{"gene":"LCMT1","run_date":"2026-06-10T02:59:49","timeline":{"discoveries":[{"year":2011,"finding":"Crystal structures of human LCMT-1 alone and in complex with PP2A (stabilized by a cofactor mimic) revealed that the LCMT-1 active-site pocket directly recognizes the carboxyl terminus of PP2A, and that the PP2A active site makes extensive contacts to LCMT-1. Activation of the PP2A active site was shown to stimulate methylation, suggesting a mechanism for efficient conversion of activated PP2A into substrate-specific holoenzymes. A dominant-negative LCMT-1 mutant attenuated the cell cycle without causing cell death.","method":"X-ray crystallography of LCMT-1 alone and in complex with PP2A; in vitro methylation assays; dominant-negative mutant cell cycle assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures with functional validation by in vitro assay and mutagenesis in a single rigorous study","pmids":["21292165"],"is_preprint":false},{"year":2016,"finding":"LCMT-1 is the major carboxyl methyltransferase not only for PP2A but also for PP4 and PP6 catalytic subunits in mouse embryonic fibroblasts (MEFs). LCMT-1 loss differentially disrupts PP4 holoenzyme complexes (PP4R1-containing complex most dramatically affected), reduces steady-state levels of PP2A B and PP4R1 regulatory subunits, and causes hyperphosphorylation of HDAC3, a target of the methylation-dependent PP4R1-PP4 complex.","method":"Antibodies specific for unmethylated phosphatases; blue native PAGE analysis of holoenzyme complexes; LCMT-1 knockout MEFs; immunoblotting for HDAC3 phosphorylation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (BN-PAGE, methylation-specific antibodies, genetic KO MEFs, phospho-substrate readout) in a single focused study","pmids":["27507813"],"is_preprint":false},{"year":2010,"finding":"Enhanced LCMT1 expression in N2a neuroblastoma cells increases methylated PP2A C subunit and PP2A/Bα levels, induces F-actin reorganization, and promotes serum-independent neuritogenesis and tau-positive process formation. These effects are blocked by LCMT1 knockdown, the methylation inhibitor SAH, expression of PME-1, or a methylation-incompetent PP2A mutant (L309Δ), and by Bα knockdown, establishing a LCMT1→PP2A methylation→Bα holoenzyme→neurite outgrowth pathway.","method":"LCMT1 overexpression and siRNA knockdown; inducible Bα knockdown; methylation-incompetent PP2A mutant; pharmacological inhibition with SAH; F-actin staining; neurite morphometry","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and pharmacological manipulations in a single study establishing epistatic pathway","pmids":["21044074"],"is_preprint":false},{"year":2013,"finding":"LCMT1-dependent methylation of PP2A controls the association of methylated PP2A and Bα holoenzymes with cholesterol-rich plasma membrane rafts in N2a cells. A methylation-incompetent PP2A mutant is excluded from rafts. Knockdown or catalytic inactivation of LCMT1, or perturbation of one-carbon metabolism, causes loss of membrane-associated PP2A and Tau and accumulation of soluble phosphorylated Tau.","method":"Subcellular fractionation of membrane microdomains/rafts; catalytically inactive LCMT1 mutant; LCMT1 siRNA knockdown; one-carbon metabolism perturbation; immunoblotting for methylated/phosphorylated PP2A and Tau","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct fractionation experiments with multiple genetic and pharmacological perturbations establishing localization-function link","pmids":["23943618"],"is_preprint":false},{"year":2013,"finding":"Hypomorphic Lcmt1 gene-trap mice with reduced LCMT1 protein and activity showed proportionally reduced PP2A carboxyl methylation, indicating LCMT1 is the sole PP2A methyltransferase in mammalian tissues. These mice exhibit an insulin-resistance phenotype, linking LCMT1-dependent PP2A methylation to insulin signaling in vivo.","method":"Gene-trap mouse model; LCMT1 activity assays; PP2A methylation quantification; insulin tolerance and glucose homeostasis assays in vivo","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model with direct enzymatic activity measurements and physiological phenotype readout","pmids":["23840384"],"is_preprint":false},{"year":2015,"finding":"The LCMT1–PME-1 methylation equilibrium controls mitotic spindle size. Depletion of LCMT1 produced long spindles; overexpression of LCMT1 produced short spindles. Disruption of this equilibrium caused mitotic arrest, spindle assembly checkpoint activation, defective cell divisions, and apoptosis.","method":"siRNA depletion of LCMT1; LCMT1 overexpression; PME-1 depletion and overexpression; spindle size measurements; spindle assembly checkpoint markers; cell viability assays","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined spindle phenotype, single lab, no in vitro reconstitution","pmids":["25839665"],"is_preprint":false},{"year":2012,"finding":"GSK-3β inhibits LCMT1 (PPMT1) activity, resulting in increased demethylation of PP2A at Leu-309. Knockdown of PPMT1 eliminated the effects of GSK-3β on PP2A demethylation, placing LCMT1 downstream of GSK-3β in a pathway that controls PP2A methylation status and PP2A regulatory subunit levels.","method":"GSK-3β overexpression/inhibition; PPMT1 siRNA knockdown; immunoblotting for dmL309-PP2Ac; PP2A regulatory subunit quantification","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic epistasis by knockdown with specific phosphorylation readout, single lab, no direct biochemical reconstitution of the GSK-3β–LCMT1 relationship","pmids":["22732552"],"is_preprint":false},{"year":2023,"finding":"LCMT1 methylates