{"gene":"PKM","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2011,"finding":"EGFR activation induces translocation of PKM2 (but not PKM1) into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of β-catenin. This PKM2–β-catenin interaction is required for recruitment to the CCND1 promoter, HDAC3 removal, histone H3 acetylation, and cyclin D1 expression, thereby promoting tumor cell proliferation.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, nuclear fractionation, site-directed mutagenesis (K433, Y333), gene reporter assays, in vivo brain tumor models","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, ChIP, mutagenesis, in vivo) in a single rigorous study with clear mechanistic dissection","pmids":["22056988"],"is_preprint":false},{"year":2012,"finding":"Nuclear PKM2 directly binds histone H3 and phosphorylates it at T11 upon EGF receptor activation. This phosphorylation causes dissociation of HDAC3 from the CCND1 and MYC promoters, leading to H3K9 acetylation and transcriptional activation of cyclin D1 and c-Myc, promoting cell-cycle progression and tumorigenesis.","method":"In vitro kinase assay with recombinant proteins, Co-IP, ChIP, mass spectrometry, site-directed mutagenesis, in vivo brain tumor models","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of histone kinase activity, mutagenesis, ChIP, and in vivo validation in one rigorous study","pmids":["22901803"],"is_preprint":false},{"year":2013,"finding":"PKM2 (but not PKM1) binds the spindle checkpoint protein Bub3 during mitosis and phosphorylates Bub3 at Y207. This phosphorylation is required for Bub3-Bub1 complex recruitment to kinetochores, correct kinetochore-microtubule attachment, mitotic/spindle-assembly checkpoint fidelity, and accurate chromosome segregation.","method":"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y207), kinetochore localization imaging, genetic rescue experiments, in vivo tumor models","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay with mutagenesis, Co-IP, and in vivo validation across multiple orthogonal methods in one study","pmids":["24316223"],"is_preprint":false},{"year":2014,"finding":"Aurora B phosphorylates PKM2 (but not PKM1) at T45, which is required for PKM2 localization to the contractile ring during cytokinesis. PKM2 then phosphorylates MLC2 at Y118, priming ROCK2 binding to MLC2 and subsequent ROCK2-dependent MLC2 S15 phosphorylation, driving cytokinesis completion and cell proliferation.","method":"In vitro kinase assay, Co-IP, site-directed mutagenesis (T45, Y118), live-cell imaging, mass spectrometry, in vivo brain tumor models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assays, mutagenesis at defined sites, Co-IP, and in vivo validation with multiple orthogonal methods","pmids":["25412762"],"is_preprint":false},{"year":2011,"finding":"Acetylation of PKM2 at Lys305 decreases its pyruvate kinase activity and targets it for chaperone-mediated autophagy and subsequent lysosomal degradation.","method":"In vitro enzymatic activity assay, acetylation mutant analysis, lysosomal degradation assays, chaperone-mediated autophagy pathway analysis","journal":"Cold Spring Harbor symposia on quantitative biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity assay and degradation pathway validation, single lab with multiple methods but abstract-level description","pmids":["22096030"],"is_preprint":false},{"year":2015,"finding":"Using [32P]-phosphoenolpyruvate (PEP) with recombinant enzyme and PKM2-deleted in vitro systems, no PKM2-dependent protein kinase activity was detected; labeled protein species required ADP and were not PKM2-dependent, and direct phosphate transfer from ATP to protein by PKM2 was not observed. This constitutes a NEGATIVE finding challenging PKM2 protein kinase activity.","method":"Radioisotope [32P]-PEP labeling assay with recombinant PKM2, genetic deletion of PKM2 in cell systems, in vitro phosphorylation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro reconstitution with genetic deletion controls, single lab but multiple orthogonal methods; result is explicitly NEGATIVE for PKM2 protein kinase activity","pmids":["26300261"],"is_preprint":false},{"year":2016,"finding":"PKM2-mediated glycolysis promotes NLRP3 and AIM2 inflammasome activation in macrophages by modulating EIF2AK2 phosphorylation. Myeloid cell-specific conditional knockout of PKM2 attenuates inflammasome activation and protects mice from lethal endotoxemia and polymicrobial sepsis.","method":"Myeloid-specific PKM2 conditional knockout mice, pharmacological inhibition, inflammasome activation assays, cytokine measurement, in vivo sepsis models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic conditional knockout with clear mechanistic pathway (PKM2→EIF2AK2→inflammasome) validated in vivo with pharmacological corroboration","pmids":["27779186"],"is_preprint":false},{"year":2019,"finding":"PKM2 interacts with mitofusin 2 (MFN2) to promote mitochondrial fusion and oxidative phosphorylation while attenuating glycolysis. mTOR modulates this interaction by phosphorylating MFN2, establishing an mTOR-MFN2-PKM2 signaling axis that coordinates glycolysis and OXPHOS.","method":"Co-immunoprecipitation, mitochondrial morphology imaging, metabolic flux analysis (Seahorse), mTOR inhibitor experiments, genetic manipulation of MFN2 and PKM2","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and metabolic assays in single lab, mechanistic pathway established with multiple methods but no structural validation","pmids":["30887444"],"is_preprint":false},{"year":2020,"finding":"PKM2 translocates into the nucleus in Th17 cells and interacts with STAT3, enhancing STAT3 activation and thereby promoting Th17 cell differentiation. T cell-specific PKM2 deletion impairs Th17 differentiation and ameliorates experimental autoimmune encephalomyelitis, independent of effects on metabolic reprogramming or proliferation.","method":"T cell-specific PKM2 conditional knockout, Co-immunoprecipitation of