{"gene":"MYT1","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1995,"finding":"Xenopus Myt1 is a membrane-associated kinase of the Wee1 family that phosphorylates Cdc2 on both Thr14 and Tyr15, making it the predominant Thr14-specific kinase in Xenopus egg extracts; it contains a putative transmembrane segment mediating membrane association, and its activity is highly regulated during the cell cycle.","method":"cDNA cloning, in vitro kinase assay, immunodepletion of Xenopus egg extracts","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assay with immunodepletion, founding paper replicated extensively across labs","pmids":["7569953"],"is_preprint":false},{"year":1997,"finding":"Human Myt1 (Myt1Hu) is a dual-specificity kinase that preferentially phosphorylates Cdc2 on Thr14 (over Tyr15) in a cyclin-dependent manner; it localizes to the endoplasmic reticulum and Golgi complex in HeLa cells via a hydrophobic C-terminal membrane-targeting domain, deletion of which redirects Myt1 to the nucleus.","method":"cDNA cloning, in vitro kinase assay with phosphorylation-site mapping, immunofluorescence localization, deletion mutagenesis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase assay with mutagenesis plus direct localization experiments, replicated by multiple labs","pmids":["9001210"],"is_preprint":false},{"year":1997,"finding":"Human Myt1 specifically phosphorylates and inactivates Cdc2-containing cyclin complexes but not Cdk2- or Cdk4-containing complexes; Myt1 remains membrane-bound throughout the cell cycle but becomes hyperphosphorylated and less active during M-phase arrest; Cdc2/cyclin B1 can phosphorylate Myt1 in vitro without affecting its kinase activity.","method":"In vitro kinase assay with substrate specificity panel, immunoprecipitation, cell cycle synchronization, Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal in vitro and cellular methods, replicated concept across labs","pmids":["9268380"],"is_preprint":false},{"year":1998,"finding":"The C-terminal regulatory domain of Xenopus Myt1 specifically binds p90rsk (a MAPK-activated kinase); p90rsk phosphorylates the Myt1 C-terminus and down-regulates its inhibitory activity on Cdc2/cyclin B in vitro; Myt1 preferentially associates with hyperphosphorylated p90rsk, and complexes are detected in immunoprecipitates from mature Xenopus oocytes, linking MAPK-p90rsk signaling to Myt1 inactivation during oocyte maturation.","method":"GST pulldown, co-immunoprecipitation from oocyte extracts, in vitro kinase assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal Co-IP plus in vitro kinase assay with functional readout, replicated by subsequent studies","pmids":["9724639"],"is_preprint":false},{"year":1999,"finding":"The C-terminal domain of Myt1 is required for: (1) interaction with Cdc2/cyclin B1 complexes, (2) efficient phosphorylation of Cdc2 in vitro, and (3) G2/M phase arrest upon Myt1 overexpression; the C-terminal domain interacts with and is phosphorylated by Cdc2, indicating cytoplasmic localization of this domain; Myt1 can inhibit cell cycle progression both by phosphorylating Cdc2 and by sequestering Cdc2/cyclin B1 complexes in the cytoplasm.","method":"Overexpression in S. pombe and human osteosarcoma cells, C-terminal truncation mutants, in vitro kinase assay, co-immunoprecipitation, cell cycle analysis","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (mutational analysis, kinase assay, cell cycle assay, Co-IP) in a single study","pmids":["10504341"],"is_preprint":false},{"year":1999,"finding":"Overproduction of either kinase-active or kinase-inactive Myt1 blocks nuclear-cytoplasmic shuttling of cyclin B1 and causes G2 delay; the COOH-terminal 63 amino acids of Myt1 constitute a Cdc2/cyclin B1 interaction domain required for cyclin B1 binding and efficient Cdc2 phosphorylation; Myt1 lacking this domain does not sequester Cdc2/cyclin B1 or perturb cell cycle progression.","method":"Overexpression of kinase-active and kinase-inactive mutants, deletion mutagenesis, in vitro kinase assay, live-cell imaging/localization of cyclin B1, cell cycle analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, kinase assay, cyclin B1 trafficking, cell cycle arrest), replicated concept","pmids":["10373560"],"is_preprint":false},{"year":2002,"finding":"Akt/PKB phosphorylates and downregulates Myt1 (a Wee1 family member) in starfish oocytes, switching the balance between Cdc25 and Wee1/Myt1 activities and causing initial activation of cyclin B-Cdc2 at the meiotic G2/M transition, identifying Myt1 as a new Akt substrate and Akt as an M-phase initiator.","method":"In vitro kinase assay, phosphorylation-site analysis, oocyte microinjection, biochemical fractionation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro kinase assay plus in vivo functional rescue, multiple orthogonal methods","pmids":["11802161"],"is_preprint":false},{"year":2002,"finding":"Mos interacts with Myt1 in Xenopus oocyte extracts and triggers Myt1 phosphorylation on certain sites in vivo independently of MAPK activation, suggesting Myt1 is a direct Mos target in the MPF activation pathway during meiotic resumption.","method":"Co-immunoprecipitation from oocyte extracts, in vivo phosphorylation analysis, MAPK-independent oocyte maturation assays","journal":"Development","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus in vivo phosphorylation data, single lab, two orthogonal approaches","pmids":["11959823"],"is_preprint":false},{"year":2003,"finding":"Plk1 phosphorylates Myt1 in vitro on four C-terminal sites matching a newly defined Plk1 consensus motif (hydrophobic at +1, acidic at −2); a Myt1-4A mutant (all four sites alanine) abolishes Plk1 phosphorylation in vitro and fails to show mitotic gel-mobility shift in nocodazole-arrested cells, establishing Myt1 as a Plk1 substrate during M phase.","method":"In vitro kinase assay with consensus motif-defined peptides, site-directed mutagenesis (4A mutant), SDS-PAGE mobility-shift analysis in nocodazole-arrested cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase assay plus mutagenesis validated in cells, multiple orthogonal methods in one study","pmids":["12738781"],"is_preprint":false},{"year":2003,"finding":"TSAP6 (a p53-inducible transmembrane protein) associates physically with the Myt1 kinase as demonstrated by yeast two-hybrid, GST pulldown, and co-immunoprecipitation; TSAP6 overexpression augments Myt1 activity.","method":"Yeast two-hybrid, GST/in vitro pulldown, co-immunoprecipitation, cell cycle analysis","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — multiple binding methods (Y2H, pulldown, Co-IP) but functional mechanistic detail is limited","pmids":["12606722"],"is_preprint":false},{"year":2005,"finding":"The Polo-like kinase Plx1 interacts with and inhibits Myt1 after fertilization of Xenopus eggs; Cdc2 phosphorylates Myt1 on Thr478 at M phase, creating a docking site for Plx1; Plx1 phosphorylates Myt1 and inhibits its kinase activity both in vitro and in vivo; this Plx1-Myt1 interaction replaces p90rsk-Myt1 interaction seen in meiosis, and is required for normal embryonic cell divisions.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Thr478), in vivo embryo microinjection experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro kinase, mutagenesis, in vivo functional rescue) in one study","pmids":["15692562"],"is_preprint":false},{"year":2005,"finding":"Myt1 and Myt1L interact with Sin3B via a protein-protein interaction domain; Myt1-Sin3B complexes include HDAC1 and HDAC2 as demonstrated by co-immunoprecipitation from transfected mammalian cells; Myt1/Myt1L interaction with the HDAC-binding isoform of Sin3B confers repression on a heterologous promoter, placing Myt1 as a transcriptional repressor through HDAC recruitment.","method":"Yeast two-hybrid, mammalian two-hybrid, co-immunoprecipitation, transcriptional reporter assay","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assay, two-hybrid confirmed in multiple systems","pmids":["15935060"],"is_preprint":false},{"year":2008,"finding":"Xenopus Myt1 is inactivated by CDK/XRINGO-mediated phosphorylation on three specific serine residues in its regulatory domain that are distinct from CDK/cyclin phosphorylation sites; mutation of these serines makes Myt1 resistant to CDK/XRINGO-mediated inhibition; CDK/XRINGO thus has substrate specificity different from CDK/cyclin complexes.","method":"In vitro kinase assay, site-directed mutagenesis, phosphorylation-site mapping, Xenopus oocyte functional assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution, mutagenesis, site-mapping, and in vivo oocyte validation in one rigorous study","pmids":["18951089"],"is_preprint":false},{"year":2008,"finding":"Myt1 is essential for Golgi and ER assembly during telophase (mitotic exit) in mammalian cells; both cyclin B1 and cyclin B2 serve as Myt1 targets for proper organelle reassembly; Myt1-mediated Cdc2 suppression is specifically required for control of intracellular membrane dynamics during mitosis.","method":"siRNA knockdown of Myt1 in mammalian cells, immunofluorescence of Golgi/ER markers, epistasis with cyclin B1/B2 depletion","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean siRNA knockdown with specific organelle phenotype and epistasis with cyclin B targets, single lab but multiple orthogonal readouts","pmids":["18378775"],"is_preprint":false},{"year":2009,"finding":"JNK1 (but not JNK2) interacts with and phosphorylates Myt1 ex vivo and in vitro; JNK1-deficient cells show suppressed Myt1 phosphorylation and reduced caspase-3 cleavage upon UVA irradiation; JNK2-deficient cells show increased Myt1 phosphorylation and caspase-3 cleavage; knockdown of Myt1 suppresses UVA-induced caspase-3 cleavage and DNA fragmentation, indicating JNK1-mediated Myt1 phosphorylation promotes UVA-induced apoptosis.","method":"Co-immunoprecipitation, in vitro kinase assay, JNK1/JNK2 knockout fibroblasts, Myt1 siRNA knockdown, caspase-3 cleavage assay, Xenopus overexpression","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple methods (Co-IP, in vitro kinase, KO cells, siRNA knockdown, functional apoptosis readout) across multiple model systems","pmids":["19204086"],"is_preprint":false},{"year":2010,"finding":"In mouse oocytes, both Wee1B (nuclear) and Myt1 (cytoplasmic) must be downregulated for meiotic resumption; mislocalized Wee1B or Myt1 (forced into wrong compartment) cannot maintain meiotic arrest, demonstrating that compartment-specific localization is functionally required; Cdc25B translocation from