the L309 residue of the PP2A C subunit, and this methylation enables formation of AB56αC heterotrimers that dephosphorylate the androgen receptor (AR) and its coactivator MED1, causing eviction of the AR-MED1 complex from chromatin. LCMT1 is degraded via S6K1-mediated phosphorylation-induced proteasomal degradation requiring β-TRCP, and this degradation drives resistance to anti-androgens. Small-molecule SMAP stabilizes LCMT1 and attenuates AR signaling.","method":"LCMT1 silencing; Co-IP/interaction assays for PP2A heterotrimers; dephosphorylation assays for AR and MED1; chromatin immunoprecipitation; S6K1 overexpression/inhibition; β-TRCP interaction; SMAP treatment; in vivo tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, dephosphorylation assay, ChIP, degradation pathway dissection) establishing mechanism in a single focused study with in vivo validation","pmids":["37644036"],"is_preprint":false},{"year":2022,"finding":"HIF-1α, induced by chronic hypoxia, decreases LCMT1 protein levels by promoting LCMT1 degradation via the autophagy–lysosomal pathway, thereby reducing PP2A methylation and activity and leading to tau hyperphosphorylation. Dual luciferase assay showed HIF-1α also acts as a transcription factor at the LCMT1 promoter, but the net effect of HIF-1α is LCMT1 protein reduction.","method":"HIF-1α overexpression and siRNA silencing in neurons and rats; dual luciferase reporter assay for LCMT1 promoter; autophagy–lysosomal inhibitor experiments; LCMT1 and PP2A activity measurements; tau phosphorylation immunoblotting","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assay plus in vivo genetic silencing with mechanistic readouts, single lab","pmids":["36555780"],"is_preprint":false},{"year":2023,"finding":"Liver-specific LCMT1 knockout increases hepatic glycogen synthesis and accumulation, reverses high-fat diet-induced downregulation of glucokinase (GCK) and glycogen synthesis genes, and improves glucose intolerance and insulin resistance, establishing that hepatic LCMT1-mediated PP2A methylation negatively regulates glycogen metabolism and glucose homeostasis.","method":"Liver-specific LCMT1 knockout mouse model; glycogen content assays; GCK and glycogen synthesis gene expression; glucose and insulin tolerance tests; siRNA in MIHA cells","journal":"The Journal of nutritional biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with metabolic phenotyping and gene expression, single lab","pmids":["36963730"],"is_preprint":false},{"year":2023,"finding":"LCMT1-mediated PP2Ac methylation regulates autophagy; liver-specific LCMT1 knockout in mice and BaP-treated primary hepatocytes showed that loss of LCMT1 activity reduces PP2Ac methylation and inhibits autophagy, leading to hepatic lipid accumulation.","method":"Liver-specific LCMT1 KO mouse model; primary hepatocyte treatment with BaP; autophagy flux assays; PP2Ac methylation immunoblotting; lipid staining","journal":"Food and chemical toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO model with direct mechanistic readouts (autophagy flux, PP2Ac methylation), single lab","pmids":["37579989"],"is_preprint":false},{"year":2020,"finding":"Reducing endogenous LCMT-1 expression (heterozygous gene-trap mice) increased sensitivity to Aβ-induced cognitive and synaptic plasticity impairments, while reducing PME-1 expression was protective, establishing that the LCMT1–PME-1 balance in PP2A methylation modulates neuronal sensitivity to Aβ.","method":"Heterozygous LCMT-1 gene-trap mice; heterozygous PME-1 KO mice; behavioral cognition assays; electrophysiological LTP recordings; acute Aβ oligomer application","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic models with behavioral and electrophysiological readouts, single lab","pmids":["32341098"],"is_preprint":false}],"current_model":"LCMT1 is a PP2A-specific (and broader PP2A-subfamily: PP4, PP6) leucine carboxyl methyltransferase that catalyzes carboxyl methylation of the conserved C-terminal leucine of the phosphatase catalytic subunit; structural studies show its active-site pocket engages the PP2A C-terminus while the PP2A active site reciprocally stimulates methylation, creating a feed-forward mechanism that converts activated PP2A into substrate-directed holoenzymes by promoting binding of B-type regulatory subunits (Bα, B56α, PP4R1); this methylation is antagonized by PME-1, and their balance controls mitotic spindle size, neurite outgrowth, tau and AR dephosphorylation, glycogen metabolism, and autophagy; LCMT1 protein levels are regulated by HIF-1α-driven autophagic degradation and by S6K1/β-TRCP-mediated proteasomal degradation."},"narrative":{"mechanistic_narrative":"LCMT1 is the principal leucine carboxyl methyltransferase that activates the PP2A subfamily of protein phosphatases by methylating the conserved C-terminal leucine (Leu-309) of their catalytic subunits, thereby directing assembly of substrate-specific holoenzymes [PMID:21292165, PMID:23840384]. Crystal structures of LCMT1 alone and bound to PP2A show that its active-site pocket engages the PP2A C-terminus while the activated PP2A active site reciprocally stimulates methylation, defining a feed-forward mechanism that converts catalytically active PP2A into B-subunit-containing holoenzymes [PMID:21292165]. Beyond PP2A, LCMT1 is the major carboxyl methyltransferase for the PP4 and PP6 catalytic subunits, and its loss selectively disrupts regulatory-subunit assembly (most dramatically the PP4R1-PP4 complex) and reduces steady-state levels of B-type and PP4R1 regulatory subunits, with downstream hyperphosphorylation of substrates