PKM2-STAT3, flow cytometry for Th17 markers, EAE mouse model","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic conditional knockout with Co-IP and in vivo disease model, multiple orthogonal methods establishing non-metabolic nuclear function","pmids":["32697823"],"is_preprint":false},{"year":2022,"finding":"Lactylation of PKM2 at K62 inhibits its tetramer-to-dimer transition, thereby promoting its pyruvate kinase activity and reducing nuclear distribution, which suppresses the Warburg effect and promotes transition of pro-inflammatory macrophages toward a reparative phenotype.","method":"Mass spectrometry identification of lactylation site, K62 mutant analysis, pyruvate kinase activity assay, native PAGE for tetramer/dimer analysis, nuclear fractionation, macrophage polarization assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-identified PTM with activity assay and oligomeric state analysis, single lab with multiple methods","pmids":["36439872"],"is_preprint":false},{"year":2020,"finding":"PKM2 regulates the cardiomyocyte cell cycle and reduces oxidative stress through anabolic pathways and β-catenin. Cardiomyocyte-specific Pkm2 deletion during cardiac development reduces cardiomyocyte cell cycle activity, cardiomyocyte numbers, and myocardial size.","method":"Cardiomyocyte-specific Pkm2 conditional knockout, modified mRNA overexpression, cardiac morphometry, cell cycle marker analysis, myocardial infarction models","journal":"Circulation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic conditional KO with clear phenotypic readout, mechanistic link to β-catenin stated but limited orthogonal biochemical validation described in abstract","pmids":["32078387"],"is_preprint":false},{"year":2023,"finding":"PHGDH prevents PKM2 K305 acetylation (catalyzed by PCAF) and subsequent autophagic degradation by directly interacting with PKM2. PHGDH also facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and enables it to phosphorylate H3T11, regulating transcription of senescence-associated genes.","method":"Co-immunoprecipitation, acetylation mutant analysis (K305, K433), in vitro kinase assay (H3T11 phosphorylation), autophagy inhibition assays, ChIP, endothelial senescence models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including in vitro kinase assay, mutagenesis at defined sites, Co-IP, ChIP in a single rigorous study","pmids":["36899022"],"is_preprint":false},{"year":2023,"finding":"Jmjd4 interacts with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, dependent on Jmjd4-catalyzed hydroxylation of K66 of Pkm2. Loss of Jmjd4 in cardiomyocytes leads to Pkm2 accumulation, impaired mitochondrial respiration, and spontaneous dilated cardiomyopathy.","method":"Cardiomyocyte-specific Jmjd4 conditional knockout, Co-IP of Jmjd4-Hsp70-Pkm2, mass spectrometry, chaperone-mediated autophagy assays, metabolite profiling, RNA-seq","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — genetic KO, biochemical Co-IP establishing ternary complex, defined PTM site (K66 hydroxylation), and multiple orthogonal methods in single rigorous study","pmids":["37066795"],"is_preprint":false},{"year":2024,"finding":"SIRT1 interacts with and deacetylates PKM2 at K135 and K206, leading to reduced PKM2 enzymatic activity and lactate production, which decreases glial activation in the brain and ameliorates Parkinson's disease phenotypes.","method":"Co-immunoprecipitation, deacetylation site mapping (K135, K206), pyruvate kinase activity assay, lactate measurement, PD mouse models with SIRT1 knockdown/overexpression and PKM2 inhibition","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and enzymatic activity assay with defined PTM sites and in vivo disease model, single lab","pmids":["39128469"],"is_preprint":false},{"year":2024,"finding":"PKM2 moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, which is essential for PGAM1 activity. Monomeric and dimeric PKM2 (but not tetrameric) efficiently phosphorylate PGAM1. Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and subsequent H11 phosphorylation.","method":"In vitro histidine kinase assay, mass spectrometry, Co-IP, site-directed mutagenesis (H11, Y119), cell-permeable peptide disruption of PKM2-PGAM1 interaction, tumor xenograft models","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution with defined substrates, mutagenesis at phosphorylation sites, peptide disruption validation; single lab but multiple orthogonal methods","pmids":["38750259"],"is_preprint":false},{"year":2024,"finding":"Nuclear PKM2 functions as a non-canonical RNA-binding protein that specifically interacts with folded RNA G-quadruplex (rG4) structures in precursor mRNAs. PKM2 occupancy at rG4s prevents binding of repressive RBPs (e.g., HNRNPF) and promotes expression of rG4-containing pre-mRNAs. Preventing nuclear PKM2 accumulation represses the rG4ome and reduces cancer cell migration and invasion.","method":"eCLIP-seq, ribosome footprinting, nuclear fractionation, RNA-binding assays, in vitro G-quadruplex binding, xenograft mouse models, competitive displacement with HNRNPF","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — eCLIP-seq identifies genome-wide binding sites, biochemical in vitro binding, functional xenograft validation; multiple orthogonal methods in one rigorous study","pmids":["39153475"],"is_preprint":false},{"year":2023,"finding":"PKM binds ribosomes in a poly-ADP ribosylation (PARylation)-dependent manner. PKM crosslinks to mRNA sequences downstream of lysine- and glutamate-encoding regions and causes translational stalling near these sequences. PKM-polysome interaction is regulated by ADP levels, linking carbohydrate metabolism to mRNA translation regulation.","method":"Proteomic polysome survey, eCLIP-seq, ribosome footprint protection sequencing, ADP titration assays, PARylation inhibition experiments","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal genome-wide and biochemical methods (eCLIP-seq, ribosome profiling, biochemical assays) in