cytoplasm to nucleus and Wee1B export from nucleus to cytoplasm before GV breakdown are regulated by PKA inactivation and MPF activation respectively.","method":"siRNA knockdown of Wee1B and/or Myt1 in mouse oocytes, forced mislocalization constructs, live imaging, cell cycle analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockdown with defined meiotic cell cycle phenotype, mislocalization experiments establishing functional requirement for proper compartmentalization","pmids":["20083600"],"is_preprint":false},{"year":2010,"finding":"Myt1 inactivation during Xenopus oocyte maturation proceeds in two steps: early CDK1/XRINGO-mediated phosphorylation reduces Myt1 activity AND facilitates docking/recruitment of p90Rsk; five p90Rsk phosphorylation sites on Myt1 (distinct from CDK1/XRINGO sites) were identified; mutation of these five sites impairs Myt1 hyperphosphorylation and makes it resistant to p90Rsk inhibition; p90Rsk-phosphorylated Myt1 does not interact with CDK1/cyclin B, preventing further CDK1 inhibition after meiosis I entry.","method":"In vitro kinase assay, phosphorylation-site mapping, site-directed mutagenesis, Xenopus oocyte microinjection, co-immunoprecipitation","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution, mutagenesis, site mapping, and in vivo oocyte validation, multiple orthogonal methods","pmids":["20362450"],"is_preprint":false},{"year":2012,"finding":"MEK1 phosphorylates and inactivates Myt1 to promote Golgi fragmentation in G2 and mitotic entry; Myt1 knockdown by siRNA increases efficiency of Golgi fragmentation by mitotic cytosol and eliminates the requirement for MEK1 in Golgi fragmentation and mitotic entry; MEK1-dependent phosphorylation of Myt1 requires another kinase but is independent of RSK, Plk, and CDK1.","method":"siRNA knockdown of Myt1, permeabilized cell Golgi fragmentation assay, MEK1 inhibition, epistasis analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — epistasis established by siRNA rescue of MEK1 inhibition phenotype, multiple orthogonal approaches in one study","pmids":["23241949"],"is_preprint":false},{"year":2012,"finding":"MYT1 contributes to DNA damage checkpoint recovery but not to checkpoint activation or normal cell cycle progression; depletion of MYT1 causes precocious mitotic entry when the checkpoint is abrogated with CHK1 or WEE1 inhibitors; MYT1 kinase activity is high during checkpoint activation and reduced during checkpoint recovery; MYT1 depletion lowers the threshold for CDK1 activation.","method":"siRNA depletion, time-lapse microscopy, CHK1/WEE1 inhibitor treatment, CDK1 activity assays, clonogenic survival, tumor xenograft models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean knockdown with time-lapse functional readout, multiple inhibitor combinations, in vivo xenograft validation","pmids":["23146904"],"is_preprint":false},{"year":2014,"finding":"MyT1 is identified as a component of a neural cell type-specific LSD1 complex; MyT1 forms a stable multiprotein complex with LSD1 through direct interaction; the LSD1-MyT1 complex directly regulates the Pten gene as revealed by microarray and ChIP assays; knockdown of either LSD1 or MyT1 derepresses target gene expression and inhibits proliferation of Neuro2a neuroblastoma cells.","method":"Biochemical purification of LSD1 complex from neural cells, co-immunoprecipitation, ChIP assay, microarray, siRNA knockdown with proliferation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical purification, direct interaction, ChIP validation of target gene, functional knockdown, multiple orthogonal methods","pmids":["24828497"],"is_preprint":false},{"year":2016,"finding":"MyT1 promotes neuronal differentiation by counteracting Notch signaling; MyT1 binding is associated with transcriptional repression in neural progenitor cells; MyT1 targets include the Notch1 receptor and downstream targets including Hes1, Sox2, Id3, and Olig1 (regulators of the neural progenitor program), establishing Ascl1-induced MyT1 as a cell-autonomous suppressor of Notch signaling.","method":"Functional overexpression/knockdown in neurogenesis models, genome-wide ChIP-seq for MyT1 binding, transcriptional profiling, epistasis with Notch signaling components","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide ChIP-seq combined with functional knockdown/overexpression and epistasis, multiple orthogonal methods","pmids":["27705795"],"is_preprint":false},{"year":2018,"finding":"When targeted to DNA via its consensus binding site, Myt1 represses transcription (whereas Myt1l activates); genome-wide analyses in a GBM cell line show largely overlapping effects of Myt1 and Myt1l on endogenous gene expression; an activation function in Myt1l maps to a poorly conserved N-terminal region absent in Myt1.","method":"Luciferase reporter assay with heterologous DNA-binding domain fusion, genome-wide RNA-seq, domain mapping by truncation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — reporter assay plus genome-wide expression, single lab, two orthogonal approaches","pmids":["29291346"],"is_preprint":false},{"year":2018,"finding":"Myt1 and Myt1l directly repress expression of YAP1 (a Hippo pathway coactivator) in GBM cells; overexpression of YAP1 overcomes the anti-proliferative effect of Myt1/Myt1l; reducing YAP1 expression slows orthotopic tumor xenograft growth, establishing YAP1 repression as a functional mechanism of Myt1-mediated anti-proliferative activity.","method":"Re-expression of Myt1/Myt1l in GBM cell lines, gene expression analysis, YAP1 overexpression/knockdown rescue experiments, orthotopic xenograft models","journal":"Biochimica et biophysica acta. Gene regulatory mechanisms","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional epistasis (YAP1 OE rescues Myt1 phenotype) plus in vivo xenograft, single lab","pmids":["30312684"],"is_preprint":false},{"year":2019,"finding":"Myt1 and Wee1 kinases are both capable of phosphorylating and inhibiting Cdk1/cyclin B; cancer cells with elevated Myt1 have acquired resistance to the Wee1 inhibitor adavosertib; downregulating Myt1 in resistant cells enhances ectopic Cdk1 activity and restores sensitivity to adavosertib, demonstrating functional redundancy between Myt1 and Wee1 for Cdk1 inhibition.","method":"Myt1 overexpression/knockdown, Cdk1 activity assays, adavosertib treatment, cell viability assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with direct Cdk1 activity readout and drug sensitivity, single lab","pmids":["31594837"],"is_preprint":false},{"year":2019,"finding":"SGK directly phosphorylates both Cdc25 and Myt1 to trigger cyclin B-Cdk1 activation at the meiotic G2/M transition in starfish oocytes; SGK activation requires cooperation between Gβγ-PI3K and an atypical Gβγ pathway downstream of hormonal stimulation.","method":"In vitro kinase assay, starfish oocyte microinjection, phosphorylation-site analysis, inhibitor/dominant-negative approaches","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus in vivo oocyte functional assays, single lab","pmids":["31537708"],"is_preprint":false},{"year":2020,"finding":"MYT1 (transcription factor) interacts physically with the LSD1/CoREST complex in neuroblastoma cells; MYT1 knockdown inhibits proliferation and promotes differentiation; depletion of LSD1 or inhibition of LSD1 by ORY-1001 decreases MYT1 expression; many MYT1-regulated differentiation genes are targets of the REST complex.","method":"Co-immunoprecipitation, siRNA knockdown, omics target gene analysis, LSD1 inhibitor treatment, differentiation/proliferation assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — Co-IP plus functional knockdown and inhibitor epistasis, single lab","pmids":["32251364"],"is_preprint":false},{"year":2020,"finding":"SMAD4 and SMAD5 (transferred via ESC-derived extracellular vesicles) activate MYT1 transcription in neural stem cells; MYT1 in turn downregulates Egln3, leading to activation of HIF-2α, NAMPT, and Sirt1 sequentially; MYT1 knockdown in young NSCs accelerates aging phenotypes and impairs proliferation and differentiation.","method":"Transcriptome analysis, shRNA knockdown of MYT1, SMAD4/5 overexpression, ESC-sEV treatment, pathway inhibition assays","journal":"Molecular therapy","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — knockdown phenotype plus pathway dissection, single lab","pmids":["33038325"],"is_preprint":false},{"year":2021,"finding":"The N-terminal region of Xenopus Myt1, specifically the PAYF motif and adjacent CDK1 phosphorylation sites (Thr11 and Thr16), is required for normal Myt1 activity in oocytes; CDK1-mediated phosphorylation at these N-terminal sites contributes to Myt1 inactivation during M phase, in addition to the previously characterized C-terminal regulation.","method":"Site-directed mutagenesis, Xenopus oocyte microinjection, in vivo phosphorylation analysis","journal":"Cells & development","confidence":"Medium","confidence_rationale":"Tier 1–2 / Weak — mutagenesis with in vivo oocyte assay, single lab, single study","pmids":["34695617"],"is_preprint":false},{"year":2006,"finding":"Myt1 autophosphorylates on Ser66 and Ser76 (identified by MALDI mass spectrometry); the Ser66Ala mutant of Xenopus Myt1 is more potent at delaying meiosis entry and is hypophosphorylated (loss of mobility shift), indicating that autophosphorylation of Ser66 is a prerequisite and/or trigger for subsequent phosphorylation and inactivation of Myt1 during meiotic G2/M transition.","method":"MALDI mass spectrometry phospho-site identification, site-directed mutagenesis (S66A, S76A), Xenopus oocyte microinjection and cell cycle timing","journal":"Cell cycle","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry site identification plus mutagenesis with functional in vivo readout, single lab","pmids":["16481744"],"is_preprint":false},{"year":2016,"finding":"In Drosophila spermatocytes, Myt1 inhibition of Cyclin A/Cdk1 (not Cyclin B/Cdk1) is essential for fusome integrity and centriole engagement during premeiotic G2 arrest; loss of Myt1 activity causes disrupted intercellular bridges and premature centriole disengagement leading to multipolar spindles; these defects are suppressed by depletion of Cyclin A or ectopic Wee1 expression.","method":"Drosophila myt1 null mutants, genetic epistasis with cyclin A depletion and Wee1 overexpression, Cdk1F phosphorylation-defective mutant phenocopying","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple alleles, null mutants plus phenocopy experiments, functional pathway