such as HDAC3 [PMID:27507813]. Methylation-dependent recruitment of specific B subunits channels PP2A toward defined outputs: a LCMT1→methyl-PP2A→Bα axis drives F-actin reorganization and neurite outgrowth and partitions PP2A and Tau into cholesterol-rich membrane rafts, with loss of LCMT1 producing soluble hyperphosphorylated Tau [PMID:21044074, PMID:23943618], while AB56αC heterotrimers dephosphorylate the androgen receptor and its coactivator MED1 to evict the complex from chromatin [PMID:37644036]. The opposing actions of LCMT1 and the demethylase PME-1 establish a methylation equilibrium that governs mitotic spindle size and checkpoint fidelity and modulates neuronal sensitivity to amyloid-β [PMID:25839665, PMID:32341098]. In vivo, LCMT1-mediated PP2A methylation controls insulin signaling, hepatic glycogen and lipid metabolism through autophagy, and glucose homeostasis [PMID:23840384, PMID:36963730, PMID:37579989]. LCMT1 abundance is itself regulated post-translationally by HIF-1α-driven autophagic-lysosomal degradation and by S6K1/β-TRCP-mediated proteasomal degradation, the latter coupling LCMT1 loss to anti-androgen resistance [PMID:37644036, PMID:36555780].","teleology":[{"year":2010,"claim":"Established that LCMT1 acts upstream of a defined PP2A holoenzyme to drive a cellular morphogenetic output, rather than being a generic housekeeping methyltransferase.","evidence":"LCMT1 overexpression/knockdown, methylation-incompetent PP2A mutant, Bα knockdown, and SAH/PME-1 perturbation in N2a neuroblastoma with neurite morphometry","pmids":["21044074"],"confidence":"High","gaps":["Did not resolve which downstream cytoskeletal substrates the Bα holoenzyme acts on","Limited to a single neuroblastoma cell context"]},{"year":2011,"claim":"Resolved the structural basis for how LCMT1 recognizes PP2A and why methylation is coupled to phosphatase activation, explaining efficient conversion of active PP2A into substrate-specific holoenzymes.","evidence":"X-ray crystallography of LCMT1 alone and in complex with PP2A, in vitro methylation assays, and a dominant-negative cell-cycle mutant","pmids":["21292165"],"confidence":"High","gaps":["Did not define how methylation selects among different B-subunit families","Cell-cycle role inferred from a dominant-negative without substrate-level detail"]},{"year":2012,"claim":"Placed LCMT1 within a signaling cascade by showing GSK-3β represses its activity to shift PP2A toward the demethylated state.","evidence":"GSK-3β overexpression/inhibition with PPMT1 (LCMT1) knockdown and dmL309-PP2Ac immunoblotting","pmids":["22732552"],"confidence":"Medium","gaps":["No direct biochemical reconstitution of GSK-3β acting on LCMT1","Mechanism of inhibition (direct phosphorylation vs indirect) not established"]},{"year":2013,"claim":"Demonstrated that LCMT1-dependent methylation determines PP2A subcellular targeting, linking methylation to membrane raft localization and Tau dephosphorylation.","evidence":"Membrane microdomain fractionation, catalytically inactive LCMT1, siRNA, and one-carbon metabolism perturbation in N2a cells","pmids":["23943618"],"confidence":"High","gaps":["The molecular determinant coupling methylation to raft partitioning is unresolved","Restricted to one cell line"]},{"year":2013,"claim":"Confirmed in vivo that LCMT1 is the sole PP2A methyltransferase in mammalian tissue and connected its activity to systemic insulin signaling.","evidence":"Hypomorphic Lcmt1 gene-trap mice with activity assays, PP2A methylation quantification, and insulin/glucose homeostasis tests","pmids":["23840384"],"confidence":"High","gaps":["Tissue and substrate mediating the insulin-resistance phenotype not pinpointed","Hypomorphic, not null, model"]},{"year":2015,"claim":"Showed the LCMT1-PME-1 methylation equilibrium quantitatively tunes mitotic spindle size and checkpoint integrity.","evidence":"Reciprocal LCMT1/PME-1 gain- and loss-of-function with spindle measurements, SAC markers, and viability assays","pmids":["25839665"],"confidence":"Medium","gaps":["No in vitro reconstitution of the spindle-size mechanism","Single lab; downstream PP2A holoenzyme on the spindle not identified"]},{"year":2016,"claim":"Broadened LCMT1's enzymatic scope to PP4 and PP6 and showed methylation selectively governs which regulatory-subunit complexes assemble.","evidence":"Methylation-specific antibodies, blue native PAGE of holoenzymes, LCMT1 knockout MEFs, and HDAC3 phospho-readout","pmids":["27507813"],"confidence":"High","gaps":["Why PP4R1-PP4 is most methylation-sensitive is not mechanistically explained","Full substrate repertoire of PP4/PP6 methylation unmapped"]},{"year":2020,"claim":"Established that the LCMT1-PME-1 methylation balance sets neuronal vulnerability to amyloid-β, linking the axis to Alzheimer-relevant pathophysiology.","evidence":"Heterozygous LCMT1 gene-trap and PME-1 KO mice with cognitive behavior, LTP electrophysiology, and acute Aβ oligomer application","pmids":["32341098"],"confidence":"Medium","gaps":["Did not identify the PP2A substrate responsible for Aβ sensitivity","Correlative genetic dosage rather than direct mechanism"]},{"year":2022,"claim":"Identified HIF-1α-driven autophagic-lysosomal degradation as a hypoxia-responsive route controlling LCMT1 protein levels and downstream Tau phosphorylation.","evidence":"HIF-1α overexpression/silencing in neurons and rats, LCMT1 promoter luciferase reporter, autophagy-lysosomal inhibitors, and PP2A activity/Tau readouts","pmids":["36555780"],"confidence":"Medium","gaps":["Relative contribution of transcriptional vs degradative regulation not