single rigorous study establishing novel function","pmids":["37224531"],"is_preprint":false},{"year":2022,"finding":"FSTL1 binds directly to PKM2 through its FK domain, promotes PKM2 phosphorylation and nuclear translocation, and reduces PKM2 ubiquitination, thereby enhancing PKM2-dependent glycolysis and macrophage M1 polarization, promoting liver fibrosis.","method":"Co-immunoprecipitation, nuclear fractionation, ubiquitination assay, myeloid-specific FSTL1 knockout mice, pharmacological PKM2 activation (DASA-58)","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with defined domain, genetic KO, and pharmacological validation; single lab with multiple methods","pmids":["35140065"],"is_preprint":false},{"year":2020,"finding":"Annexin A5 directly interacts with PKM2 at ASP101, LEU104, and ARG106, inhibits phosphorylation of Y105, and promotes PKM2 tetramer formation, thereby switching macrophage metabolism from glycolysis to oxidative phosphorylation and promoting M2 polarization.","method":"Pull-down assay, molecular docking, site-directed mutagenesis (D101, L104, R106), PKM2 Y105E phosphomimetic mutant, native PAGE for oligomeric state, metabolic flux analysis","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding with defined residues, mutant validation, oligomeric state assay; single lab with multiple orthogonal methods","pmids":["32863213"],"is_preprint":false},{"year":2022,"finding":"PKM2 regulates post-ischemic inflammation in peripheral neutrophils by promoting STAT3 phosphorylation. Myeloid cell-specific PKM2 deletion reduced neutrophil extracellular traps, cerebral thrombo-inflammation, and infarct volume after stroke. Inhibiting PKM2 nuclear translocation pharmacologically reduced neutrophil hyperactivation.","method":"Myeloid-specific PKM2 conditional knockout mice, STAT3 phosphorylation assay, neutrophil extracellular trap quantification, stroke models (filament/clot), laser speckle imaging, small-molecule nuclear translocation inhibitor","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic conditional KO with defined signaling readout (STAT3 phosphorylation), corroborated by pharmacological inhibition with multiple in vivo models","pmids":["34529778"],"is_preprint":false},{"year":2022,"finding":"GTPBP4 facilitates SUMO1-mediated sumoylation of PKM2, which promotes PKM2 dimer formation and aerobic glycolysis. Sumoylated PKM2 relocates from cytoplasm to nucleus, activating EMT and STAT3 signaling in hepatocellular carcinoma.","method":"Co-immunoprecipitation, sumoylation assay, nuclear fractionation, UBA2 activation assay, gain/loss-of-function studies, in vitro and in vivo tumor models","journal":"Redox biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and sumoylation assay with defined pathway components; single lab, multiple methods","pmids":["36116159"],"is_preprint":false},{"year":2021,"finding":"Extracellular PKM2 (EcPKM2) secreted by myofibroblasts interacts with integrin αvβ3 on myofibroblast surfaces to activate FAK-PI3K signaling, which activates NF-κB survival pathway (preventing apoptosis) and suppresses PTEN to upregulate arginase-1, facilitating proline biosynthesis and collagen production in organ fibrosis.","method":"Co-immunoprecipitation of EcPKM2-integrin αvβ3, FAK-PI3K phosphorylation assays, NF-κB reporter, arginase-1 assay, antibody blocking experiments, in vivo fibrosis models","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing extracellular binding partner, signaling pathway validation, antibody disruption in vivo; single lab","pmids":["34693222"],"is_preprint":false},{"year":2022,"finding":"Celastrol binds covalently to Cys424 of PKM2, inhibiting its enzymatic activity and suppressing aerobic glycolysis (Warburg effect) in macrophages, thereby attenuating inflammatory responses in sepsis.","method":"Activity-based protein profiling (ABPP), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), point mutagenesis (Cys424), gene knockdown","journal":"Military Medical Research","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — biophysical binding assays (SPR, CETSA), defined covalent binding site via mutagenesis; single lab with multiple orthogonal methods","pmids":["35596191"],"is_preprint":false},{"year":2022,"finding":"PKM2-C31 palmitoylation (mediated by palmitoyl acyltransferase zDHHC13) impairs PKM2 tetramerization, inhibits its pyruvate kinase activity and endothelial glycolysis, causing palmitic acid-induced endothelial injury and cardiovascular dysfunction. PKM2-C31S mutation prevents these effects.","method":"Palmitoyl-proteomics, site-directed mutagenesis (C31S), endothelial-specific AAV-mediated expression, pyruvate kinase activity assay, native PAGE for tetramerization, palmitoyl-transferase inhibitor/activator experiments, ApoE-/- mouse model","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — defined palmitoylation site with mutagenesis rescue, enzymatic activity assay, oligomeric state analysis, and in vivo validation; multiple orthogonal methods","pmids":["39665133"],"is_preprint":false},{"year":2022,"finding":"Prohibitin 2 (PHB2), through its C-terminus, directly interacts with hnRNPA1 (a key modulator of PKM alternative splicing) to counteract hnRNPA1-mediated PKM2 expression and glycolysis, thereby maintaining the contractile VSMC phenotype.","method":"Co-immunoprecipitation, mammalian two-hybrid assay, protein interactome analysis, PKM splicing analysis (RT-PCR), metabolic flux analysis, PHB2-deficient mouse model, neointima formation model","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and mammalian two-hybrid with defined domain, splicing and metabolic phenotype validation; single lab","pmids":["36200440"],"is_preprint":false},{"year":2025,"finding":"PINK1 phosphorylates PKM2 at Ser127, preserving its active tetrameric form and inhibiting its nuclear translocation and interaction with β-catenin, resulting in a metabolic shift toward energy production. SIRT3 deacetylates PINK1 to promote this pathway (SIRT3-PINK1-PKM2 