placement","pmids":["27170181"],"is_preprint":false},{"year":2020,"finding":"In Drosophila midgut, Myt1 depletion alters cell cycle kinetics and promotes ectopic mitoses of enteroblast progenitors at the expense of differentiation; these aberrant enteroblast mitoses rely on Cyclin A, implicating Myt1 inhibition of Cyclin A/Cdk1 as the mechanism coupling mitotic exit with enteroblast-to-enterocyte differentiation.","method":"myt1 null mutants, cell-specific RNAi, genetic epistasis with Cyclin A depletion, cell cycle and differentiation marker analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — null mutant plus RNAi plus epistasis, single lab but multiple genetic approaches","pmids":["33207203"],"is_preprint":false},{"year":2023,"finding":"Myt1 overexpression confers resistance to inhibitors of Wee1 (adavosertib/PD166285), CHK1 (UCN-01), and ATR (AZD6738) by compensating for CDK1 inhibition; Myt1 overexpression reduces premature mitotic entry and decreases mitosis length, increasing survival in checkpoint-abrogated cells.","method":"Myt1 overexpression, kinase inhibitor treatment, mitotic entry assays (time-lapse), clonogenic survival assays","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional overexpression with multiple inhibitors and direct Cdk1 activity readout, single lab","pmids":["38020882"],"is_preprint":false},{"year":2016,"finding":"MYT1 overexpression in cells downregulates retinoic acid receptor beta (RARB) expression, whereas OAVS-associated MYT1 mutants fail to do so, placing MYT1 in the retinoic acid signaling pathway and demonstrating loss-of-function consequences for OAVS-associated variants.","method":"MYT1 overexpression in cell culture, RARB expression analysis, comparison of wild-type vs. mutant MYT1, zebrafish morpholino knockdown of myt1a","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — cell-based functional assay plus zebrafish knockdown, two orthogonal model systems, single lab","pmids":["27358179"],"is_preprint":false},{"year":2017,"finding":"MYT1 overexpression downregulates all RA receptor genes (RARA, RARB, RARG) but not CYP26A1; a novel OAVS-associated MYT1 missense variant (p.Ser108Leu) impacts the expression of RA receptor genes, further supporting MYT1 function in the RA signaling pathway.","method":"MYT1 overexpression, wild-type vs. mutant comparison, RT-PCR quantification of RA pathway genes","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — cell-based functional assay comparing wild-type and mutant, single lab, single method","pmids":["28612832"],"is_preprint":false},{"year":2019,"finding":"ZTF-11 (C. elegans Myt1 homolog) functions together with the MuvB corepressor complex to suppress activation of non-neuronal genes in neurons; loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis; ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons.","method":"ztf-11 loss-of-function, ectopic expression, MuvB complex co-function analysis, single-cell resolution expression profiling","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular mechanism (MuvB co-repressor), single lab","pmids":["31386623"],"is_preprint":false}],"current_model":"MYT1 encodes two functionally distinct proteins sharing the gene locus: (1) a membrane-associated dual-specificity kinase (the cell-cycle MYT1/PKMYT1) that preferentially phosphorylates CDK1/Cdc2 on Thr14 and Tyr15 at the ER/Golgi to inhibit CDK1/cyclin B and prevent premature mitotic entry, is inactivated during M-phase through a two-step mechanism involving CDK1/XRINGO-mediated phosphorylation (facilitating p90Rsk docking) and subsequent p90Rsk-mediated C-terminal hyperphosphorylation (also regulated by Plk1/Plx1, Akt, SGK, MEK1, and JNK1), and is additionally required for Golgi/ER reassembly during mitotic exit; and (2) a C2HC zinc finger transcription factor (the neural MYT1) that represses non-neuronal and progenitor genes by recruiting HDAC-containing Sin3B and LSD1/CoREST complexes, counteracts Notch signaling to promote neuronal differentiation, and regulates YAP1 and RA receptor expression."},"narrative":{"mechanistic_narrative":"The MYT1 locus encodes two functionally distinct activities documented in this corpus: a membrane-associated cell-cycle kinase and a neural zinc-finger transcriptional repressor. As a kinase, MYT1 is a Wee1-family dual-specificity enzyme that preferentially phosphorylates CDK1/Cdc2 on Thr14 (and Tyr15) in a cyclin-dependent manner to inhibit Cdc2/cyclin B and restrain mitotic entry [PMID:7569953, PMID:9001210, PMID:9268380]. It is anchored to the endoplasmic reticulum and Golgi through a C-terminal hydrophobic membrane-targeting domain, whose removal redirects the protein to the nucleus [PMID:9001210]; a distinct C-terminal segment both binds Cdc2/cyclin B1 and supports cytoplasmic sequestration of the complex, so MYT1 enforces G2/M arrest by phosphorylation and by physical sequestration [PMID:10504341, PMID:10373560]. MYT1 is inactivated at M phase by a multi-kinase program: CDK1/XRINGO-mediated phosphorylation lowers activity and licenses p90Rsk docking, after which p90Rsk hyperphosphorylates the C-terminus and abolishes CDK1/cyclin B binding [PMID:18951089, PMID:20362450], with parallel inhibitory input from Plk1/Plx1 (via a Cdc2-created Thr478 docking site), Akt, SGK, and MEK1 [PMID:12738781, PMID:15692562, PMID:11802161, PMID:31537708, PMID:23241949]. Beyond preventing premature mitosis, MYT1-mediated Cdc2 suppression is required for Golgi/ER reassembly during mitotic exit, contributes to DNA-damage checkpoint recovery, and is functionally redundant with Wee1 such that elevated MYT1 confers resistance to Wee1/CHK1/ATR inhibitors [PMID:18378775, PMID:23146904, PMID:31594837, PMID:38020882]. The neural MYT1 is a transcriptional repressor that recruits HDAC-containing Sin3B and LSD1/CoREST complexes to repress non-neuronal and progenitor genes, counteracts Notch signaling to drive neuronal differentiation, and represses YAP1 and retinoic-acid receptor genes [PMID:15935060, PMID:24828497, PMID:27705795, PMID:32251364, PMID:30312684]. Loss-of-function MYT1 variants associated with oculo-auriculo-vertebral spectrum (OAVS) fail to downregulate RA receptor expression, linking MYT1 to this developmental disorder through the retinoic-acid signaling pathway [PMID:27358179, PMID:28612832].","teleology":[{"year":1995,"claim":"Established the founding biochemical identity of MYT1: what enzyme provides Thr14-directed inhibition of Cdc2 was unknown, and this work identified a membrane-associated Wee1-family kinase as the predominant Thr14 kinase regulating the cell cycle.","evidence":"cDNA cloning, in vitro kinase assay, and immunodepletion of Xenopus egg extracts","pmids":["7569953"],"confidence":"High","gaps":["Membrane anchor and its targeting domain not yet mapped","Human ortholog substrate preference not yet defined"]},{"year":1997,"claim":"Defined the human enzyme's substrate selectivity and subcellular address, showing MYT1 is a dual-specificity kinase preferring Thr14 on Cdc2 and is tethered to the ER/Golgi by a C-terminal hydrophobic domain.","evidence":"cDNA cloning, in vitro kinase assays with site mapping, immunofluorescence, and deletion mutagenesis in HeLa cells","pmids":["9001210","9268380"],"confidence":"High","gaps":["Mechanism of M-phase hyperphosphorylation/inactivation not defined","Upstream regulatory kinases unidentified"]},{"year":1999,"claim":"Resolved how MYT1 enforces arrest beyond catalysis, showing the C-terminal 63-residue domain binds Cdc2/cyclin B1 and that MYT1 blocks cyclin B1 nuclear shuttling and arrests cells independent of catalytic activity.","evidence":"Deletion mutagenesis, kinase-dead overexpression, cyclin B1 localization imaging, and cell cycle analysis in fission yeast and human cells","pmids":["10504341","10373560"],"confidence":"High","gaps":["Physiological balance between catalytic vs sequestration roles unquantified"]},{"year":2002,"claim":"Began mapping the kinase network that switches MYT1 off at the G2/M transition, identifying MYT1 as a substrate of Akt and of Mos during oocyte/meiotic maturation.","evidence":"In vitro kinase assays, co-IP, and oocyte microinjection in starfish and Xenopus","pmids":["11802161","11959823"],"confidence":"Medium","gaps":["Mos result is a single-lab Co-IP plus in vivo phosphorylation without site mapping","Direct vs indirect Akt action on MYT1 in somatic cells unclear"]},{"year":2005,"claim":"Distinguished context-specific inactivation pathways, showing p90Rsk down-regulates MYT1 in meiosis whereas a Cdc2-primed Thr478 docking site recruits Plx1 to inhibit MYT1 in the embryonic cell cycle.","evidence":"GST pulldown, reciprocal co-IP, in vitro kinase assays, Thr478 mutagenesis, and embryo microinjection (Xenopus)","pmids":["9724639","15692562"],"confidence":"High","gaps":["Quantitative contribution of each kinase to net MYT1 inactivation not resolved"]},{"year":2003,"claim":"Extended the inhibitory kinase set and identified a positive regulator, establishing MYT1 as a Plk1 substrate at four consensus C-terminal sites and TSAP6 as a physical interactor that augments MYT1 activity.","evidence":"In vitro kinase assays with 4A mutant and mobility shifts; yeast two-hybrid, GST pulldown, and co-IP for TSAP6","pmids":["12738781","12606722"],"confidence":"High","gaps":["TSAP6 mechanism of activation undefined and Medium-confidence","In vivo consequence of Plk1 sites on mitotic timing not isolated"]},{"year":2006,"claim":"Identified an intramolecular priming event, showing MYT1 autophosphorylation on Ser66 is a prerequisite/trigger for subsequent inhibitory phosphorylation during the meiotic G2/M transition.","evidence":"MALDI mass spectrometry site identification and S66A/S76A mutagenesis with oocyte cell-cycle timing","pmids":["16481744"],"confidence":"Medium","gaps":["Single lab; autophosphorylation kinetics in somatic mitosis untested"]},{"year":2008,"claim":"Delineated the ordered two-step inactivation and a non-cell-cycle organelle role, showing CDK/XRINGO phosphorylates three regulatory serines distinct from CDK/cyclin sites, and that MYT1 is required for Golgi/ER reassembly at mitotic exit via cyclin B targeting.","evidence":"In vitro kinase assays with site mapping and mutagenesis (Xenopus); siRNA knockdown with Golgi/ER imaging and cyclin B1/B2 epistasis (mammalian cells)","pmids":["18951089","18378775"],"confidence":"High","gaps":["How membrane-tethered MYT1 locally couples Cdc2 suppression to organelle dynamics not mechanistically resolved"]},{"year":2005,"claim":"Opened the transcription-factor branch of MYT1 biology, showing