Affinage

MSLN

Mesothelin · UniProt Q13421

Round 2 corrected
Length
630 aa
Mass
69.0 kDa
Annotated
2026-04-28
130 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1992 High

    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

    PMID:1727378

    Open questions at the time
    • Protein sequence unknown at this stage
    • Physiological ligand unidentified
    • Normal tissue function not addressed
  2. 1996 High

    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

    PMID:8552591

    Open questions at the time
    • Protease responsible for precursor cleavage unidentified
    • Binding partner and cellular function unknown
  3. 1999 High

    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

    PMID:10500211

    Open questions at the time
    • Sheddase identity unknown
    • Functional role of soluble mesothelin versus membrane-bound form not distinguished
  4. 2003 High

    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

    PMID:14676194

    Open questions at the time
    • Binding affinity not quantified
    • Binding domain on mesothelin unmapped
    • Downstream signaling unknown
  5. 2006 High

    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

    PMID:17067392

    Open questions at the time
    • Structural basis of glycan requirement unresolved
    • Mesothelin residues mediating binding not yet mapped
  6. 2007 High

    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

    PMID:17909009

    Open questions at the time
    • Identity of the cancer-specific cofactor of TEF-1 unknown
    • Epigenetic regulation not addressed
  7. 2008 High

    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

    PMID:18281514 PMID:19075018

    Open questions at the time
    • Crystal structure of mesothelin or mesothelin–MUC16 complex unavailable
    • Downstream signaling pathways from mesothelin–MUC16 interaction not yet delineated
  8. 2011 High

    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

    PMID:21880146

    Open questions at the time
    • Proximal signaling event linking GPI-anchored mesothelin to Akt activation unknown
    • Whether the survival axis requires MUC16 engagement not tested
  9. 2012 High

    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

    PMID:21999204 PMID:22371455

    Open questions at the time
    • Direct physical link between mesothelin and MAPK activation not identified
    • Relative contribution of MMP-7 vs MMP-9 across cancer types unclear
  10. 2013 High

    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

    PMID:23694968

    Open questions at the time
    • Adaptor protein linking GPI-anchored mesothelin to p38 MAPK unknown
    • Whether other mesothelin ligands can trigger the same cascade not tested
  11. 2021 High

    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

    PMID:34253615

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 4 GO:0048018 receptor ligand activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005576 extracellular region 1
Pathway
R-HSA-1500931 Cell-Cell communication 3 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3
Partners
MMP7MMP9MUC16TEAD1THY1

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1992 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. PI-PLC treatment followed by RIA and immunoblotting; acid-wash internalization assay; immunotoxin cytotoxicity assay Cancer research High 1727378
1996 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. cDNA cloning, transfection into COS/NIH 3T3 cells, PI-PLC release assay, MAb K1 immunoreactivity Proceedings of the National Academy of Sciences of the United States of America High 8552591
1999 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. Immunoadsorption, sandwich ELISA, fusion protein binding assays (D1Ig vs D2Ig), cDNA cloning of novel splice variant Proceedings of the National Academy of Sciences of the United States of America High 10500211
2000 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. Genomic cloning, transient transfection reporter assays, promoter deletion analysis Molecular cell biology research communications : MCBRC Medium 10683314
2003 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. Expression cloning, flow cytometry, co-immunoprecipitation, cell adhesion blocking assay with anti-mesothelin antibody The Journal of biological chemistry High 14676194
2006 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. Flow cytometry binding kinetics with recombinant mesothelin-Fc, glycan oxidation/removal assays, lectin inhibition, MUC16 knockdown cell adhesion assay Molecular cancer High 17067392
2007 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. Promoter deletion/mutation analysis, EMSA, chromatin immunoprecipitation, TEF-1 siRNA knockdown Cancer research High 17909009
2008 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. Truncation and alanine-replacement mutagenesis, Western blot overlay assay, ELISA quantification, flow cytometry on cancer cells, cell adhesion inhibition assay The Journal of biological chemistry High 19075018
2008 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. Stable overexpression and siRNA knockdown, cell proliferation assay, migration assay, nude mouse xenograft model Molecular cancer therapeutics High 18281514
2011 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. 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 Molecular cancer High 21880146
2012 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. 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 Clinical cancer research High 22371455
2012 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. MSLN overexpression, ERK/JNK pathway inhibitors, decoy AP-1 oligonucleotide, in vitro invasion/migration assay, in vivo mouse tumor model The Biochemical journal High 21999204
2013 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. Bioengineering/microfluidic motility assays, MMP-7 knockdown, p38 MAPK inhibition, invasion assay, MSLN-MUC16 co-expression system Scientific reports High 23694968
2014 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. Dual luciferase reporter assay with alternative alleles, miRNA mimic transfection, Western blot for endogenous MSLN protein Journal of thoracic oncology Medium 25436799
2021 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. Msln-/- and Thy1-/- knockout mouse models (multiple fibrosis models), anti-MSLN immunotoxin treatment, collagen deposition assay, human activated portal fibroblast studies Proceedings of the National Academy of Sciences of the United States of America High 34253615
2021 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. Metformin treatment, MSLN overexpression, siRNA knockdown, IL-6/STAT3 pathway Western blot, cell growth/migration/apoptosis assays, capillary-like structure formation assay Cell transplantation Medium 34238029