quantified","Autophagy receptor mediating LCMT1 turnover unknown"]},{"year":2023,"claim":"Defined a methylation-dependent AB56αC holoenzyme that dephosphorylates AR/MED1 and an S6K1/β-TRCP degradation pathway whose disruption confers anti-androgen resistance, establishing LCMT1 as a tractable target in prostate cancer.","evidence":"LCMT1 silencing, Co-IP of PP2A heterotrimers, AR/MED1 dephosphorylation and ChIP assays, S6K1/β-TRCP degradation dissection, SMAP stabilization, and in vivo tumor models","pmids":["37644036"],"confidence":"High","gaps":["Whether SMAP-mediated LCMT1 stabilization is durable in vivo not fully resolved","Generality across other AR-dependent contexts untested"]},{"year":2023,"claim":"Demonstrated tissue-specific roles for hepatic LCMT1 in negatively regulating glycogen metabolism and in supporting autophagy to limit lipid accumulation.","evidence":"Liver-specific LCMT1 knockout mice with glycogen, GCK/glycogen-gene expression, glucose/insulin tolerance, autophagy flux, lipid staining, and MIHA/hepatocyte models","pmids":["36963730","37579989"],"confidence":"Medium","gaps":["The specific PP2A holoenzyme and substrate controlling glycogen/autophagy outputs not identified","Reconciliation with whole-body insulin-resistance phenotype not addressed"]},{"year":null,"claim":"How methylation status is decoded to select among distinct B-subunit families to produce tissue- and substrate-specific PP2A/PP4/PP6 outputs remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of methyl-PP2A bound to competing B subunits","Substrate-level mediators of metabolic, mitotic, and neuronal phenotypes largely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,7]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[10]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[7]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[7,8]}],"complexes":[],"partners":["PPP2CA","PME-1","PP4R1","B56Α","GSK-3Β","S6K1","Β-TRCP","HIF-1Α"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UIC8","full_name":"Leucine carboxyl methyltransferase 1","aliases":["Protein-leucine O-methyltransferase","[Phosphatase 2A protein]-leucine-carboxy methyltransferase 1"],"length_aa":334,"mass_kda":38.4,"function":"Methylates the carboxyl group of the C-terminal leucine residue of protein phosphatase 2A catalytic subunits to form alpha-leucine ester residues","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9UIC8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LCMT1","classification":"Not Classified","n_dependent_lines":419,"n_total_lines":1208,"dependency_fraction":0.3468543046357616},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LCMT1","total_profiled":1310},"omim":[{"mim_id":"610286","title":"LEUCINE CARBOXYL METHYLTRANSFERASE 1; LCMT1","url":"https://www.omim.org/entry/610286"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LCMT1"},"hgnc":{"alias_symbol":["CGI-68","PPMT1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UIC8","domains":[{"cath_id":"3.40.50.150","chopping":"39-330","consensus_level":"high","plddt":97.179,"start":39,"end":330}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIC8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIC8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UIC8-F1-predicted_aligned_error_v6.png","plddt_mean":93.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LCMT1","jax_strain_url":"https://www.jax.org/strain/search?query=LCMT1"},"sequence":{"accession":"Q9UIC8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UIC8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UIC8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UIC8"}},"corpus_meta":[{"pmid":"21292165","id":"PMC_21292165","title":"The structural basis for tight control of PP2A methylation and function by LCMT-1.","date":"2011","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/21292165","citation_count":123,"is_preprint":false},{"pmid":"21044074","id":"PMC_21044074","title":"Regulation of protein phosphatase 2A methylation by LCMT1 and PME-1 plays a critical role in differentiation of neuroblastoma cells.","date":"2010","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21044074","citation_count":45,"is_preprint":false},{"pmid":"27507813","id":"PMC_27507813","title":"Leucine Carboxyl Methyltransferase 1 (LCMT-1) Methylates Protein Phosphatase 4 (PP4) and Protein Phosphatase 6 (PP6) and Differentially Regulates the Stable Formation of Different PP4 Holoenzymes.","date":"2016","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27507813","citation_count":43,"is_preprint":false},{"pmid":"23943618","id":"PMC_23943618","title":"Leucine carboxyl methyltransferase 1 (LCMT1)-dependent methylation regulates the association of protein phosphatase 2A and Tau protein with plasma membrane microdomains in neuroblastoma cells.