MYT1 binds Sin3B and recruits HDAC1/HDAC2 to repress a heterologous promoter.","evidence":"Yeast and mammalian two-hybrid, co-IP, and reporter assays","pmids":["15935060"],"confidence":"High","gaps":["Endogenous target genes of the MYT1-Sin3B-HDAC complex not yet identified"]},{"year":2009,"claim":"Linked MYT1 to stress-induced apoptosis, showing JNK1 (not JNK2) binds and phosphorylates MYT1 and that MYT1 is required for UVA-induced caspase-3 cleavage and DNA fragmentation.","evidence":"Co-IP, in vitro kinase assays, JNK1/JNK2 knockout fibroblasts, MYT1 siRNA, and apoptosis readouts","pmids":["19204086"],"confidence":"High","gaps":["Mechanistic link between MYT1 phosphorylation and apoptotic execution undefined"]},{"year":2010,"claim":"Established that compartmentalization is functionally essential and refined the meiotic two-step model, showing cytoplasmic MYT1 must be down-regulated for meiotic resumption and that CDK1/XRINGO priming both reduces activity and recruits p90Rsk, which then abolishes CDK1/cyclin B binding.","evidence":"siRNA and forced-mislocalization in mouse oocytes; site mapping, mutagenesis, co-IP, and microinjection in Xenopus","pmids":["20083600","20362450"],"confidence":"High","gaps":["How localization is dynamically controlled in somatic mitosis not addressed"]},{"year":2012,"claim":"Connected MYT1 to additional mitotic-entry inputs and the DNA-damage response, showing MEK1-dependent phosphorylation inactivates MYT1 to permit Golgi fragmentation/mitotic entry and that MYT1 contributes specifically to checkpoint recovery by raising the CDK1 activation threshold.","evidence":"siRNA epistasis with MEK1 inhibition and permeabilized-cell Golgi assays; time-lapse with CHK1/WEE1 inhibitors and xenografts","pmids":["23241949","23146904"],"confidence":"High","gaps":["The MEK1-dependent intermediary kinase (independent of RSK/Plk/CDK1) unidentified","MYT1 dispensable for checkpoint activation/normal cycling — role bounded to recovery"]},{"year":2014,"claim":"Defined the neural epigenetic repressor mechanism, showing MYT1 is a stable subunit of a neural LSD1 complex that directly represses Pten and supports neuroblastoma proliferation.","evidence":"Biochemical purification, co-IP, ChIP, microarray, and siRNA proliferation assays in Neuro2a cells","pmids":["24828497"],"confidence":"High","gaps":["Stoichiometry and recruitment determinants of MYT1 within the LSD1 complex not defined"]},{"year":2016,"claim":"Placed MYT1 in neuronal differentiation and developmental disease, showing genome-wide MYT1 binding represses Notch pathway genes to drive neurogenesis and that OAVS-associated variants fail to repress RA receptor expression.","evidence":"ChIP-seq, overexpression/knockdown with Notch epistasis; MYT1 wild-type vs OAVS-mutant RARB assays and zebrafish myt1a knockdown","pmids":["27705795","27358179","27170181"],"confidence":"High","gaps":["Direct vs indirect repression of individual Notch/RA targets not all resolved","Drosophila spermatocyte data implicate Cyclin A/Cdk1 rather than the transcription-factor role — two activities not unified"]},{"year":2018,"claim":"Identified anti-proliferative transcriptional targets in glioblastoma, showing DNA-targeted MYT1 represses transcription and that MYT1/MYT1L directly repress YAP1, whose forced expression rescues proliferation.","evidence":"Reporter assays, genome-wide RNA-seq, YAP1 rescue, and orthotopic xenografts in GBM cells","pmids":["29291346","30312684"],"confidence":"Medium","gaps":["Single-lab functional epistasis; direct MYT1 occupancy at the YAP1 locus not shown","Distinction of MYT1 vs MYT1L contributions incomplete"]},{"year":2017,"claim":"Strengthened the MYT1-retinoic-acid link in OAVS, showing MYT1 overexpression downregulates RARA/RARB/RARG and a novel OAVS missense variant perturbs this regulation.","evidence":"Overexpression with wild-type vs mutant comparison and RT-PCR of RA pathway genes","pmids":["28612832"],"confidence":"Medium","gaps":["Single method, single lab; whether RAR repression is direct unknown"]},{"year":2019,"claim":"Established therapeutic relevance and redundancy, showing MYT1 and Wee1 redundantly inhibit Cdk1/cyclin B and that elevated MYT1 confers Wee1-inhibitor resistance reversible by MYT1 knockdown; SGK was added as another inhibitory upstream kinase.","evidence":"MYT1 overexpression/knockdown with Cdk1 activity and adavosertib sensitivity assays; in vitro kinase and starfish oocyte assays for SGK","pmids":["31594837","31537708"],"confidence":"Medium","gaps":["Mechanistic basis of redundancy (shared vs distinct CDK1 pools) not defined","SGK data single-lab oocyte system"]},{"year":2019,"claim":"Extended the neural repressor mechanism across species, showing the C. elegans homolog ZTF-11 acts with the MuvB corepressor to suppress non-neuronal genes and is sufficient to drive ectopic neurogenesis.","evidence":"Loss- and gain-of-function with MuvB co-function analysis and single-cell expression profiling in C. elegans","pmids":["31386623"],"confidence":"Medium","gaps":["Conservation of MuvB partnership in mammalian MYT1 untested"]},{"year":2020,"claim":"Broadened tissue contexts for both MYT1 activities, linking the transcription factor to LSD1/CoREST-dependent neuroblastoma differentiation, NSC aging via SMAD-driven activation, and the kinase to Drosophila enteroblast differentiation through Cyclin A/Cdk1 inhibition.","evidence":"Co-IP and LSD1-inhibitor epistasis (neuroblastoma); shRNA and pathway dissection (NSC); null mutants/RNAi with Cyclin A epistasis (Drosophila midgut)","pmids":["32251364","33038325","33207203"],"confidence":"Medium","gaps":["Each context is single-lab","How a single locus partitions kinase vs transcription-factor functions across cell types unresolved"]},{"year":2021,"claim":"Refined the inactivation map to the N-terminus, showing the PAYF motif and CDK1 sites Thr11/Thr16 contribute to MYT1 inactivation during M phase alongside C-terminal regulation.","evidence":"Site-directed mutagenesis and in vivo phosphorylation analysis in Xenopus oocytes","pmids":["34695617"],"confidence":"Medium","gaps":["Single lab/study","Relative weight of N- vs C-terminal regulation not quantified"]},{"year":2023,"claim":"Consolidated MYT1 as a multi-checkpoint resistance node, showing MYT1 overexpression compensates for CDK1 inhibition to confer resistance to Wee1, CHK1, and ATR inhibitors.","evidence":"Overexpression with multiple kinase inhibitors, time-lapse mitotic-entry assays, and clonogenic survival","pmids":["38020882"],"confidence":"Medium","gaps":["Single lab; clinical predictive value untested"]},{"year":null,"claim":"It remains unresolved how a single MYT1 locus produces and partitions two biochemically unrelated activities — a membrane-tethered CDK1-inhibitory kinase and a nuclear zinc-finger repressor — across cell types, and whether these activities ever co-regulate one another in the same cell.","evidence":"No discovery in the timeline reconciles the kinase and transcription-factor functions mechanistically","pmids":[],"confidence":"Low","gaps":["No isoform-resolved expression map linking kinase vs TF outputs","No structural model of either MYT1 activity in the corpus","Direct MYT1 occupancy at most reported target loci not demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2,8,10,12,16]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,8]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[11,19,20,21,25]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1,13]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,13,17]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,19,20]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,5,15]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,2,5,13,18,23]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,19,20,22,25]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[11,19,25]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[20,32,33,34]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[15,16,27,29]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[14]}],"complexes":["LSD1/CoREST complex","Sin3B-HDAC1/HDAC2 complex"],"partners":["CDK1","CCNB1","RPS6KA (P90RSK)","PLK1","TSAP6","MAPK8 (JNK1)","SIN3B","KDM1A (LSD1)"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01538","full_name":"Myelin transcription factor 1","aliases":["Myelin transcription factor I","MyTI","PLPB1","Proteolipid protein-binding protein"],"length_aa":1121,"mass_kda":122.3,"function":"Binds to the promoter region of genes encoding proteolipid proteins of the central nervous system. May play a role in the development of neurons and oligodendroglia in the CNS. May regulate a critical transition point in oligodendrocyte lineage development by modulating oligodendrocyte progenitor proliferation relative to terminal differentiation and up-regulation of myelin gene transcription","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/Q01538/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYT1","classification":"Not Classified","n_dependent_lines":16,"n_total_lines":1208,"dependency_fraction":0.013245033112582781},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYT1","total_profiled":1310},"omim":[{"mim_id":"617200","title":"OLIGODENDROCYTIC MYELIN PARANODAL AND INNER LOOP PROTEIN; OPALIN","url":"https://www.omim.org/entry/617200"},{"mim_id":"613084","title":"MYELIN TRANSCRIPTION FACTOR 1-LIKE; MYT1L","url":"https://www.omim.org/entry/613084"},{"mim_id":"610401","title":"NETRIN 4; NTN4","url":"https://www.omim.org/entry/610401"},{"mim_id":"609671","title":"STEAP3 METALLOREDUCTASE; STEAP3","url":"https://www.omim.org/entry/609671"},{"mim_id":"609132","title":"LYSINE DEMETHYLASE 1A; KDM1A","url":"https://www.omim.org/entry/609132"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"brain","ntpm":32.9}],"url":"https://www.proteinatlas.org/search/MYT1"},"hgnc":{"alias_symbol":["MTF1","MYTI","ZC2HC4A","NZF2","ZC2H2C1"],"prev_symbol":["PLPB1"]},"alphafold":{"accession":"Q01538","domains":[{"cath_id":"1.20.5","chopping":"1074-1121","consensus_level":"medium","plddt":83.044,"start":1074,"end":1121}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01538","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01538-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01538-F1-predicted_aligned_error_v6.png","plddt_mean":58.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYT1","jax_strain_url":"https://www.jax.org/strain/search?query=MYT1"},"sequence":{"accession":"Q01538","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01538.