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1988 The Xenopus cdc2 protein is a component of MPF, a cytoplasmic regulator of mitosis. Cell 748 3293802
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1996 Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proceedings of the National Academy of Sciences of the United States of America 619 8552591
1993 Phosphorylation and activation of human cdc25-C by cdc2--cyclin B and its involvement in the self-amplification of MPF at mitosis. The EMBO journal 586 8428594
1988 cdc2 is a component of the M phase-specific histone H1 kinase: evidence for identity with MPF. Cell 497 2844417
1989 MPF from starfish oocytes at first meiotic metaphase is a heterodimer containing one molecule of cdc2 and one molecule of cyclin B. The EMBO journal 491 2531073
2014 Regional delivery of mesothelin-targeted CAR T cell therapy generates potent and long-lasting CD4-dependent tumor immunity. Science translational medicine 472 25378643
2003 Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion. The Journal of biological chemistry 456 14676194
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1993 Calmodulin-dependent protein kinase II mediates inactivation of MPF and CSF upon fertilization of Xenopus eggs. Nature 404 8232587
2004 Mesothelin: a new target for immunotherapy. Clinical cancer research : an official journal of the American Association for Cancer Research 381 15217923
1994 Microtubule and chromatin behavior follow MAP kinase activity but not MPF activity during meiosis in mouse oocytes. Development (Cambridge, England) 356 7600950
1989 Purification of MPF from starfish: identification as the H1 histone kinase p34cdc2 and a possible mechanism for its periodic activation. Cell 338 2649251
2006 Mesothelin-MUC16 binding is a high affinity, N-glycan dependent interaction that facilitates peritoneal metastasis of ovarian tumors. Molecular cancer 332 17067392
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
1998 MPF localization is controlled by nuclear export. The EMBO journal 291 9670027
1998 PKA and MPF-activated polo-like kinase regulate anaphase-promoting complex activity and mitosis progression. Molecular cell 280 9660921
1991 Xenopus M phase MAP kinase: isolation of its cDNA and activation by MPF. The EMBO journal 265 1714387
1999 Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma. Proceedings of the National Academy of Sciences of the United States of America 263 10500211
2021 IL-7 and CCL19-secreting CAR-T cell therapy for tumors with positive glypican-3 or mesothelin. Journal of hematology & oncology 248 34325726
2006 Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer. Clinical cancer research : an official journal of the American Association for Cancer Research 226 16428485
1991 INH, a negative regulator of MPF, is a form of protein phosphatase 2A. Cell 226 1846321
2014 Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer research 213 24824231
2011 Toward an understanding of the protein interaction network of the human liver. Molecular systems biology 207 21988832
1988 Regulation of MPF activity in vitro. Cell 195 2834064
2013 Mesothelin binding to CA125/MUC16 promotes pancreatic cancer cell motility and invasion via MMP-7 activation. Scientific reports 191 23694968
1998 The Polo-like kinase Plx1 is a component of the MPF amplification loop at the G2/M-phase transition of the cell cycle in Xenopus eggs. Journal of cell science 181 9601104
1989 Okadaic acid, a specific protein phosphatase inhibitor, induces maturation and MPF formation in Xenopus laevis oocytes. FEBS letters 174 2538367
2012 Serum mesothelin for diagnosing malignant pleural mesothelioma: an individual patient data meta-analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 166 22412141
1991 Cyclin B in Xenopus oocytes: implications for the mechanism of pre-MPF activation. The EMBO journal 166 1824935
1991 Independent inactivation of MPF and cytostatic factor (Mos) upon fertilization of Xenopus eggs. Nature 164 1830371
2012 Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clinical cancer research : an official journal of the American Association for Cancer Research 163 22371455
1996 Protein phosphatase 2A regulates MPF activity and sister chromatid cohesion in budding yeast. Current biology : CB 162 8994825
2008 A binding domain on mesothelin for CA125/MUC16. The Journal of biological chemistry 158 19075018
2013 Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 152 24334761