axis) protecting against osteoarthritis.","method":"PINK1 knockout/overexpression mouse models, Co-immunoprecipitation, phosphorylation site analysis (S127), native PAGE for tetramer confirmation, nuclear fractionation, double-knockout mouse model","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic models with Co-IP and phosphorylation site identification; single lab with multiple orthogonal methods but abstract-level detail","pmids":["40087281"],"is_preprint":false},{"year":2022,"finding":"DEUBIQUITINASE JOSD2 interacts with PKM2 and reduces its K433 acetylation, thereby blocking PKM2 nuclear localization and downstream non-glycolytic gene expression in acute myeloid leukemia, without affecting PKM2 protein stability.","method":"Co-immunoprecipitation, mass spectrometry, co-immunofluorescence, K433 acetylation assay, nuclear fractionation, gene expression analysis, in vivo AML progression model","journal":"Experimental hematology & oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mass spectrometry, defined PTM site, nuclear fractionation; single lab, multiple methods","pmids":["35836282"],"is_preprint":false},{"year":2025,"finding":"March2 promotes K33-linked polyubiquitination of PKM2, facilitating PKM2 dimer-to-tetramer conversion. Deficiency of March2 lessens PKM2 tetramerization, promotes glycolysis-derived H3K18 lactylation, and drives p53-dependent apoptotic transcription, accelerating aortic aneurysm/dissection pathogenesis.","method":"Co-immunoprecipitation, ubiquitination type analysis (K33-linkage specific), native PAGE for oligomeric state, ChIP for H3K18 lactylation (CUT&TAG), smooth muscle cell-specific March2 knockout mice, PKM2 activator (TEPP-46) rescue","journal":"Circulation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, defined ubiquitin linkage, oligomeric state assay, genetic KO and pharmacological rescue; single lab, multiple methods","pmids":["40079144"],"is_preprint":false},{"year":2025,"finding":"PKM2-derived pyruvate is converted to lactate, which lactylates histone H3 at K9 (H3K9la), upregulating Sox family transcription factors through epigenetic modification to control cochlear development. PKM2 deletion causes a metabolic switch from glycolysis to OXPHOS and impairs cochlear sensory epithelium morphogenesis.","method":"Conditional PKM2 knockout in cochlear progenitors, cochlear organoids, H3K9la ChIP, metabolic flux analysis, gene expression (Sox factors), human and mouse cochlear explants with PKM2 overexpression","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined epigenetic mechanism (H3K9la ChIP), multiple model systems; single lab","pmids":["39773029"],"is_preprint":false},{"year":2025,"finding":"Tetrameric PKM2 (promoted by TEPP-46) increases ATP production from glycolysis; extracellular ATP is converted to adenosine via ectonucleotidases, activating adenosine receptor A2a (A2aR) to enhance IL-10 production in macrophages. This effect is abolished in PKM2-deficient macrophages.","method":"PKM2-deficient macrophages, TEPP-46 pharmacological activation, extracellular ATP/adenosine measurement, A2aR antagonist, ectonucleotidase inhibition, IL-10 ELISA, metabolic flux analysis","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PKM2 KO abolishment of effect, defined metabolic-signaling pathway with pharmacological dissection; single lab, multiple methods","pmids":["39772395"],"is_preprint":false},{"year":2022,"finding":"PKM2 dimerization is induced by PKM2 sumoylation (via GTPBP4-SUMO1-UBA2 axis), and dimeric PKM2 promotes aerobic glycolysis and nuclear translocation. Separately, PKM2 nuclear translocation is required for complex formation with STAT3, HIF1α-mediated angiogenesis, and tumor maintenance in bladder cancer.","method":"PKM2 knockout, PKM2 overexpression (PKM2 vs PKM1), Co-IP of PKM2-STAT3, nuclear fractionation, VEGF/HIF1α pathway analysis, inducible PKM2 expression mouse models","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation comparing PKM1 vs PKM2, Co-IP, nuclear fractionation; single lab with multiple in vivo and in vitro methods","pmids":["34903602"],"is_preprint":false},{"year":2022,"finding":"Dimeric/monomeric PKM2 nuclear translocation is promoted by ROS-induced oxidation at Cys423/Cys424, leading to glutathionylation of PKM2. Nuclear PKM2 then acts as a co-factor to promote HIF-1α-dependent gene induction, contributing to cardioprotective adaptive responses.","method":"Cys423/424 mutagenesis, glutathionylation assay, nuclear fractionation, HIF-1α reporter, cardiac-specific Pkm2 knockdown, ROS measurement, ischemia mouse model","journal":"Acta pharmaceutica Sinica. B","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis at defined Cys sites with glutathionylation assay and nuclear fractionation; single lab, in vitro and in vivo validation","pmids":["36815040"],"is_preprint":false},{"year":2024,"finding":"PKM2 aggregates form in senescent cells and organs from aged mice, impairing PKM2 enzymatic activity and glycolytic flux, thereby driving cells into senescence. Small molecules capable of dissolving PKM2 aggregates alleviate senescence and extend lifespan in mouse models.","method":"PKM2 aggregate detection (biochemical fractionation, imaging), pyruvate kinase activity assay in senescent vs non-senescent cells, small molecule library screening, senescence marker analysis (SA-β-Gal, p16), lifespan measurement in aging mouse models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical aggregate characterization, enzymatic activity impairment, small molecule rescue; single lab with multiple methods including in vivo lifespan","pmids":["38982055"],"is_preprint":false},{"year":2021,"finding":"PKM2 interacts with NF-κB and induces nuclear translocation of both PKM2 and NF-κB with assistance of importin 4. In the nucleus, PKM2-NF-κB complexes augment VEGFA transcription, promoting tumor angiogenesis. FBP promotes assembly of a FOXM1D-PKM2 heterooctamer that reduces PKM2 metabolic activity.","method":"Co-immunoprecipitation, nuclear