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01538/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01538"}},"corpus_meta":[{"pmid":"7569953","id":"PMC_7569953","title":"Myt1: 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it contains a putative transmembrane segment mediating membrane association, and its activity is highly regulated during the cell cycle.\",\n      \"method\": \"cDNA cloning, in vitro kinase assay, immunodepletion of Xenopus egg extracts\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assay with immunodepletion, founding paper replicated extensively across labs\",\n      \"pmids\": [\"7569953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human Myt1 (Myt1Hu) is a dual-specificity kinase that preferentially phosphorylates Cdc2 on Thr14 (over Tyr15) in a cyclin-dependent manner; it localizes to the endoplasmic reticulum and Golgi complex in HeLa cells via a hydrophobic C-terminal membrane-targeting domain, deletion of which redirects Myt1 to the nucleus.\",\n      \"method\": \"cDNA cloning, in vitro kinase assay with phosphorylation-site mapping, immunofluorescence localization, deletion mutagenesis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase assay with mutagenesis plus direct localization experiments, replicated by multiple labs\",\n      \"pmids\": [\"9001210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Human Myt1 specifically phosphorylates and inactivates Cdc2-containing cyclin complexes but not Cdk2- or Cdk4-containing complexes; Myt1 remains membrane-bound throughout the cell cycle but becomes hyperphosphorylated and less active during M-phase arrest; Cdc2/cyclin B1 can phosphorylate Myt1 in vitro without affecting its kinase activity.\",\n      \"method\": \"In vitro kinase assay with substrate specificity panel, immunoprecipitation, cell cycle synchronization, Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal in vitro and cellular methods, replicated concept across labs\",\n      \"pmids\": [\"9268380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"The C-terminal regulatory domain of Xenopus Myt1 specifically binds p90rsk (a MAPK-activated kinase); p90rsk phosphorylates the Myt1 C-terminus and down-regulates its inhibitory activity on Cdc2/cyclin B in vitro; Myt1 preferentially associates with hyperphosphorylated p90rsk, and complexes are detected in immunoprecipitates from mature Xenopus oocytes, linking MAPK-p90rsk signaling to Myt1 inactivation during oocyte maturation.\",\n      \"method\": \"GST pulldown, co-immunoprecipitation from oocyte extracts, in vitro kinase assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal Co-IP plus in vitro kinase assay with functional readout, replicated by subsequent studies\",\n      \"pmids\": [\"9724639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The C-terminal domain of Myt1 is required for: (1) interaction with Cdc2/cyclin B1 complexes, (2) efficient phosphorylation of Cdc2 in vitro, and (3) G2/M phase arrest upon Myt1 overexpression; the C-terminal domain interacts with and is phosphorylated by Cdc2, indicating cytoplasmic localization of this domain; Myt1 can inhibit cell cycle progression both by phosphorylating Cdc2 and by sequestering Cdc2/cyclin B1 complexes in the cytoplasm.\",\n      \"method\": \"Overexpression in S. pombe and human osteosarcoma cells, C-terminal truncation mutants, in vitro kinase assay, co-immunoprecipitation, cell cycle analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (mutational analysis, kinase assay, cell cycle assay, Co-IP) in a single study\",\n      \"pmids\": [\"10504341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Overproduction of either kinase-active or kinase-inactive Myt1 blocks nuclear-cytoplasmic shuttling of cyclin B1 and causes G2 delay; the COOH-terminal 63 amino acids of Myt1 constitute a Cdc2/cyclin B1 interaction domain required for cyclin B1 binding and efficient Cdc2 phosphorylation; Myt1 lacking this domain does not sequester Cdc2/cyclin B1 or perturb cell cycle progression.\",\n      \"method\": \"Overexpression of kinase-active and kinase-inactive mutants, deletion mutagenesis, in vitro kinase assay, live-cell imaging/localization of cyclin B1, cell cycle analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (mutagenesis, kinase assay, cyclin B1 trafficking, cell cycle arrest), replicated concept\",\n      \"pmids\": [\"10373560\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Akt/PKB phosphorylates and downregulates Myt1 (a Wee1 family member) in starfish oocytes, switching the balance between Cdc25 and Wee1/Myt1 activities and causing initial activation of cyclin B-Cdc2 at the meiotic G2/M transition, identifying Myt1 as a new Akt substrate and Akt as an M-phase initiator.\",\n      \"method\": \"In vitro kinase assay, phosphorylation-site analysis, oocyte microinjection, biochemical fractionation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro kinase assay plus in vivo functional rescue, multiple orthogonal methods\",\n      \"pmids\": [\"11802161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Mos interacts with Myt1 in Xenopus oocyte extracts and triggers Myt1 phosphorylation on certain sites in vivo independently of MAPK activation, suggesting Myt1 is a direct Mos target in the MPF activation pathway during meiotic resumption.\",\n      \"method\": \"Co-immunoprecipitation from oocyte extracts, in vivo phosphorylation analysis, MAPK-independent oocyte maturation assays\",\n      \"journal\": \"Development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus in vivo phosphorylation data, single lab, two orthogonal approaches\",\n      \"pmids\": [\"11959823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Plk1 phosphorylates Myt1 in vitro on four C-terminal sites matching a newly defined Plk1 consensus motif (hydrophobic at +1, acidic at −2); a Myt1-4A mutant (all four sites alanine) abolishes Plk1 phosphorylation in vitro and fails to show mitotic gel-mobility shift in nocodazole-arrested cells, establishing Myt1 as a Plk1 substrate during M phase.\",\n      \"method\": \"In vitro kinase assay with consensus motif-defined peptides, site-directed mutagenesis (4A mutant), SDS-PAGE mobility-shift analysis in nocodazole-arrested cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase assay plus mutagenesis validated in cells, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12738781\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"TSAP6 (a p53-inducible transmembrane protein) associates physically with the Myt1 kinase as demonstrated by yeast two-hybrid, GST pulldown, and co-immunoprecipitation; TSAP6 overexpression augments Myt1 activity.\",\n      \"method\": \"Yeast two-hybrid, GST/in vitro pulldown, co-immunoprecipitation, cell cycle analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — multiple binding methods (Y2H, pulldown, Co-IP) but functional mechanistic detail is limited\",\n      \"pmids\": [\"12606722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The Polo-like kinase Plx1 interacts with and inhibits Myt1 after fertilization of Xenopus eggs; Cdc2 phosphorylates Myt1 on Thr478 at M phase, creating a docking site for Plx1; Plx1 phosphorylates Myt1 and inhibits its kinase activity both in vitro and in vivo; this Plx1-Myt1 interaction replaces p90rsk-Myt1 interaction seen in meiosis, and is required for normal embryonic cell divisions.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Thr478), in vivo embryo microinjection experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (Co-IP, in vitro kinase, mutagenesis, in vivo functional rescue) in one study\",\n      \"pmids\": [\"15692562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Myt1 and Myt1L interact with Sin3B via a protein-protein interaction domain; Myt1-Sin3B complexes include HDAC1 and HDAC2 as demonstrated by co-immunoprecipitation from transfected mammalian cells; Myt1/Myt1L interaction with the HDAC-binding isoform of Sin3B confers repression on a heterologous promoter, placing Myt1 as a transcriptional repressor through HDAC recruitment.\",\n      \"method\": \"Yeast two-hybrid, mammalian two-hybrid, co-immunoprecipitation, transcriptional reporter assay\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional reporter assay, two-hybrid confirmed in multiple systems\",\n      \"pmids\": [\"15935060\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Xenopus Myt1 is inactivated by CDK/XRINGO-mediated phosphorylation on three specific serine residues in its regulatory domain that are distinct from CDK/cyclin phosphorylation sites; mutation of these serines makes Myt1 resistant to CDK/XRINGO-mediated inhibition; CDK/XRINGO thus has substrate specificity different from CDK/cyclin complexes.\",\n      \"method\": \"In vitro kinase assay, site-directed mutagenesis, phosphorylation-site mapping, Xenopus oocyte functional assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution, mutagenesis, site-mapping, and in vivo oocyte validation in one rigorous study\",\n      \"pmids\": [\"18951089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Myt1 is essential for Golgi and ER assembly during telophase (mitotic exit) in mammalian cells; both cyclin B1 and cyclin B2 serve as Myt1 targets for proper organelle reassembly; Myt1-mediated Cdc2 suppression is specifically required for control of intracellular membrane dynamics during mitosis.\",\n      \"method\": \"siRNA knockdown of Myt1 in mammalian cells, immunofluorescence of Golgi/ER markers, epistasis with cyclin B1/B2 depletion\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean siRNA knockdown with specific organelle phenotype and epistasis with cyclin B targets, single lab but multiple orthogonal readouts\",\n      \"pmids\": [\"18378775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"JNK1 (but not JNK2) interacts with and phosphorylates Myt1 ex vivo and in vitro; JNK1-deficient cells show suppressed Myt1 phosphorylation and reduced caspase-3 cleavage upon UVA irradiation; JNK2-deficient cells show increased Myt1 phosphorylation and caspase-3 cleavage; knockdown of Myt1 suppresses UVA-induced caspase-3 cleavage and DNA fragmentation, indicating JNK1-mediated Myt1 phosphorylation promotes UVA-induced apoptosis.