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23943618","citation_count":42,"is_preprint":false},{"pmid":"29281045","id":"PMC_29281045","title":"Protein Phosphatase 2A and Its Methylation Modulating Enzymes LCMT-1 and PME-1 Are Dysregulated in Tauopathies of Progressive Supranuclear Palsy and Alzheimer Disease.","date":"2018","source":"Journal of neuropathology and experimental neurology","url":"https://pubmed.ncbi.nlm.nih.gov/29281045","citation_count":40,"is_preprint":false},{"pmid":"22732552","id":"PMC_22732552","title":"Glycogen synthase kinase-3β regulates leucine-309 demethylation of protein phosphatase-2A via PPMT1 and PME-1.","date":"2012","source":"FEBS 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for the British Industrial Biological Research Association","url":"https://pubmed.ncbi.nlm.nih.gov/37579989","citation_count":14,"is_preprint":false},{"pmid":"25839665","id":"PMC_25839665","title":"A LCMT1-PME-1 methylation equilibrium controls mitotic spindle size.","date":"2015","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/25839665","citation_count":12,"is_preprint":false},{"pmid":"31037485","id":"PMC_31037485","title":"Functional characterization of metallothionein-like genes from Physcomitrella patens: expression profiling, yeast heterologous expression, and disruption of PpMT1.2a gene.","date":"2019","source":"Planta","url":"https://pubmed.ncbi.nlm.nih.gov/31037485","citation_count":12,"is_preprint":false},{"pmid":"23840384","id":"PMC_23840384","title":"Circumventing embryonic lethality with Lcmt1 deficiency: generation of hypomorphic Lcmt1 mice with reduced protein phosphatase 2A methyltransferase expression and defects in insulin signaling.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23840384","citation_count":12,"is_preprint":false},{"pmid":"30898057","id":"PMC_30898057","title":"Proteomics and phosphoproteomics study of LCMT1 overexpression and oxidative stress: overexpression of LCMT1 arrests H2O2-induced lose of cells viability.","date":"2019","source":"Redox report : communications in free radical research","url":"https://pubmed.ncbi.nlm.nih.gov/30898057","citation_count":6,"is_preprint":false},{"pmid":"32341098","id":"PMC_32341098","title":"Reduced Expression of the PP2A Methylesterase, PME-1, or the PP2A Methyltransferase, LCMT-1, Alters Sensitivity to Beta-Amyloid-Induced Cognitive and Electrophysiological Impairments in Mice.","date":"2020","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32341098","citation_count":5,"is_preprint":false},{"pmid":"36963730","id":"PMC_36963730","title":"Hepatic leucine carboxyl methyltransferase 1 (LCMT1) contributes to high fat diet-induced glucose intolerance through regulation of glycogen metabolism.","date":"2023","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/36963730","citation_count":3,"is_preprint":false},{"pmid":"41388803","id":"PMC_41388803","title":"PP2A methylesterase, PME-1, and PP2A methyltransferase, LCMT-1, control sensitivity to impairments caused by injury-related oligomeric tau.","date":"2025","source":"Alzheimer's & dementia : the journal of the Alzheimer's Association","url":"https://pubmed.ncbi.nlm.nih.gov/41388803","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":10689,"output_tokens":3508,"usd":0.042343,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":11294,"output_tokens":4310,"usd":0.08211,"stage2_stop_reason":"end_turn"},"total_usd":0.124453,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structures of human LCMT-1 alone and in complex with PP2A (stabilized by a cofactor mimic) revealed that the LCMT-1 active-site pocket directly recognizes the carboxyl terminus of PP2A, and that the PP2A active site makes extensive contacts to LCMT-1. Activation of the PP2A active site was shown to stimulate methylation, suggesting a mechanism for efficient conversion of activated PP2A into substrate-specific holoenzymes. A dominant-negative LCMT-1 mutant attenuated the cell cycle without causing cell death.\",\n      \"method\": \"X-ray crystallography of LCMT-1 alone and in complex with PP2A; in vitro methylation assays; dominant-negative mutant cell cycle assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures with functional validation by in vitro assay and mutagenesis in a single rigorous study\",\n      \"pmids\": [\"21292165\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LCMT-1 is the major carboxyl methyltransferase not only for PP2A but also for PP4 and PP6 catalytic subunits in mouse embryonic fibroblasts (MEFs). LCMT-1 loss differentially disrupts PP4 holoenzyme complexes (PP4R1-containing complex most dramatically affected), reduces steady-state levels of PP2A B and PP4R1 regulatory subunits, and causes hyperphosphorylation of HDAC3, a target of the methylation-dependent PP4R1-PP4 complex.\",\n      \"method\": \"Antibodies specific for unmethylated phosphatases; blue native PAGE analysis of holoenzyme complexes; LCMT-1 knockout MEFs; immunoblotting for HDAC3 phosphorylation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (BN-PAGE, methylation-specific antibodies, genetic KO MEFs, phospho-substrate readout) in a single focused study\",\n      \"pmids\": [\"27507813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Enhanced LCMT1 expression in N2a neuroblastoma cells increases methylated PP2A C subunit and PP2A/Bα levels, induces F-actin reorganization, and promotes serum-independent neuritogenesis and tau-positive process formation. These effects are blocked by LCMT1 knockdown, the methylation inhibitor SAH, expression of PME-1, or a methylation-incompetent PP2A mutant (L309Δ), and by Bα knockdown, establishing a LCMT1→PP2A methylation→Bα holoenzyme→neurite outgrowth pathway.\",\n      \"method\": \"LCMT1 overexpression and siRNA knockdown; inducible Bα knockdown; methylation-incompetent PP2A mutant; pharmacological inhibition with SAH; F-actin staining; neurite morphometry\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and pharmacological manipulations in a single study establishing epistatic pathway\",\n      \"pmids\": [\"21044074\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LCMT1-dependent methylation of PP2A controls the association of methylated PP2A and Bα holoenzymes with cholesterol-rich plasma membrane rafts in N2a cells. A methylation-incompetent PP2A mutant is excluded from rafts. Knockdown or catalytic inactivation of LCMT1, or perturbation of one-carbon metabolism, causes loss of membrane-associated PP2A and Tau and accumulation of soluble phosphorylated Tau.