fractionation, importin 4 knockdown, VEGFA promoter reporter, exosome-mediated VEGFA secretion assay, metabolic activity assay, tumor angiogenesis model","journal":"Molecular oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for multiple complexes, nuclear translocation assay, reporter assay; single lab with multiple methods","pmids":["33314660"],"is_preprint":false},{"year":2022,"finding":"CXCL12 signaling through CXCR4 and ACKR3 stimulates protein interactions among β-arrestin 2, PKM2, and ERK2, leading to dissociation of PKM2 from β-arrestin 2, reduced PKM2 oligomerization (tetramers to dimers/monomers), and increased glycolytic intermediates and pentose phosphate pathway metabolites.","method":"Luciferase protein complementation assays for protein-protein interactions, mass spectrometry of metabolites with isotopically labeled glucose, PKM2 oligomerization assay, tumor xenograft model","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative protein interaction assay, isotopic metabolite tracing, oligomerization measurement; single lab, multiple orthogonal methods","pmids":["35681470"],"is_preprint":false},{"year":2021,"finding":"PKM2 interacts with Oct4 in glioma stem cells, and this interaction is implicated in the regulation of glioma stemness. Silencing PKM2 enhances apoptosis and differentiation of glioma spheroids. DCA (a PDK inhibitor) increases PKM2/Oct4 complex formation and inhibits Oct4-dependent gene expression.","method":"Co-immunoprecipitation of PKM2-Oct4, PKM2 siRNA knockdown, apoptosis assays, differentiation markers, DCA treatment and Oct4 reporter","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing PKM2-Oct4 interaction, loss-of-function with defined phenotypic readouts; single lab","pmids":["24481450"],"is_preprint":false},{"year":2021,"finding":"PKM2 promotes IL-10 production via tetramerization-dependent ATP release and adenosine signaling, and PKM2 mediates autophagic activation by increasing phosphorylation of Beclin-1 in NPM1-mutated AML cells, contributing to cell survival.","method":"PKM2 knockdown, Beclin-1 phosphorylation assay, autophagy flux assay, cell viability assays","journal":"International journal of biological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single method for Beclin-1 phosphorylation; limited mechanistic biochemical detail in abstract","pmids":["30906218"],"is_preprint":false},{"year":2021,"finding":"PKM2 regulates lipid homeostasis through an ER transmembrane protein TMEM33. Loss of PKM2 upregulates TMEM33, which recruits E3 ligase RNF5 to promote SCAP degradation. TMEM33 is transcriptionally regulated by NRF1, whose cleavage is controlled by PKM2 levels.","method":"Co-immunoprecipitation, SCAP degradation assay, NRF1 cleavage assay, TMEM33 promoter analysis, PKM2 global knockout mice (cholesterol measurement), allograft tumor model","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, defined degradation pathway with biochemical assays, genetic KO with physiological readout; single lab","pmids":["34487377"],"is_preprint":false},{"year":2022,"finding":"Vitamin B5 (pantothenate) is catabolized to coenzyme A (CoA) in a PANK-dependent manner, and CoA binds directly to PKM2, impeding its phosphorylation and nuclear translocation, thus inhibiting glycolysis and STAT3 phosphorylation, and suppressing Th17 cell differentiation.","method":"PKM2-CoA binding assay, PKM2 phosphorylation assay, nuclear fractionation, STAT3 phosphorylation assay, Th17 differentiation assay, EAE and colitis mouse models","journal":"Cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay for CoA-PKM2, nuclear translocation assay, defined signaling readout; single lab, multiple methods","pmids":["36450257"],"is_preprint":false},{"year":2024,"finding":"Mannose directly binds PKM2, inhibiting its enzymatic activity and reducing lactate production, leading to decreased PKM2 lactylation and increased PKM2 acetylation, which causes nuclear translocation of PKM2 and NF-κB pathway activation, inducing NLRP1/Caspase-1/GSDMD/IL-1β-dependent pyroptosis in bladder cancer.","method":"Direct binding assay (mannose-PKM2), pyruvate kinase activity assay, lactate measurement, lactylation/acetylation assays on PKM2, nuclear fractionation, NF-κB pathway assay, pyroptosis markers, xenograft and organoid models","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding assay, PTM characterization, nuclear translocation, downstream pathway; single lab, multiple methods","pmids":["40312519"],"is_preprint":false}],"current_model":"PKM2 is a multifunctional glycolytic enzyme that, in its cytoplasmic tetrameric form, catalyzes the conversion of PEP to pyruvate; its dimer/monomer forms can translocate to the nucleus where it acts as a protein kinase (phosphorylating histone H3-T11, Bub3-Y207, MLC2-Y118, and PGAM1-H11 via PEP-dependent mechanisms), a co-transcriptional activator (binding β-catenin, STAT3, NF-κB, and Oct4 to regulate gene expression), and a non-canonical RNA-binding protein (interacting with RNA G-quadruplex structures to regulate pre-mRNA expression); its oligomeric state, subcellular localization, and activities are tightly regulated by post-translational modifications including phosphorylation (Aurora B at T45, PINK1 at S127, Src at Y105), acetylation (PCAF at K305 targeting it for autophagy; p300 at K433 promoting nuclear entry), sumoylation, glutathionylation (Cys423/424), lactylation (K62 promoting tetramerization), palmitoylation (C31 impairing tetramerization), and hydroxylation (Jmjd4 at K66 promoting CMA degradation), as well as allosteric regulators and interactions with binding partners such as MFN2, PHGDH, Annexin A5, FSTL1, CoA, and integrin αvβ3."