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, JNK1/JNK2 knockout fibroblasts, Myt1 siRNA knockdown, caspase-3 cleavage assay, Xenopus overexpression\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple methods (Co-IP, in vitro kinase, KO cells, siRNA knockdown, functional apoptosis readout) across multiple model systems\",\n      \"pmids\": [\"19204086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In mouse oocytes, both Wee1B (nuclear) and Myt1 (cytoplasmic) must be downregulated for meiotic resumption; mislocalized Wee1B or Myt1 (forced into wrong compartment) cannot maintain meiotic arrest, demonstrating that compartment-specific localization is functionally required; Cdc25B translocation from cytoplasm to nucleus and Wee1B export from nucleus to cytoplasm before GV breakdown are regulated by PKA inactivation and MPF activation respectively.\",\n      \"method\": \"siRNA knockdown of Wee1B and/or Myt1 in mouse oocytes, forced mislocalization constructs, live imaging, cell cycle analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockdown with defined meiotic cell cycle phenotype, mislocalization experiments establishing functional requirement for proper compartmentalization\",\n      \"pmids\": [\"20083600\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Myt1 inactivation during Xenopus oocyte maturation proceeds in two steps: early CDK1/XRINGO-mediated phosphorylation reduces Myt1 activity AND facilitates docking/recruitment of p90Rsk; five p90Rsk phosphorylation sites on Myt1 (distinct from CDK1/XRINGO sites) were identified; mutation of these five sites impairs Myt1 hyperphosphorylation and makes it resistant to p90Rsk inhibition; p90Rsk-phosphorylated Myt1 does not interact with CDK1/cyclin B, preventing further CDK1 inhibition after meiosis I entry.\",\n      \"method\": \"In vitro kinase assay, phosphorylation-site mapping, site-directed mutagenesis, Xenopus oocyte microinjection, co-immunoprecipitation\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution, mutagenesis, site mapping, and in vivo oocyte validation, multiple orthogonal methods\",\n      \"pmids\": [\"20362450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MEK1 phosphorylates and inactivates Myt1 to promote Golgi fragmentation in G2 and mitotic entry; Myt1 knockdown by siRNA increases efficiency of Golgi fragmentation by mitotic cytosol and eliminates the requirement for MEK1 in Golgi fragmentation and mitotic entry; MEK1-dependent phosphorylation of Myt1 requires another kinase but is independent of RSK, Plk, and CDK1.\",\n      \"method\": \"siRNA knockdown of Myt1, permeabilized cell Golgi fragmentation assay, MEK1 inhibition, epistasis analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — epistasis established by siRNA rescue of MEK1 inhibition phenotype, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"23241949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"MYT1 contributes to DNA damage checkpoint recovery but not to checkpoint activation or normal cell cycle progression; depletion of MYT1 causes precocious mitotic entry when the checkpoint is abrogated with CHK1 or WEE1 inhibitors; MYT1 kinase activity is high during checkpoint activation and reduced during checkpoint recovery; MYT1 depletion lowers the threshold for CDK1 activation.\",\n      \"method\": \"siRNA depletion, time-lapse microscopy, CHK1/WEE1 inhibitor treatment, CDK1 activity assays, clonogenic survival, tumor xenograft models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean knockdown with time-lapse functional readout, multiple inhibitor combinations, in vivo xenograft validation\",\n      \"pmids\": [\"23146904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MyT1 is identified as a component of a neural cell type-specific LSD1 complex; MyT1 forms a stable multiprotein complex with LSD1 through direct interaction; the LSD1-MyT1 complex directly regulates the Pten gene as revealed by microarray and ChIP assays; knockdown of either LSD1 or MyT1 derepresses target gene expression and inhibits proliferation of Neuro2a neuroblastoma cells.\",\n      \"method\": \"Biochemical purification of LSD1 complex from neural cells, co-immunoprecipitation, ChIP assay, microarray, siRNA knockdown with proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical purification, direct interaction, ChIP validation of target gene, functional knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"24828497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MyT1 promotes neuronal differentiation by counteracting Notch signaling; MyT1 binding is associated with transcriptional repression in neural progenitor cells; MyT1 targets include the Notch1 receptor and downstream targets including Hes1, Sox2, Id3, and Olig1 (regulators of the neural progenitor program), establishing Ascl1-induced MyT1 as a cell-autonomous suppressor of Notch signaling.\",\n      \"method\": \"Functional overexpression/knockdown in neurogenesis models, genome-wide ChIP-seq for MyT1 binding, transcriptional profiling, epistasis with Notch signaling components\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide ChIP-seq combined with functional knockdown/overexpression and epistasis, multiple orthogonal methods\",\n      \"pmids\": [\"27705795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"When targeted to DNA via its consensus binding site, Myt1 represses transcription (whereas Myt1l activates); genome-wide analyses in a GBM cell line show largely overlapping effects of Myt1 and Myt1l on endogenous gene expression; an activation function in Myt1l maps to a poorly conserved N-terminal region absent in Myt1.\",\n      \"method\": \"Luciferase reporter assay with heterologous DNA-binding domain fusion, genome-wide RNA-seq, domain mapping by truncation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — reporter assay plus genome-wide expression, single lab, two orthogonal approaches\",\n      \"pmids\": [\"29291346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Myt1 and Myt1l directly repress expression of YAP1 (a Hippo pathway coactivator) in GBM cells; overexpression of YAP1 overcomes the anti-proliferative effect of Myt1/Myt1l; reducing YAP1 expression slows orthotopic tumor xenograft growth, establishing YAP1 repression as a functional mechanism of Myt1-mediated anti-proliferative activity.\",\n      \"method\": \"Re-expression of Myt1/Myt1l in GBM cell lines, gene expression analysis, YAP1 overexpression/knockdown rescue experiments, orthotopic xenograft models\",\n      \"journal\": \"Biochimica et biophysica acta. Gene regulatory mechanisms\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional epistasis (YAP1 OE rescues Myt1 phenotype) plus in vivo xenograft, single lab\",\n      \"pmids\": [\"30312684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Myt1 and Wee1 kinases are both capable of phosphorylating and inhibiting Cdk1/cyclin B; cancer cells with elevated Myt1 have acquired resistance to the Wee1 inhibitor adavosertib; downregulating Myt1 in resistant cells enhances ectopic Cdk1 activity and restores sensitivity to adavosertib, demonstrating functional redundancy between Myt1 and Wee1 for Cdk1 inhibition.\",\n      \"method\": \"Myt1 overexpression/knockdown, Cdk1 activity assays, adavosertib treatment, cell viability assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with direct Cdk1 activity readout and drug sensitivity, single lab\",\n      \"pmids\": [\"31594837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SGK directly phosphorylates both Cdc25 and Myt1 to trigger cyclin B-Cdk1 activation at the meiotic G2/M transition in starfish oocytes; SGK activation requires cooperation between Gβγ-PI3K and an atypical Gβγ pathway downstream of hormonal stimulation.\",\n      \"method\": \"In vitro kinase assay, starfish oocyte microinjection, phosphorylation-site analysis, inhibitor/dominant-negative approaches\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus in vivo oocyte functional assays, single lab\",\n      \"pmids\": [\"31537708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MYT1 (transcription factor) interacts physically with the LSD1/CoREST complex in neuroblastoma cells; MYT1 knockdown inhibits proliferation and promotes differentiation; depletion of LSD1 or inhibition of LSD1 by ORY-1001 decreases MYT1 expression; many MYT1-regulated differentiation genes are targets of the REST complex.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, omics target gene analysis, LSD1 inhibitor treatment, differentiation/proliferation assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — Co-IP plus functional knockdown and inhibitor epistasis, single lab\",\n      \"pmids\": [\"32251364\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SMAD4 and SMAD5 (transferred via ESC-derived extracellular vesicles) activate MYT1 transcription in neural stem cells; MYT1 in turn downregulates Egln3, leading to activation of HIF-2α, NAMPT, and Sirt1 sequentially; MYT1 knockdown in young NSCs accelerates aging phenotypes and impairs proliferation and differentiation.\",\n      \"method\": \"Transcriptome analysis, shRNA knockdown of MYT1, SMAD4/5 overexpression, ESC-sEV treatment, pathway inhibition assays\",\n      \"journal\": \"Molecular therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — knockdown phenotype plus pathway dissection, single lab\",\n      \"pmids\": [\"33038325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The N-terminal region of Xenopus Myt1, specifically the PAYF motif and adjacent CDK1 phosphorylation sites (Thr11 and Thr16), is required for normal Myt1 activity in oocytes; CDK1-mediated phosphorylation at these N-terminal sites contributes to Myt1 inactivation during M phase, in addition to the previously characterized C-terminal regulation.\",\n      \"method\": \"Site-directed mutagenesis, Xenopus oocyte microinjection, in vivo phosphorylation analysis\",\n      \"journal\": \"Cells & development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Weak — mutagenesis with in vivo oocyte assay, single lab, single study\",\n      \"pmids\": [\"34695617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Myt1 autophosphorylates on Ser66 and Ser76 (identified by MALDI mass spectrometry); the Ser66Ala mutant of Xenopus Myt1 is more potent at delaying meiosis entry and is hypophosphorylated (loss of mobility shift), indicating that autophosphorylation of Ser66 is a prerequisite and/or trigger for subsequent phosphorylation and inactivation of Myt1 during meiotic G2/M transition.