexpression with STAT3 pathway western blots in ovarian cancer cells\",\n      \"pmids\": [\"34253615\", \"34238029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Biochemical mechanism by which the Msln–Thy1 interaction activates fibroblasts is unknown\",\n        \"Whether IL-6/STAT3 signaling is a direct or indirect consequence of MSLN activity is unresolved\",\n        \"Structural basis for Msln–Thy1 interaction has not been determined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct enzymatic or signaling activity of the mature mesothelin protein remains undefined: no catalytic function, receptor kinase coupling mechanism, or high-resolution structure has been reported, and the identity of the cancer-specific TEF-1 cofactor driving CanScript-dependent overexpression is still unknown.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No intrinsic enzymatic or catalytic activity has been assigned to mesothelin\",\n        \"Structural model of the mature GPI-anchored protein is lacking\",\n        \"The TEF-1 cofactor conferring cancer-specific CanScript activation has not been identified\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [5, 6]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [0]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-162582\",\n        \"supporting_discovery_ids\": [5, 6]\n      }\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"THY1\",\n      \"TEAD1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"Mesothelin is a GPI-anchored cell-surface glycoprotein generated by proteolytic processing of a 69 kDa precursor into the 40 kDa membrane-bound mesothelin and a shed 31 kDa megakaryocyte potentiating factor (MPF) [PMID:8552591, PMID:10500211]. Mesothelin binds CA125/MUC16 with high affinity (Kd ~5–10 nM) through an N-terminal domain (residues 296–359, critically dependent on Y318) in an N-glycan-dependent manner, mediating heterotypic cell adhesion that promotes peritoneal metastasis [PMID:14676194, PMID:17067392, PMID:19075018]. Downstream of this interaction, mesothelin activates MAPK/ERK, JNK, and p38 MAPK signaling to induce MMP-7 and MMP-9 secretion driving invasion, and constitutively activates Akt/PI3K/NF-κB→IL-6→Mcl-1 signaling to confer apoptosis resistance in pancreatic and ovarian cancers [PMID:21880146, PMID:21999204, PMID:23694968]. Beyond cancer, mesothelin forms a signaling complex with Thy1 on fibroblasts that is required for fibroblast activation across liver, lung, and kidney fibrosis models [PMID:34253615].\",\n  \"teleology\": [\n    {\n      \"year\": 1992,\n      \"claim\": \"Establishing the biophysical identity of the mesothelin antigen as a GPI-anchored cell-surface protein resolved how the K1 antibody target is tethered to the membrane and why it resists internalization.\",\n      \"evidence\": \"PI-PLC enzymatic release, SDS-PAGE immunoblotting, and internalization assays on K1-reactive cells\",\n      \"pmids\": [\"1727378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protein sequence unknown at this stage\", \"Physiological ligand unidentified\", \"Normal tissue function not addressed\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Cloning the MSLN cDNA revealed that a 69 kDa precursor is proteolytically processed to yield the 40 kDa GPI-anchored mesothelin and a released fragment (MPF), defining the gene product's molecular architecture.\",\n      \"evidence\": \"cDNA cloning and transfection into COS/NIH 3T3 cells with PI-PLC release confirmation\",\n      \"pmids\": [\"8552591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Protease responsible for precursor cleavage unidentified\", \"Binding partner and cellular function unknown\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Detection of soluble mesothelin in sera of ovarian cancer patients and identification of an alternatively spliced constitutively soluble variant demonstrated that mesothelin exists in both membrane-bound and shed forms with potential biomarker utility.\",\n      \"evidence\": \"Sandwich ELISA, immunoadsorption, and domain-mapping with D1Ig/D2Ig fusion proteins on patient sera\",\n      \"pmids\": [\"10500211\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Sheddase identity unknown\", \"Functional role of soluble mesothelin versus membrane-bound form not distinguished\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of CA125/MUC16 as mesothelin's binding partner answered the long-standing question of mesothelin's adhesion function and linked it mechanistically to ovarian cancer metastasis.\",\n      \"evidence\": \"Expression cloning, co-immunoprecipitation, flow cytometry, and antibody-blocking cell adhesion assays\",\n      \"pmids\": [\"14676194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding affinity not quantified\", \"Binding domain on mesothelin unmapped\", \"Downstream signaling unknown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Quantitative binding studies established mesothelin–MUC16 interaction as high-affinity (Kd ~5–10 nM) and N-glycan-dependent, explaining why glycan-rich tumor surfaces support robust heterotypic adhesion.