},"narrative":{"mechanistic_narrative":"PKM (PKM2 isoform) is a multifunctional glycolytic pyruvate kinase whose tetrameric form drives metabolic flux but whose dimeric/monomeric forms acquire non-canonical activities upon translocation to the nucleus, coordinating metabolism with gene expression, cell-cycle control, and inflammation [PMID:22056988, PMID:24316223]. The interconversion between oligomeric states is the central regulatory switch: tetramerization favors enzymatic pyruvate kinase activity, whereas dimer/monomer formation favors nuclear functions, and this balance is tuned by an extensive set of post-translational modifications including lactylation at K62 [PMID:36439872], palmitoylation at C31 [PMID:39665133], glutathionylation at Cys423/424 [PMID:36815040], sumoylation [PMID:36116159], and several ubiquitin linkages [PMID:40079144]. In the nucleus, PKM2 acts as a co-transcriptional activator that binds c-Src-phosphorylated β-catenin to drive CCND1 transcription [PMID:22056988], and phosphorylates histone H3 at T11 to evict HDAC3 and activate cyclin D1 and c-Myc [PMID:22901803, PMID:36899022]. During mitosis it phosphorylates the spindle-checkpoint protein Bub3 at Y207 to ensure correct kinetochore-microtubule attachment [PMID:24316223], and during cytokinesis Aurora-B-primed PKM2 phosphorylates MLC2 at Y118 at the contractile ring [PMID:25412762]; it also moonlights as a PEP-dependent histidine kinase phosphorylating PGAM1 at H11 [PMID:38750259]. Nuclear PKM2 additionally functions as a non-canonical RNA-binding protein that occupies RNA G-quadruplex structures in pre-mRNAs to promote their expression and cancer cell invasion [PMID:39153475], and binds ribosomes in a PARylation- and ADP-dependent manner to stall translation [PMID:37224531]. Through nuclear partnership with STAT3 and NF-κB, PKM2 controls Th17 differentiation, macrophage and neutrophil inflammatory programs, and tumor angiogenesis [PMID:32697823, PMID:34529778, PMID:33314660]. PKM2 abundance is governed by chaperone-mediated autophagy following K305 acetylation or Jmjd4-catalyzed K66 hydroxylation [PMID:22096030, PMID:37066795]. An in vitro reconstitution study using [32P]-PEP failed to detect PKM2-dependent protein kinase activity, defining a point of contention over the protein-kinase model [PMID:26300261].","teleology":[{"year":2011,"claim":"Established that PKM2, unlike PKM1, has a nuclear non-metabolic role by showing growth-signal-induced nuclear translocation and a direct interaction with β-catenin required for oncogenic transcription, reframing a metabolic enzyme as a transcriptional coactivator.","evidence":"Co-IP, ChIP, nuclear fractionation, K433/Y333 mutagenesis, and in vivo brain tumor models","pmids":["22056988"],"confidence":"High","gaps":["Did not resolve how PKM2 oligomeric state controls nuclear entry","Structural basis of the PKM2-β-catenin interface not defined"]},{"year":2011,"claim":"Linked a specific PTM to PKM2 turnover by showing K305 acetylation lowers enzymatic activity and routes PKM2 to chaperone-mediated autophagy, connecting acetylation status to enzyme abundance.","evidence":"In vitro activity assay, acetylation mutant analysis, lysosomal/CMA degradation assays","pmids":["22096030"],"confidence":"Medium","gaps":["Abstract-level detail only","Acetyltransferase and deacetylase not defined in this study"]},{"year":2012,"claim":"Provided the first proposed protein-kinase mechanism for nuclear PKM2 by demonstrating direct histone H3-T11 phosphorylation that evicts HDAC3 to activate cyclin D1 and c-Myc, defining an epigenetic output of PKM2.","evidence":"In vitro kinase assay with recombinant proteins, Co-IP, ChIP, mass spectrometry, mutagenesis, in vivo tumor models","pmids":["22901803"],"confidence":"High","gaps":["Phosphate-donor mechanism (PEP vs ATP) not definitively resolved","Later challenged by negative reconstitution data"]},{"year":2013,"claim":"Extended the PKM2 protein-kinase model to mitosis by showing isoform-specific phosphorylation of Bub3 at Y207 controls kinetochore attachment and spindle-checkpoint fidelity, implicating PKM2 in chromosome segregation.","evidence":"Co-IP, in vitro kinase assay, Y207 mutagenesis, kinetochore imaging, rescue and in vivo tumor models","pmids":["24316223"],"confidence":"High","gaps":["Phosphotransfer chemistry not independently confirmed","How mitotic PKM2 is targeted to kinetochores unclear"]},{"year":2014,"claim":"Connected upstream mitotic kinase signaling to PKM2 localization, showing Aurora B phosphorylation at T45 directs PKM2 to the contractile ring where it primes MLC2 for ROCK2, integrating PKM2 into cytokinesis.","evidence":"In vitro kinase assays, Co-IP, T45/Y118 mutagenesis, live-cell imaging, in vivo tumor models","pmids":["25412762"],"confidence":"High","gaps":["Generality beyond tumor models not established","Does not resolve the broader controversy over PKM2 kinase activity"]},{"year":2015,"claim":"Directly challenged the PKM2 protein-kinase paradigm by failing to detect PKM2-dependent protein phosphorylation in reconstituted [32P]-PEP assays with genetic deletion controls, defining a methodological dispute central to the field.","evidence":"Radioisotope [32P]-PEP labeling with recombinant PKM2 and PKM2-deleted cell systems","pmids":["26300261"],"confidence":"High","gaps":["Negative result does not exclude context-dependent kinase activity in cells","Does not reconcile with positive reconstitution reports"]},{"year":2016,"claim":"Established a metabolism-driven role for PKM2 in innate immunity, showing glycolytic PKM2 promotes inflammasome activation via EIF2AK2 and that myeloid PKM2 loss protects against sepsis.","evidence":"Myeloid-specific conditional knockout, pharmacological inhibition, inflammasome and cytokine assays, in vivo sepsis models","pmids":["27779186"],"confidence":"High","gaps":["Whether the effect is purely metabolic or involves nuclear PKM2 not dissected","Direct PKM2-EIF2AK2 biochemistry not shown"]},{"year":2019,"claim":"Identified a direct mitochondrial partner, showing PKM2-MFN2 interaction promotes fusion and OXPHOS while restraining glycolysis under mTOR control, establishing PKM2 as a node balancing glycolysis and respiration.","evidence":"Co-IP, mitochondrial imaging, Seahorse flux, mTOR inhibitor and genetic