\",\n      \"method\": \"Subcellular fractionation of membrane microdomains/rafts; catalytically inactive LCMT1 mutant; LCMT1 siRNA knockdown; one-carbon metabolism perturbation; immunoblotting for methylated/phosphorylated PP2A and Tau\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct fractionation experiments with multiple genetic and pharmacological perturbations establishing localization-function link\",\n      \"pmids\": [\"23943618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Hypomorphic Lcmt1 gene-trap mice with reduced LCMT1 protein and activity showed proportionally reduced PP2A carboxyl methylation, indicating LCMT1 is the sole PP2A methyltransferase in mammalian tissues. These mice exhibit an insulin-resistance phenotype, linking LCMT1-dependent PP2A methylation to insulin signaling in vivo.\",\n      \"method\": \"Gene-trap mouse model; LCMT1 activity assays; PP2A methylation quantification; insulin tolerance and glucose homeostasis assays in vivo\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model with direct enzymatic activity measurements and physiological phenotype readout\",\n      \"pmids\": [\"23840384\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The LCMT1–PME-1 methylation equilibrium controls mitotic spindle size. Depletion of LCMT1 produced long spindles; overexpression of LCMT1 produced short spindles. Disruption of this equilibrium caused mitotic arrest, spindle assembly checkpoint activation, defective cell divisions, and apoptosis.\",\n      \"method\": \"siRNA depletion of LCMT1; LCMT1 overexpression; PME-1 depletion and overexpression; spindle size measurements; spindle assembly checkpoint markers; cell viability assays\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain/loss-of-function with defined spindle phenotype, single lab, no in vitro reconstitution\",\n      \"pmids\": [\"25839665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"GSK-3β inhibits LCMT1 (PPMT1) activity, resulting in increased demethylation of PP2A at Leu-309. Knockdown of PPMT1 eliminated the effects of GSK-3β on PP2A demethylation, placing LCMT1 downstream of GSK-3β in a pathway that controls PP2A methylation status and PP2A regulatory subunit levels.\",\n      \"method\": \"GSK-3β overexpression/inhibition; PPMT1 siRNA knockdown; immunoblotting for dmL309-PP2Ac; PP2A regulatory subunit quantification\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic epistasis by knockdown with specific phosphorylation readout, single lab, no direct biochemical reconstitution of the GSK-3β–LCMT1 relationship\",\n      \"pmids\": [\"22732552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LCMT1 methylates the L309 residue of the PP2A C subunit, and this methylation enables formation of AB56αC heterotrimers that dephosphorylate the androgen receptor (AR) and its coactivator MED1, causing eviction of the AR-MED1 complex from chromatin. LCMT1 is degraded via S6K1-mediated phosphorylation-induced proteasomal degradation requiring β-TRCP, and this degradation drives resistance to anti-androgens. Small-molecule SMAP stabilizes LCMT1 and attenuates AR signaling.\",\n      \"method\": \"LCMT1 silencing; Co-IP/interaction assays for PP2A heterotrimers; dephosphorylation assays for AR and MED1; chromatin immunoprecipitation; S6K1 overexpression/inhibition; β-TRCP interaction; SMAP treatment; in vivo tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, dephosphorylation assay, ChIP, degradation pathway dissection) establishing mechanism in a single focused study with in vivo validation\",\n      \"pmids\": [\"37644036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HIF-1α, induced by chronic hypoxia, decreases LCMT1 protein levels by promoting LCMT1 degradation via the autophagy–lysosomal pathway, thereby reducing PP2A methylation and activity and leading to tau hyperphosphorylation. Dual luciferase assay showed HIF-1α also acts as a transcription factor at the LCMT1 promoter, but the net effect of HIF-1α is LCMT1 protein reduction.\",\n      \"method\": \"HIF-1α overexpression and siRNA silencing in neurons and rats; dual luciferase reporter assay for LCMT1 promoter; autophagy–lysosomal inhibitor experiments; LCMT1 and PP2A activity measurements; tau phosphorylation immunoblotting\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assay plus in vivo genetic silencing with mechanistic readouts, single lab\",\n      \"pmids\": [\"36555780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Liver-specific LCMT1 knockout increases hepatic glycogen synthesis and accumulation, reverses high-fat diet-induced downregulation of glucokinase (GCK) and glycogen synthesis genes, and improves glucose intolerance and insulin resistance, establishing that hepatic LCMT1-mediated PP2A methylation negatively regulates glycogen metabolism and glucose homeostasis.\",\n      \"method\": \"Liver-specific LCMT1 knockout mouse model; glycogen content assays; GCK and glycogen synthesis gene expression; glucose and insulin tolerance tests; siRNA in MIHA cells\",\n      \"journal\": \"The Journal of nutritional biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with metabolic phenotyping and gene expression, single lab\",\n      \"pmids\": [\"36963730\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LCMT1-mediated PP2Ac methylation regulates autophagy; liver-specific LCMT1 knockout in mice and BaP-treated primary hepatocytes showed that loss of LCMT1 activity reduces PP2Ac methylation and inhibits autophagy, leading to hepatic lipid accumulation.