\",\n      \"evidence\": \"Flow cytometry binding kinetics with mesothelin-Fc, glycan oxidation/removal and lectin inhibition, MUC16 knockdown adhesion assay\",\n      \"pmids\": [\"17067392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of glycan requirement unresolved\", \"Mesothelin residues mediating binding not yet mapped\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that the TEF-1/TEAD1 transcription factor drives cancer-specific MSLN overexpression through an MCAT enhancer element explained how mesothelin expression is restricted to tumors and mesothelial tissues.\",\n      \"evidence\": \"Promoter deletion/mutation, EMSA, chromatin immunoprecipitation, and TEF-1 siRNA knockdown\",\n      \"pmids\": [\"17909009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the cancer-specific cofactor of TEF-1 unknown\", \"Epigenetic regulation not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Mapping the MUC16-binding domain to residues 296–359 with critical dependence on Y318, combined with demonstration that mesothelin drives proliferation and migration in pancreatic cancer xenografts, established mesothelin as a functional oncogenic driver acting through a defined binding interface.\",\n      \"evidence\": \"Systematic truncation and alanine-scanning mutagenesis with binding assays; reciprocal overexpression and siRNA knockdown in vitro and in nude mouse xenografts\",\n      \"pmids\": [\"19075018\", \"18281514\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of mesothelin or mesothelin–MUC16 complex unavailable\", \"Downstream signaling pathways from mesothelin–MUC16 interaction not yet delineated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Delineation of the Akt/PI3K/NF-κB→IL-6→Mcl-1 survival axis downstream of mesothelin explained how mesothelin confers apoptosis resistance in pancreatic cancer cells.\",\n      \"evidence\": \"Stable MSLN overexpression and shRNA knockdown, NF-κB reporter, PI3K/IKK inhibitors, IL-6 siRNA, caspase/TUNEL assays\",\n      \"pmids\": [\"21880146\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal signaling event linking GPI-anchored mesothelin to Akt activation unknown\", \"Whether the survival axis requires MUC16 engagement not tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of MAPK/ERK and JNK pathways converging on MMP-7 (ovarian cancer) and MMP-9 (mesothelioma) as mesothelin-regulated invasion effectors established the downstream proteolytic program through which mesothelin drives tumor invasion.\",\n      \"evidence\": \"ERK/JNK-specific inhibitors, AP-1 decoy oligonucleotide, gain/loss-of-function in vitro and in vivo mouse models, tissue microarray correlation\",\n      \"pmids\": [\"21999204\", \"22371455\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical link between mesothelin and MAPK activation not identified\", \"Relative contribution of MMP-7 vs MMP-9 across cancer types unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Placing mesothelin–MUC16 binding upstream of p38 MAPK→MMP-7 in pancreatic cancer established that intercellular adhesion through the mesothelin–MUC16 axis directly triggers a defined intracellular signaling cascade promoting motility.\",\n      \"evidence\": \"Microfluidic motility assays, MMP-7 knockdown and p38 inhibition epistasis in MSLN-MUC16 co-expression system\",\n      \"pmids\": [\"23694968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Adaptor protein linking GPI-anchored mesothelin to p38 MAPK unknown\", \"Whether other mesothelin ligands can trigger the same cascade not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that mesothelin forms a signaling complex with Thy1 required for fibroblast activation across liver, lung, and kidney fibrosis models expanded mesothelin's functional role beyond cancer to organ fibrosis.\",\n      \"evidence\": \"Msln−/− and Thy1−/− knockout mice in cholestatic liver, bleomycin lung, and UUO kidney fibrosis models; anti-MSLN immunotoxin treatment\",\n      \"pmids\": [\"34253615\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular details of the Msln–Thy1 signaling complex (stoichiometry, intermediaries) unresolved\", \"Whether Msln–Thy1 signals through the same MAPK/Akt axes identified in cancer unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The proximal signaling mechanism by which a GPI-anchored protein lacking an intracellular domain activates Akt, MAPK, and NF-κB pathways remains unknown, and no atomic-resolution structure of mesothelin or the mesothelin–MUC16 complex is available.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No transmembrane co-receptor or adaptor identified that transduces signal from GPI-anchored mesothelin\", \"No crystal or cryo-EM structure of mesothelin or mesothelin–MUC16 complex\", \"Protease(s) responsible for precursor cleavage and ectodomain shedding remain unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098631\", \"supporting_discovery_ids\": [4, 5, 7, 12]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [4, 5, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [9, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 11, 12]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [4, 5, 7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 11]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MUC16\", \"THY1\", \"TEAD1\", \"MMP7\", \"MMP9\"],\n    \"other_free_text\": []\n  }\n}\n```"}