2000 High developmental competence of cattle oocytes maintained at the germinal vesicle stage for 24 hours in culture by specific inhibition of MPF kinase activity. Molecular reproduction and development 151 10602278
1990 Translational control by cytoplasmic polyadenylation during Xenopus oocyte maturation: characterization of cis and trans elements and regulation by cyclin/MPF. The EMBO journal 151 2145153
2020 The exosomes derived from CAR-T cell efficiently target mesothelin and reduce triple-negative breast cancer growth. Cellular immunology 143 33373818
2008 Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer. Molecular cancer therapeutics 139 18281514
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2012 Mesothelin enhances invasion of ovarian cancer by inducing MMP-7 through MAPK/ERK and JNK pathways. The Biochemical journal 134 21999204
2005 Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients. Clinical cancer research : an official journal of the American Association for Cancer Research 134 15897581
2011 Mesothelin confers pancreatic cancer cell resistance to TNF-α-induced apoptosis through Akt/PI3K/NF-κB activation and IL-6/Mcl-1 overexpression. Molecular cancer 132 21880146
2009 High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma. British journal of cancer 132 19293794
2001 From oocyte maturation to the in vitro cell cycle: the history of discoveries of Maturation-Promoting Factor (MPF) and Cytostatic Factor (CSF). Differentiation; research in biological diversity 132 11776390
1992 Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 present on ovarian cancers and normal mesothelium. Cancer research 132 1727378
2001 The interplay between cyclin-B-Cdc2 kinase (MPF) and MAP kinase during maturation of oocytes. Journal of cell science 121 11148128
1990 The cyclin B2 component of MPF is a substrate for the c-mos(xe) proto-oncogene product. Cell 118 2140529
1992 Regulation of a major microtubule-associated protein by MPF and MAP kinase. The EMBO journal 108 1327753
1992 Oscillation of MPF is accompanied by periodic association between cdc25 and cdc2-cyclin B. Cell 104 1310257
2007 How eggs arrest at metaphase II: MPF stabilisation plus APC/C inhibition equals Cytostatic Factor. Cell division 92 17257429
2000 A role for cyclin A1 in the activation of MPF and G2-M transition during meiosis of male germ cells in mice. Developmental biology 88 10926775
2019 Mesothelin-Targeted Thorium-227 Conjugate (MSLN-TTC): Preclinical Evaluation of a New Targeted Alpha Therapy for Mesothelin-Positive Cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 86 31064781
1999 Phosphatase 2A and polo kinase, two antagonistic regulators of cdc25 activation and MPF auto-amplification. Journal of cell science 83 10523510
1999 Dissociation of MAP kinase activation and MPF activation in hormone-stimulated maturation of Xenopus oocytes. Development (Cambridge, England) 82 10498688
1992 An extra copy of nimEcyclinB elevates pre-MPF levels and partially suppresses mutation of nimTcdc25 in Aspergillus nidulans. The EMBO journal 79 1534750
1975 Effects of cycloheximide on the "autocatalytic" nature of the maturation promoting factor (MPF) in oocytes of Xenopus laevis. Cell 77 1122557
1990 Characterization of MPF activation by okadaic acid in Xenopus oocyte. Cell differentiation and development : the official journal of the International Society of Developmental Biologists 72 1689204
2017 Quercetin delays postovulatory aging of mouse oocytes by regulating SIRT expression and MPF activity. Oncotarget 67 28418847
2012 Centrosomal MPF triggers the mitotic and morphogenetic switches of fission yeast. Nature cell biology 65 23222840
1998 Cak1 is required for Kin28 phosphorylation and activation in vivo. Molecular and cellular biology 62 9774652
1991 A model for the adjustment of the mitotic clock by cyclin and MPF levels. Science (New York, N.Y.) 61 1825521
2006 Cyclin B dissociation from CDK1 precedes its degradation upon MPF inactivation in mitotic extracts of Xenopus laevis embryos. Cell cycle (Georgetown, Tex.) 58 16921258
1992 Frequent expression of the tumor antigen CAK1 in squamous-cell carcinomas. International journal of cancer 58 1351045
1988 Monoclonal antibodies specific for thiophosphorylated proteins recognize Xenopus MPF. Developmental biology 56 3044877