manipulation","pmids":["30887444"],"confidence":"Medium","gaps":["No structural validation of the interaction","Single lab; reciprocal validation limited"]},{"year":2020,"claim":"Demonstrated a metabolism-independent nuclear function in adaptive immunity, where PKM2-STAT3 interaction drives Th17 differentiation independent of metabolic reprogramming.","evidence":"T cell-specific conditional knockout, PKM2-STAT3 Co-IP, flow cytometry, EAE model","pmids":["32697823"],"confidence":"High","gaps":["Direct vs indirect enhancement of STAT3 not fully separated","Oligomeric state required for STAT3 binding not defined"]},{"year":2020,"claim":"Extended PKM2 cell-cycle and redox functions to developmental physiology, showing cardiomyocyte PKM2 supports proliferation and limits oxidative stress via β-catenin during heart development.","evidence":"Cardiomyocyte-specific conditional knockout, modified mRNA overexpression, morphometry, MI models","pmids":["32078387"],"confidence":"Medium","gaps":["Limited orthogonal biochemical validation of the β-catenin link","Mechanism of oxidative-stress reduction not detailed"]},{"year":2021,"claim":"Defined an extracellular, receptor-mediated PKM2 function, where secreted PKM2 engages integrin αvβ3 to activate FAK-PI3K-NF-κB survival and pro-fibrotic collagen synthesis.","evidence":"Co-IP of EcPKM2-integrin, FAK-PI3K assays, NF-κB reporter, antibody blocking, in vivo fibrosis models","pmids":["34693222"],"confidence":"Medium","gaps":["Mechanism of PKM2 secretion not defined","Single lab; structural basis of integrin binding unknown"]},{"year":2021,"claim":"Broadened nuclear partner repertoire by showing PKM2-NF-κB complexes (importin-4-dependent) drive VEGFA transcription and that an FBP-induced FOXM1D-PKM2 heterooctamer suppresses metabolic activity, linking oligomerization to angiogenesis.","evidence":"Co-IP, nuclear fractionation, importin-4 knockdown, VEGFA reporter, metabolic assays, angiogenesis model","pmids":["33314660"],"confidence":"Medium","gaps":["Heterooctamer stoichiometry not structurally resolved","Single lab"]},{"year":2022,"claim":"Identified lactylation at K62 as a PTM that locks PKM2 in its tetramer, raising enzymatic activity and reducing nuclear distribution to reprogram macrophage phenotype, formalizing a PTM-oligomer-function axis.","evidence":"Mass spectrometry, K62 mutagenesis, activity assay, native PAGE, nuclear fractionation, polarization assays","pmids":["36439872"],"confidence":"Medium","gaps":["Enzyme catalyzing K62 lactylation not defined","Single lab"]},{"year":2022,"claim":"Showed multiple PTM and binding-partner routes converge on the tetramer-dimer equilibrium: sumoylation (GTPBP4-SUMO1) and CXCL12-driven β-arrestin-2/ERK2 interactions favor dimers/nuclear PKM2, while Annexin A5 binding and CoA binding favor tetramers and block nuclear translocation.","evidence":"Co-IP, sumoylation and oligomerization assays, pull-down with residue mapping, metabolite tracing, binding assays, immune/tumor models","pmids":["36116159","35681470","32863213","36450257"],"confidence":"Medium","gaps":["These regulators were studied in separate systems and not integrated","Quantitative hierarchy of competing inputs unknown"]},{"year":2022,"claim":"Defined pharmacological and lipid-based covalent control of PKM2 activity, with celastrol binding Cys424 and zDHHC13-mediated C31 palmitoylation both impairing tetramerization and activity in inflammatory and vascular disease contexts.","evidence":"ABPP, CETSA, SPR, palmitoyl-proteomics, C31S/Cys424 mutagenesis, activity and native PAGE assays, in vivo models","pmids":["35596191","39665133"],"confidence":"Medium","gaps":["Off-target effects of celastrol not fully excluded","Interplay between palmitoylation and other C31-proximal modifications unknown"]},{"year":2022,"claim":"Linked PKM2 abundance and isoform choice to vascular and fibrotic disease through ubiquitin regulation (JOSD2 deubiquitinase blocks K433 acetylation/nuclear entry; FSTL1 reduces ubiquitination to enhance nuclear PKM2) and splicing control (PHB2-hnRNPA1 axis sets PKM2 expression).","evidence":"Co-IP, mass spectrometry, ubiquitination and acetylation assays, mammalian two-hybrid, splicing RT-PCR, genetic KO models","pmids":["35836282","35140065","36200440"],"confidence":"Medium","gaps":["Reciprocal validation of some interactions limited","Single-lab studies"]},{"year":2022,"claim":"Showed a redox-sensing nuclear function in which ROS-induced Cys423/424 glutathionylation drives dimer/monomer nuclear translocation where PKM2 acts as a HIF-1α cofactor for cardioprotective gene induction.","evidence":"Cys423/424 mutagenesis, glutathionylation assay, nuclear fractionation, HIF-1α reporter, cardiac knockdown, ischemia model","pmids":["36815040"],"confidence":"Medium","gaps":["Direct HIF-1α cofactor mechanism not biochemically detailed","Single lab"]},{"year":2023,"claim":"Resolved a degradation mechanism by showing Jmjd4-catalyzed K66 hydroxylation, together with Hsp70, routes PKM2 to chaperone-mediated autophagy, with loss causing PKM2 accumulation and dilated cardiomyopathy.","evidence":"Cardiomyocyte-specific Jmjd4 knockout, Jmjd4-Hsp70-PKM2 Co-IP, mass spectrometry, CMA assays, metabolite profiling","pmids":["37066795"],"confidence":"High","gaps":["How hydroxylation creates a CMA-targeting signal not structurally defined","Generality beyond cardiomyocytes untested"]},{"year":2023,"claim":"Connected serine-pathway metabolism to PKM2 stability and nuclear function, showing PHGDH binding blocks K305 acetylation/autophagy while promoting p300-mediated K433 acetylation, nuclear entry, and H3T11 phosphorylation governing senescence genes.","evidence":"Co-IP, K305/K433 mutagenesis, in vitro H3T11 kinase assay, autophagy inhibition, ChIP, endothelial senescence models","pmids":["36899022"],"confidence":"High","gaps":["Reconciliation with negative protein-kinase data not addressed","Direct PHGDH-PKM2 interface not structurally mapped"]},{"year":2023,"claim":"Established PKM2 as