\",\n      \"method\": \"MALDI mass spectrometry phospho-site identification, site-directed mutagenesis (S66A, S76A), Xenopus oocyte microinjection and cell cycle timing\",\n      \"journal\": \"Cell cycle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry site identification plus mutagenesis with functional in vivo readout, single lab\",\n      \"pmids\": [\"16481744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"In Drosophila spermatocytes, Myt1 inhibition of Cyclin A/Cdk1 (not Cyclin B/Cdk1) is essential for fusome integrity and centriole engagement during premeiotic G2 arrest; loss of Myt1 activity causes disrupted intercellular bridges and premature centriole disengagement leading to multipolar spindles; these defects are suppressed by depletion of Cyclin A or ectopic Wee1 expression.\",\n      \"method\": \"Drosophila myt1 null mutants, genetic epistasis with cyclin A depletion and Wee1 overexpression, Cdk1F phosphorylation-defective mutant phenocopying\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple alleles, null mutants plus phenocopy experiments, functional pathway placement\",\n      \"pmids\": [\"27170181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Drosophila midgut, Myt1 depletion alters cell cycle kinetics and promotes ectopic mitoses of enteroblast progenitors at the expense of differentiation; these aberrant enteroblast mitoses rely on Cyclin A, implicating Myt1 inhibition of Cyclin A/Cdk1 as the mechanism coupling mitotic exit with enteroblast-to-enterocyte differentiation.\",\n      \"method\": \"myt1 null mutants, cell-specific RNAi, genetic epistasis with Cyclin A depletion, cell cycle and differentiation marker analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — null mutant plus RNAi plus epistasis, single lab but multiple genetic approaches\",\n      \"pmids\": [\"33207203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Myt1 overexpression confers resistance to inhibitors of Wee1 (adavosertib/PD166285), CHK1 (UCN-01), and ATR (AZD6738) by compensating for CDK1 inhibition; Myt1 overexpression reduces premature mitotic entry and decreases mitosis length, increasing survival in checkpoint-abrogated cells.\",\n      \"method\": \"Myt1 overexpression, kinase inhibitor treatment, mitotic entry assays (time-lapse), clonogenic survival assays\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional overexpression with multiple inhibitors and direct Cdk1 activity readout, single lab\",\n      \"pmids\": [\"38020882\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"MYT1 overexpression in cells downregulates retinoic acid receptor beta (RARB) expression, whereas OAVS-associated MYT1 mutants fail to do so, placing MYT1 in the retinoic acid signaling pathway and demonstrating loss-of-function consequences for OAVS-associated variants.\",\n      \"method\": \"MYT1 overexpression in cell culture, RARB expression analysis, comparison of wild-type vs. mutant MYT1, zebrafish morpholino knockdown of myt1a\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — cell-based functional assay plus zebrafish knockdown, two orthogonal model systems, single lab\",\n      \"pmids\": [\"27358179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYT1 overexpression downregulates all RA receptor genes (RARA, RARB, RARG) but not CYP26A1; a novel OAVS-associated MYT1 missense variant (p.Ser108Leu) impacts the expression of RA receptor genes, further supporting MYT1 function in the RA signaling pathway.\",\n      \"method\": \"MYT1 overexpression, wild-type vs. mutant comparison, RT-PCR quantification of RA pathway genes\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — cell-based functional assay comparing wild-type and mutant, single lab, single method\",\n      \"pmids\": [\"28612832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZTF-11 (C. elegans Myt1 homolog) functions together with the MuvB corepressor complex to suppress activation of non-neuronal genes in neurons; loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis; ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons.\",\n      \"method\": \"ztf-11 loss-of-function, ectopic expression, MuvB complex co-function analysis, single-cell resolution expression profiling\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function with defined molecular mechanism (MuvB co-repressor), single lab\",\n      \"pmids\": [\"31386623\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYT1 encodes two functionally distinct proteins sharing the gene locus: (1) a membrane-associated dual-specificity kinase (the cell-cycle MYT1/PKMYT1) that preferentially phosphorylates CDK1/Cdc2 on Thr14 and Tyr15 at the ER/Golgi to inhibit CDK1/cyclin B and prevent premature mitotic entry, is inactivated during M-phase through a two-step mechanism involving CDK1/XRINGO-mediated phosphorylation (facilitating p90Rsk docking) and subsequent p90Rsk-mediated C-terminal hyperphosphorylation (also regulated by Plk1/Plx1, Akt, SGK, MEK1, and JNK1), and is additionally required for Golgi/ER reassembly during mitotic exit; and (2) a C2HC zinc finger transcription factor (the neural MYT1) that represses non-neuronal and progenitor genes by recruiting HDAC-containing Sin3B and LSD1/CoREST complexes, counteracts Notch signaling to promote neuronal differentiation, and regulates YAP1 and RA receptor expression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"The MYT1 locus encodes two functionally distinct activities documented in this corpus: a membrane-associated cell-cycle kinase and a neural zinc-finger transcriptional repressor. As a kinase, MYT1 is a Wee1-family dual-specificity enzyme that preferentially phosphorylates CDK1/Cdc2 on Thr14 (and Tyr15) in a cyclin-dependent manner to inhibit Cdc2/cyclin B and restrain mitotic entry [#0, #1, #2]. It is anchored to the endoplasmic reticulum and Golgi through a C-terminal hydrophobic membrane-targeting domain, whose removal redirects the protein to the nucleus [#1]; a distinct C-terminal segment both binds Cdc2/cyclin B1 and supports cytoplasmic sequestration of the complex, so MYT1 enforces G2/M arrest by phosphorylation and by physical sequestration [#4, #5]. MYT1 is inactivated at M phase by a multi-kinase program: CDK1/XRINGO-mediated phosphorylation lowers activity and licenses p90Rsk docking, after which p90Rsk hyperphosphorylates the C-terminus and abolishes CDK1/cyclin B binding [#12, #16], with parallel inhibitory input from Plk1/Plx1 (via a Cdc2-created Thr478 docking site), Akt, SGK, and MEK1 [#8, #10, #6, #24, #17]. Beyond preventing premature mitosis, MYT1-mediated Cdc2 suppression is required for Golgi/ER reassembly during mitotic exit, contributes to DNA-damage checkpoint recovery, and is functionally redundant with Wee1 such that elevated MYT1 confers resistance to Wee1/CHK1/ATR inhibitors [#13, #18, #23, #31]. The neural MYT1 is a transcriptional repressor that recruits HDAC-containing Sin3B and LSD1/CoREST complexes to repress non-neuronal and progenitor genes, counteracts Notch signaling to drive neuronal differentiation, and represses YAP1 and retinoic-acid receptor genes [#11, #19, #20, #25, #22]. Loss-of-function MYT1 variants associated with oculo-auriculo-vertebral spectrum (OAVS) fail to downregulate RA receptor expression, linking MYT1 to this developmental disorder through the retinoic-acid signaling pathway [#32, #33].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Established the founding biochemical identity of MYT1: what enzyme provides Thr14-directed inhibition of Cdc2 was unknown, and this work identified a membrane-associated Wee1-family kinase as the predominant Thr14 kinase regulating the cell cycle.\",\n      \"evidence\": \"cDNA cloning, in vitro kinase assay, and immunodepletion of Xenopus egg extracts\",\n      \"pmids\": [\"7569953\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Membrane anchor and its targeting domain not yet mapped\", \"Human ortholog substrate preference not yet defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined the human enzyme's substrate selectivity and subcellular address, showing MYT1 is a dual-specificity kinase preferring Thr14 on Cdc2 and is tethered to the ER/Golgi by a C-terminal hydrophobic domain.\",\n      \"evidence\": \"cDNA cloning, in vitro kinase assays with site mapping, immunofluorescence, and deletion mutagenesis in HeLa cells\",\n      \"pmids\": [\"9001210\", \"9268380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of M-phase hyperphosphorylation/inactivation not defined\", \"Upstream regulatory kinases unidentified\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Resolved how MYT1 enforces arrest beyond catalysis, showing the C-terminal 63-residue domain binds Cdc2/cyclin B1 and that MYT1 blocks cyclin B1 nuclear shuttling and arrests cells independent of catalytic activity.\",\n      \"evidence\": \"Deletion mutagenesis, kinase-dead overexpression, cyclin B1 localization imaging, and cell cycle analysis in fission yeast and human cells\",\n      \"pmids\": [\"10504341\", \"10373560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological balance between catalytic vs sequestration roles unquantified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Began mapping the kinase network that switches MYT1 off at the G2/M transition, identifying MYT1 as a substrate of Akt and of Mos during oocyte/meiotic maturation.\",\n      \"evidence\": \"In vitro kinase assays, co-IP, and oocyte microinjection in starfish and Xenopus\",\n      \"pmids\": [\"11802161\", \"11959823\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mos result is a single-lab Co-IP plus in vivo phosphorylation without site mapping\", \"Direct vs indirect Akt action on MYT1 in somatic cells unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Distinguished context-specific inactivation pathways, showing p90Rsk down-regulates MYT1 in meiosis whereas a Cdc2-primed Thr478 docking site recruits Plx1 to inhibit MYT1 in the embryonic cell cycle.\",\n      \"evidence\": \"GST pulldown, reciprocal co-IP, in vitro kinase assays, Thr478 mutagenesis, and embryo microinjection (Xenopus)\",\n      \"pmids\": [\"9724639\", \"15692562\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each kinase to net MYT1 inactivation not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended the inhibitory kinase set and identified a positive regulator, establishing MYT1 as a Plk1 substrate at four consensus C-terminal sites and TSAP6 as a physical interactor that augments MYT1 activity.\",\n      \"evidence\": \"In vitro kinase assays with 4A mutant and mobility shifts; yeast two-hybrid, GST pulldown, and co-IP for TSAP6\",\n      \"pmids\": [\"12738781\", \"12606722\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"TSAP6 mechanism of activation undefined and Medium-confidence\", \"In vivo consequence of Plk1 sites on mitotic timing not isolated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified an intramolecular priming event, showing MYT1 autophosphorylation on Ser66 is a prerequisite/trigger for subsequent inhibitory phosphorylation during the meiotic G2/M transition.