\",\n      \"method\": \"Liver-specific LCMT1 KO mouse model; primary hepatocyte treatment with BaP; autophagy flux assays; PP2Ac methylation immunoblotting; lipid staining\",\n      \"journal\": \"Food and chemical toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO model with direct mechanistic readouts (autophagy flux, PP2Ac methylation), single lab\",\n      \"pmids\": [\"37579989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Reducing endogenous LCMT-1 expression (heterozygous gene-trap mice) increased sensitivity to Aβ-induced cognitive and synaptic plasticity impairments, while reducing PME-1 expression was protective, establishing that the LCMT1–PME-1 balance in PP2A methylation modulates neuronal sensitivity to Aβ.\",\n      \"method\": \"Heterozygous LCMT-1 gene-trap mice; heterozygous PME-1 KO mice; behavioral cognition assays; electrophysiological LTP recordings; acute Aβ oligomer application\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic models with behavioral and electrophysiological readouts, single lab\",\n      \"pmids\": [\"32341098\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LCMT1 is a PP2A-specific (and broader PP2A-subfamily: PP4, PP6) leucine carboxyl methyltransferase that catalyzes carboxyl methylation of the conserved C-terminal leucine of the phosphatase catalytic subunit; structural studies show its active-site pocket engages the PP2A C-terminus while the PP2A active site reciprocally stimulates methylation, creating a feed-forward mechanism that converts activated PP2A into substrate-directed holoenzymes by promoting binding of B-type regulatory subunits (Bα, B56α, PP4R1); this methylation is antagonized by PME-1, and their balance controls mitotic spindle size, neurite outgrowth, tau and AR dephosphorylation, glycogen metabolism, and autophagy; LCMT1 protein levels are regulated by HIF-1α-driven autophagic degradation and by S6K1/β-TRCP-mediated proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LCMT1 is the principal leucine carboxyl methyltransferase that activates the PP2A subfamily of protein phosphatases by methylating the conserved C-terminal leucine (Leu-309) of their catalytic subunits, thereby directing assembly of substrate-specific holoenzymes [#0, #4]. Crystal structures of LCMT1 alone and bound to PP2A show that its active-site pocket engages the PP2A C-terminus while the activated PP2A active site reciprocally stimulates methylation, defining a feed-forward mechanism that converts catalytically active PP2A into B-subunit-containing holoenzymes [#0]. Beyond PP2A, LCMT1 is the major carboxyl methyltransferase for the PP4 and PP6 catalytic subunits, and its loss selectively disrupts regulatory-subunit assembly (most dramatically the PP4R1-PP4 complex) and reduces steady-state levels of B-type and PP4R1 regulatory subunits, with downstream hyperphosphorylation of substrates such as HDAC3 [#1]. Methylation-dependent recruitment of specific B subunits channels PP2A toward defined outputs: a LCMT1\\u2192methyl-PP2A\\u2192B\\u03b1 axis drives F-actin reorganization and neurite outgrowth and partitions PP2A and Tau into cholesterol-rich membrane rafts, with loss of LCMT1 producing soluble hyperphosphorylated Tau [#2, #3], while AB56\\u03b1C heterotrimers dephosphorylate the androgen receptor and its coactivator MED1 to evict the complex from chromatin [#7]. The opposing actions of LCMT1 and the demethylase PME-1 establish a methylation equilibrium that governs mitotic spindle size and checkpoint fidelity and modulates neuronal sensitivity to amyloid-\\u03b2 [#5, #11]. In vivo, LCMT1-mediated PP2A methylation controls insulin signaling, hepatic glycogen and lipid metabolism through autophagy, and glucose homeostasis [#4, #9, #10]. LCMT1 abundance is itself regulated post-translationally by HIF-1\\u03b1-driven autophagic-lysosomal degradation and by S6K1/\\u03b2-TRCP-mediated proteasomal degradation, the latter coupling LCMT1 loss to anti-androgen resistance [#7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established that LCMT1 acts upstream of a defined PP2A holoenzyme to drive a cellular morphogenetic output, rather than being a generic housekeeping methyltransferase.\",\n      \"evidence\": \"LCMT1 overexpression/knockdown, methylation-incompetent PP2A mutant, B\\u03b1 knockdown, and SAH/PME-1 perturbation in N2a neuroblastoma with neurite morphometry\",\n      \"pmids\": [\"21044074\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which downstream cytoskeletal substrates the B\\u03b1 holoenzyme acts on\", \"Limited to a single neuroblastoma cell context\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Resolved the structural basis for how LCMT1 recognizes PP2A and why methylation is coupled to phosphatase activation, explaining efficient conversion of active PP2A into substrate-specific holoenzymes.\",\n      \"evidence\": \"X-ray crystallography of LCMT1 alone and in complex with PP2A, in vitro methylation assays, and a dominant-negative cell-cycle mutant\",\n      \"pmids\": [\"21292165\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how methylation selects among different B-subunit families\", \"Cell-cycle role inferred from a dominant-negative without substrate-level detail\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Placed LCMT1 within a signaling cascade by showing GSK-3\\u03b2 represses its activity to shift PP2A toward the demethylated state.