2007 High cancer-specific expression of mesothelin (MSLN) is attributable to an upstream enhancer containing a transcription enhancer factor dependent MCAT motif. Cancer research 55 17909009
1999 Activation of MPF at meiosis reinitiation in starfish oocytes. Developmental biology 55 10491252
2015 Entry into mitosis: a solution to the decades-long enigma of MPF. Chromosoma 54 25712366
1997 The CDK-activating kinase CAK1 can dosage suppress sporulation defects of smk1 MAP kinase mutants and is required for spore wall morphogenesis in Saccharomyces cerevisiae. The EMBO journal 54 9135146
2000 Cdc37 promotes the stability of protein kinases Cdc28 and Cak1. Molecular and cellular biology 53 10629030
2021 Tandem CAR-T cells targeting FOLR1 and MSLN enhance the antitumor effects in ovarian cancer. International journal of biological sciences 52 34803504
1992 A novel homo-oligomeric protein responsible for an MPF-dependent microtubule-severing activity. The EMBO journal 51 1361167
1998 A propagated wave of MPF activation accompanies surface contraction waves at first mitosis in Xenopus. Journal of cell science 50 9427686
2023 Tuned activation of MSLN-CAR T cells induces superior antitumor responses in ovarian cancer models. Journal for immunotherapy of cancer 49 36746513
1994 Molecular cloning of the human CAK1 gene encoding a cyclin-dependent kinase-activating kinase. Oncogene 48 8208556
1993 p21ras-induced meiotic maturation of Xenopus oocytes in the absence of protein synthesis: MPF activation is preceded by activation of MAP and S6 kinases. Oncogene 48 8381222
2018 MPF-based meiotic cell cycle control: Half a century of lessons from starfish oocytes. Proceedings of the Japan Academy. Series B, Physical and biological sciences 44 29643273
2002 Activation of the Bur1-Bur2 cyclin-dependent kinase complex by Cak1. Molecular and cellular biology 44 12215532
2002 Association of MPF, MAPK, and nuclear progression dynamics during activation of young and aged bovine oocytes. Molecular reproduction and development 41 11933170
2006 Effect of oocyte diameter on meiotic competence, embryo development, p34 (cdc2) expression and MPF activity in prepubertal goat oocytes. Theriogenology 40 17014901
2002 CAK1 promotes meiosis and spore formation in Saccharomyces cerevisiae in a CDC28-independent fashion. Molecular and cellular biology 40 11739722
2016 Bypass of Candida albicans Filamentation/Biofilm Regulators through Diminished Expression of Protein Kinase Cak1. PLoS genetics 39 27935965
2018 MSLN (Mesothelin), ANTXR1 (TEM8), and MUC3A are the potent antigenic targets for CAR T cell therapy of gastric adenocarcinoma. Journal of cellular biochemistry 37 30260046
2002 Discrimination of the roles of MPF and MAP kinase in morphological changes that occur during oocyte maturation. Developmental biology 36 12482715
1998 Changes in cyclin B during oocyte maturation and early embryonic cell cycle in the newt, Cynops pyrrhogaster: requirement of germinal vesicle for MPF activation. Developmental biology 36 9520324
2022 Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality. Oncoimmunology 35 35898704
2012 A MSLN-targeted multifunctional nanoimmunoliposome for MRI and targeting therapy in pancreatic cancer. International journal of nanomedicine 35 23028227
2006 M-phase MELK activity is regulated by MPF and MAPK. Cell cycle (Georgetown, Tex.) 35 16628004
2004 Polo-like kinase confers MPF autoamplification competence to growing Xenopus oocytes. Development (Cambridge, England) 35 14985258
2013 Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum. Disease markers 34 24167356
1994 Microinjection of Cdc25 protein phosphatase into Xenopus prophase oocyte activates MPF and arrests meiosis at metaphase I. Biology of the cell 34 7735115
1991 The Role of "Cytostatic Factor (CSF)" in the Control of Oocyte Cell Cycles: A Summary of 20 Years of Study: (CSF/MPF/Cell Cycle/Metaphase Arrest). Development, growth & differentiation 34 37280838
2000 Nuclei and microtubule asters stimulate maturation/M phase promoting factor (MPF) activation in Xenopus eggs and egg cytoplasmic extracts. The Journal of cell biology 33 10973988
2013 Removal of centrosomal PP1 by NIMA kinase unlocks the MPF feedback loop to promote mitotic commitment in S. pombe. Current biology : CB 32 23333317
1997 Protein kinase C is required for the disappearance of MPF upon artificial activation in mouse eggs. Molecular reproduction and development 31 9291480
2021 Metformin Antagonizes Ovarian Cancer Cells Malignancy Through MSLN Mediated IL-6/STAT3 Signaling. Cell transplantation 30 34238029