\",\n      \"evidence\": \"MALDI mass spectrometry site identification and S66A/S76A mutagenesis with oocyte cell-cycle timing\",\n      \"pmids\": [\"16481744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; autophosphorylation kinetics in somatic mitosis untested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Delineated the ordered two-step inactivation and a non-cell-cycle organelle role, showing CDK/XRINGO phosphorylates three regulatory serines distinct from CDK/cyclin sites, and that MYT1 is required for Golgi/ER reassembly at mitotic exit via cyclin B targeting.\",\n      \"evidence\": \"In vitro kinase assays with site mapping and mutagenesis (Xenopus); siRNA knockdown with Golgi/ER imaging and cyclin B1/B2 epistasis (mammalian cells)\",\n      \"pmids\": [\"18951089\", \"18378775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How membrane-tethered MYT1 locally couples Cdc2 suppression to organelle dynamics not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Opened the transcription-factor branch of MYT1 biology, showing MYT1 binds Sin3B and recruits HDAC1/HDAC2 to repress a heterologous promoter.\",\n      \"evidence\": \"Yeast and mammalian two-hybrid, co-IP, and reporter assays\",\n      \"pmids\": [\"15935060\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous target genes of the MYT1-Sin3B-HDAC complex not yet identified\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked MYT1 to stress-induced apoptosis, showing JNK1 (not JNK2) binds and phosphorylates MYT1 and that MYT1 is required for UVA-induced caspase-3 cleavage and DNA fragmentation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assays, JNK1/JNK2 knockout fibroblasts, MYT1 siRNA, and apoptosis readouts\",\n      \"pmids\": [\"19204086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between MYT1 phosphorylation and apoptotic execution undefined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that compartmentalization is functionally essential and refined the meiotic two-step model, showing cytoplasmic MYT1 must be down-regulated for meiotic resumption and that CDK1/XRINGO priming both reduces activity and recruits p90Rsk, which then abolishes CDK1/cyclin B binding.\",\n      \"evidence\": \"siRNA and forced-mislocalization in mouse oocytes; site mapping, mutagenesis, co-IP, and microinjection in Xenopus\",\n      \"pmids\": [\"20083600\", \"20362450\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How localization is dynamically controlled in somatic mitosis not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected MYT1 to additional mitotic-entry inputs and the DNA-damage response, showing MEK1-dependent phosphorylation inactivates MYT1 to permit Golgi fragmentation/mitotic entry and that MYT1 contributes specifically to checkpoint recovery by raising the CDK1 activation threshold.\",\n      \"evidence\": \"siRNA epistasis with MEK1 inhibition and permeabilized-cell Golgi assays; time-lapse with CHK1/WEE1 inhibitors and xenografts\",\n      \"pmids\": [\"23241949\", \"23146904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The MEK1-dependent intermediary kinase (independent of RSK/Plk/CDK1) unidentified\", \"MYT1 dispensable for checkpoint activation/normal cycling — role bounded to recovery\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the neural epigenetic repressor mechanism, showing MYT1 is a stable subunit of a neural LSD1 complex that directly represses Pten and supports neuroblastoma proliferation.\",\n      \"evidence\": \"Biochemical purification, co-IP, ChIP, microarray, and siRNA proliferation assays in Neuro2a cells\",\n      \"pmids\": [\"24828497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and recruitment determinants of MYT1 within the LSD1 complex not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed MYT1 in neuronal differentiation and developmental disease, showing genome-wide MYT1 binding represses Notch pathway genes to drive neurogenesis and that OAVS-associated variants fail to repress RA receptor expression.\",\n      \"evidence\": \"ChIP-seq, overexpression/knockdown with Notch epistasis; MYT1 wild-type vs OAVS-mutant RARB assays and zebrafish myt1a knockdown\",\n      \"pmids\": [\"27705795\", \"27358179\", \"27170181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect repression of individual Notch/RA targets not all resolved\", \"Drosophila spermatocyte data implicate Cyclin A/Cdk1 rather than the transcription-factor role — two activities not unified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified anti-proliferative transcriptional targets in glioblastoma, showing DNA-targeted MYT1 represses transcription and that MYT1/MYT1L directly repress YAP1, whose forced expression rescues proliferation.\",\n      \"evidence\": \"Reporter assays, genome-wide RNA-seq, YAP1 rescue, and orthotopic xenografts in GBM cells\",\n      \"pmids\": [\"29291346\", \"30312684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab functional epistasis; direct MYT1 occupancy at the YAP1 locus not shown\", \"Distinction of MYT1 vs MYT1L contributions incomplete\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Strengthened the MYT1-retinoic-acid link in OAVS, showing MYT1 overexpression downregulates RARA/RARB/RARG and a novel OAVS missense variant perturbs this regulation.\",\n      \"evidence\": \"Overexpression with wild-type vs mutant comparison and RT-PCR of RA pathway genes\",\n      \"pmids\": [\"28612832\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method, single lab; whether RAR repression is direct unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established therapeutic relevance and redundancy, showing MYT1 and Wee1 redundantly inhibit Cdk1/cyclin B and that elevated MYT1 confers Wee1-inhibitor resistance reversible by MYT1 knockdown; SGK was added as another inhibitory upstream kinase.\",\n      \"evidence\": \"MYT1 overexpression/knockdown with Cdk1 activity and adavosertib sensitivity assays; in vitro kinase and starfish oocyte assays for SGK\",\n      \"pmids\": [\"31594837\", \"31537708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic basis of redundancy (shared vs distinct CDK1 pools) not defined\", \"SGK data single-lab oocyte system\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended the neural repressor mechanism across species, showing the C. elegans homolog ZTF-11 acts with the MuvB corepressor to suppress non-neuronal genes and is sufficient to drive ectopic neurogenesis.\",\n      \"evidence\": \"Loss- and gain-of-function with MuvB co-function analysis and single-cell expression profiling in C. elegans\",\n      \"pmids\": [\"31386623\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of MuvB partnership in mammalian MYT1 untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Broadened tissue contexts for both MYT1 activities, linking the transcription factor to LSD1/CoREST-dependent neuroblastoma differentiation, NSC aging via SMAD-driven activation, and the kinase to Drosophila enteroblast differentiation through Cyclin A/Cdk1 inhibition.\",\n      \"evidence\": \"Co-IP and LSD1-inhibitor epistasis (neuroblastoma); shRNA and pathway dissection (NSC); null mutants/RNAi with Cyclin A epistasis (Drosophila midgut)\",\n      \"pmids\": [\"32251364\", \"33038325\", \"33207203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each context is single-lab\", \"How a single locus partitions kinase vs transcription-factor functions across cell types unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Refined the inactivation map to the N-terminus, showing the PAYF motif and CDK1 sites Thr11/Thr16 contribute to MYT1 inactivation during M phase alongside C-terminal regulation.\",\n      \"evidence\": \"Site-directed mutagenesis and in vivo phosphorylation analysis in Xenopus oocytes\",\n      \"pmids\": [\"34695617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab/study\", \"Relative weight of N- vs C-terminal regulation not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Consolidated MYT1 as a multi-checkpoint resistance node, showing MYT1 overexpression compensates for CDK1 inhibition to confer resistance to Wee1, CHK1, and ATR inhibitors.\",\n      \"evidence\": \"Overexpression with multiple kinase inhibitors, time-lapse mitotic-entry assays, and clonogenic survival\",\n      \"pmids\": [\"38020882\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; clinical predictive value untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how a single MYT1 locus produces and partitions two biochemically unrelated activities — a membrane-tethered CDK1-inhibitory kinase and a nuclear zinc-finger repressor — across cell types, and whether these activities ever co-regulate one another in the same cell.\",\n      \"evidence\": \"No discovery in the timeline reconciles the kinase and transcription-factor functions mechanistically\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No isoform-resolved expression map linking kinase vs TF outputs\", \"No structural model of either MYT1 activity in the corpus\", \"Direct MYT1 occupancy at most reported target loci not demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2, 8, 10, 12, 16]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 8]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [11, 19, 20, 21, 25]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1, 13]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 13, 17]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 19, 20]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 5, 15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 2, 5, 13, 18, 23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 19, 20, 22, 25]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [11, 19, 25]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [20, 32, 33, 34]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [15, 16, 27, 29]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [\n      \"LSD1/CoREST complex\",\n      \"Sin3B-HDAC1/HDAC2 complex\"\n    ],\n    \"partners\": [\n      \"CDK1\",\n      \"CCNB1\",\n      \"RPS6KA (p90Rsk)\",\n      \"PLK1\",\n      \"TSAP6\",\n      \"MAPK8 (JNK1)\",\n      \"SIN3B\",\n      \"KDM1A (LSD1)\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}