\",\n      \"evidence\": \"GSK-3\\u03b2 overexpression/inhibition with PPMT1 (LCMT1) knockdown and dmL309-PP2Ac immunoblotting\",\n      \"pmids\": [\"22732552\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical reconstitution of GSK-3\\u03b2 acting on LCMT1\", \"Mechanism of inhibition (direct phosphorylation vs indirect) not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated that LCMT1-dependent methylation determines PP2A subcellular targeting, linking methylation to membrane raft localization and Tau dephosphorylation.\",\n      \"evidence\": \"Membrane microdomain fractionation, catalytically inactive LCMT1, siRNA, and one-carbon metabolism perturbation in N2a cells\",\n      \"pmids\": [\"23943618\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The molecular determinant coupling methylation to raft partitioning is unresolved\", \"Restricted to one cell line\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Confirmed in vivo that LCMT1 is the sole PP2A methyltransferase in mammalian tissue and connected its activity to systemic insulin signaling.\",\n      \"evidence\": \"Hypomorphic Lcmt1 gene-trap mice with activity assays, PP2A methylation quantification, and insulin/glucose homeostasis tests\",\n      \"pmids\": [\"23840384\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue and substrate mediating the insulin-resistance phenotype not pinpointed\", \"Hypomorphic, not null, model\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed the LCMT1-PME-1 methylation equilibrium quantitatively tunes mitotic spindle size and checkpoint integrity.\",\n      \"evidence\": \"Reciprocal LCMT1/PME-1 gain- and loss-of-function with spindle measurements, SAC markers, and viability assays\",\n      \"pmids\": [\"25839665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vitro reconstitution of the spindle-size mechanism\", \"Single lab; downstream PP2A holoenzyme on the spindle not identified\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Broadened LCMT1's enzymatic scope to PP4 and PP6 and showed methylation selectively governs which regulatory-subunit complexes assemble.\",\n      \"evidence\": \"Methylation-specific antibodies, blue native PAGE of holoenzymes, LCMT1 knockout MEFs, and HDAC3 phospho-readout\",\n      \"pmids\": [\"27507813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why PP4R1-PP4 is most methylation-sensitive is not mechanistically explained\", \"Full substrate repertoire of PP4/PP6 methylation unmapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that the LCMT1-PME-1 methylation balance sets neuronal vulnerability to amyloid-\\u03b2, linking the axis to Alzheimer-relevant pathophysiology.\",\n      \"evidence\": \"Heterozygous LCMT1 gene-trap and PME-1 KO mice with cognitive behavior, LTP electrophysiology, and acute A\\u03b2 oligomer application\",\n      \"pmids\": [\"32341098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not identify the PP2A substrate responsible for A\\u03b2 sensitivity\", \"Correlative genetic dosage rather than direct mechanism\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified HIF-1\\u03b1-driven autophagic-lysosomal degradation as a hypoxia-responsive route controlling LCMT1 protein levels and downstream Tau phosphorylation.\",\n      \"evidence\": \"HIF-1\\u03b1 overexpression/silencing in neurons and rats, LCMT1 promoter luciferase reporter, autophagy-lysosomal inhibitors, and PP2A activity/Tau readouts\",\n      \"pmids\": [\"36555780\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of transcriptional vs degradative regulation not quantified\", \"Autophagy receptor mediating LCMT1 turnover unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a methylation-dependent AB56\\u03b1C holoenzyme that dephosphorylates AR/MED1 and an S6K1/\\u03b2-TRCP degradation pathway whose disruption confers anti-androgen resistance, establishing LCMT1 as a tractable target in prostate cancer.\",\n      \"evidence\": \"LCMT1 silencing, Co-IP of PP2A heterotrimers, AR/MED1 dephosphorylation and ChIP assays, S6K1/\\u03b2-TRCP degradation dissection, SMAP stabilization, and in vivo tumor models\",\n      \"pmids\": [\"37644036\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SMAP-mediated LCMT1 stabilization is durable in vivo not fully resolved\", \"Generality across other AR-dependent contexts untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated tissue-specific roles for hepatic LCMT1 in negatively regulating glycogen metabolism and in supporting autophagy to limit lipid accumulation.\",\n      \"evidence\": \"Liver-specific LCMT1 knockout mice with glycogen, GCK/glycogen-gene expression, glucose/insulin tolerance, autophagy flux, lipid staining, and MIHA/hepatocyte models\",\n      \"pmids\": [\"36963730\", \"37579989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The specific PP2A holoenzyme and substrate controlling glycogen/autophagy outputs not identified\", \"Reconciliation with whole-body insulin-resistance phenotype not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How methylation status is decoded to select among distinct B-subunit families to produce tissue- and substrate-specific PP2A/PP4/PP6 outputs remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of methyl-PP2A bound to competing B subunits\", \"Substrate-level mediators of metabolic, mitotic, and neuronal phenotypes largely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 7]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [7, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PPP2CA\", \"PME-1\", \"PP4R1\", \"B56\\u03b1\", \"GSK-3\\u03b2\", \"S6K1\", \"\\u03b2-TRCP\", \"HIF-1\\u03b1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}