2005 Phosphorylation by Cak1 regulates the C-terminal domain kinase Ctk1 in Saccharomyces cerevisiae. Molecular and cellular biology 29 15870265
2004 Protein synthesis and mRNA storage in cattle oocytes maintained under meiotic block by roscovitine inhibition of MPF activity. Molecular reproduction and development 29 15457512
2007 Zinc regulates the ability of Cdc25C to activate MPF/cdk1. Journal of cellular physiology 27 17443687
2000 Structure of the Mesothelin/MPF gene and characterization of its promoter. Molecular cell biology research communications : MCBRC 27 10683314
1996 Radiation with 1 Gy prevents the activation of the mitotic inducers mitosis-promoting factor (MPF) and cdc25-C in HeLa cells. Cancer research 27 8625296
2004 Activation with ethanol improves embryo development of ICSI-derived oocytes by regulation of kinetics of MPF activity. The Journal of reproduction and development 26 15118243
1990 MPF and cyclin: modelling of the cell cycle minimum oscillator. Bio Systems 26 2147396
2019 Microcystin-LR promotes zebrafish (Danio rerio) oocyte (in vivo) maturation by activating ERK1/2-MPF signaling pathways, and cAMP is involved in this process. Environmental pollution (Barking, Essex : 1987) 25 31887595
2010 Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter. Human pathology 25 20573372
2014 MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma. PloS one 24 24465798
2011 The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma. Epigenetics 24 21775819
1993 The egg nucleus regulates the behavior of sperm nuclei as well as cycling of MPF in physiologically polyspermic newt eggs. Developmental biology 24 8224532
2021 Immunotherapy-based targeting of MSLN+ activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis. Proceedings of the National Academy of Sciences of the United States of America 23 34253615
2013 The phosphorylation of ARPP19 by Greatwall renders the auto-amplification of MPF independently of PKA in Xenopus oocytes. Journal of cell science 23 23781026
2002 In vitro maturation of bovine oocytes requires polyadenylation of mRNAs coding proteins for chromatin condensation, spindle assembly, MPF and MAP kinase activation. Animal reproduction science 23 12363437
1988 The cell cycle can occur in starfish oocytes and embryos without the production of transferable MPF (maturation-promoting factor). Developmental biology 23 2838346
2002 Characterization of MPF and MAPK activities during meiotic maturation of Xenopus tropicalis oocytes. Developmental biology 22 11977986
2014 A common polymorphism within MSLN affects miR-611 binding site and soluble mesothelin levels in healthy people. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20 25436799
2004 Timing of Plk1 and MPF activation during porcine oocyte maturation. Molecular reproduction and development 20 15278898
2003 Independent activation of MAP kinase and MPF during the initiation of meiotic maturation in pig oocytes. Reproduction (Cambridge, England) 20 12713427
1988 Does autocatalytic amplification of maturation-promoting factor (MPF) exist in mammalian oocytes? Gamete research 20 3068110
2009 Characterization and in vitro control of MPF activity in zebrafish eggs. Zebrafish 18 19292671
2003 Activated M-phase-promoting factor (MPF) is exported from the nucleus of starfish oocytes to increase the sensitivity of the Ins(1,4,5)P3 receptors. Biochemical Society transactions 18 12546658
2019 Mutagenicity assessment of food contact material migrates with the Ames MPF assay. Food additives & contaminants. Part A, Chemistry, analysis, control, exposure & risk assessment 17 31287381
2016 The effect of conspecific ampulla oviductal epithelial cells during in vitro maturation on oocyte developmental competence and maturation-promoting factor (MPF) activity in sheep. Theriogenology 17 28234231
1995 Brefeldin A provokes indirect activation of cdc2 kinase (MPF) in Xenopus oocytes, resulting in meiotic cell division. Developmental biology 17 7541376
1994 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. Journal of cellular biochemistry 17 7962177
1986 Partial purification of the maturation-promoting factor MPF from unfertilized eggs of Xenopus laevis. European journal of biochemistry 17 3539598
1993 Kinetics of MPF and histone H1 kinase activity differ during the G2- to M-phase transition in mouse oocytes. The International journal of developmental biology 16 8180003