a metabolism-responsive translational regulator, showing PARylation- and ADP-dependent ribosome binding and crosslinking to codon-specific mRNA regions that stall translation, coupling carbohydrate metabolism to protein synthesis.","evidence":"Polysome proteomics, eCLIP-seq, ribosome footprint profiling, ADP titration, PARylation inhibition","pmids":["37224531"],"confidence":"High","gaps":["Direct RNA-binding interface on PKM2 not defined","Physiological consequences of stalling not fully mapped"]},{"year":2024,"claim":"Defined a moonlighting histidine-kinase activity in which monomeric/dimeric PKM2 phosphorylates PGAM1 H11 (PEP-dependent, primed by Src Y119 phosphorylation), tying PKM2 oligomeric state to a specific glycolytic substrate.","evidence":"In vitro histidine kinase assay, mass spectrometry, Co-IP, H11/Y119 mutagenesis, peptide disruption, xenografts","pmids":["38750259"],"confidence":"High","gaps":["Independent reconstitution in light of prior negative kinase data lacking","Chemistry of histidine phosphotransfer not structurally resolved"]},{"year":2024,"claim":"Identified a sequence-specific non-canonical RNA function, showing nuclear PKM2 binds RNA G-quadruplexes in pre-mRNAs to exclude repressive RBPs like HNRNPF and promote rG4-containing transcript expression and invasion.","evidence":"eCLIP-seq, ribosome footprinting, in vitro G-quadruplex binding, nuclear fractionation, HNRNPF competition, xenografts","pmids":["39153475"],"confidence":"High","gaps":["RNA-binding domain/residues of PKM2 not mapped","Relationship to PKM2 kinase activity unknown"]},{"year":2024,"claim":"Showed SIRT1 deacetylates PKM2 at K135/K206 to lower enzymatic activity and lactate, reducing glial activation in Parkinson's disease models, adding a deacetylation node to PKM2 regulation.","evidence":"Co-IP, K135/K206 site mapping, activity and lactate assays, PD mouse models with SIRT1 and PKM2 manipulation","pmids":["39128469"],"confidence":"Medium","gaps":["Single lab","Whether deacetylation affects oligomeric state not addressed"]},{"year":2024,"claim":"Demonstrated that PKM2 aggregation in senescent and aged tissues impairs its enzymatic activity and glycolysis to drive senescence, and that dissolving aggregates extends lifespan, linking PKM2 conformational state to aging.","evidence":"Aggregate detection, activity assays, small-molecule screening, senescence markers, lifespan measurement","pmids":["38982055"],"confidence":"Medium","gaps":["Structural nature of aggregates undefined","Single lab"]},{"year":2025,"claim":"Identified additional ubiquitin- and phospho-based tetramer-promoting inputs (PINK1 S127 phosphorylation; March2 K33-linked ubiquitination) that block nuclear translocation and constrain glycolysis-derived histone lactylation in osteoarthritis and aortic disease.","evidence":"Genetic KO/overexpression models, Co-IP, S127 phosphorylation and K33-ubiquitination analysis, native PAGE, CUT&TAG, pharmacological rescue","pmids":["40087281","40079144"],"confidence":"Medium","gaps":["Single-lab studies","How distinct ubiquitin linkages mechanistically alter oligomerization not resolved"]},{"year":2025,"claim":"Extended PKM2-derived lactate to developmental epigenetics and immune metabolite signaling, with H3K9 lactylation controlling Sox factors in cochlear development and tetramer-driven ATP/adenosine-A2aR signaling enhancing macrophage IL-10.","evidence":"Conditional KO, organoids, H3K9la ChIP, metabolic flux, TEPP-46 activation, ATP/adenosine measurement, A2aR antagonism, IL-10 ELISA","pmids":["39773029","39772395"],"confidence":"Medium","gaps":["Direct vs metabolite-mediated effects not fully separated in all contexts","Single-lab studies"]},{"year":null,"claim":"The central unresolved question remains whether PKM2's reported protein/histidine kinase activities reflect a genuine intrinsic catalytic mechanism or are artifacts/indirect effects, and how a single quaternary-structure equilibrium is quantitatively partitioned among its glycolytic, kinase, transcriptional, RNA-binding, and translational roles in a given cell.","evidence":"","pmids":[],"confidence":"Low","gaps":["Positive (H3T11, Bub3, MLC2, PGAM1) and negative reconstitution results not reconciled","No unified structural model linking oligomeric state to each non-canonical activity","Quantitative flux partitioning among competing functions unmeasured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,14]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,8,33]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[15,16]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[1,14]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,1,8,15,30,33]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,18,34]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[7]},{"term_id":"GO:0005840","term_label":"ribosome","supporting_discovery_ids":[16]},{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,9,18,23,29]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,8,33]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,8,19,29]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[2,3,10]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[15,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[4,12,36]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[31,32]}],"complexes":[],"partners":["CTNNB1","STAT3","MFN2","PHGDH","PGAM1","MARCH2","ANXA5","FSTL1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P14618","full_name":"Pyruvate kinase PKM","aliases":["Cytosolic thyroid hormone-binding protein","CTHBP","Opa-interacting protein 3","OIP-3","Pyruvate kinase 2/3","Pyruvate kinase muscle isozyme","Threonine-protein kinase PKM2","Thyroid hormone-binding protein 1","THBP1","Tumor M2-PK","Tyrosine-protein kinase PKM2","p58"],"length_aa":531,"mass_kda":57.9,"function":"Catalyzes the final rate-limiting step of glycolysis by mediating the transfer of a phosphoryl group from phosphoenolpyruvate (PEP) to ADP, generating ATP (PubMed:15996096, PubMed:1854723, PubMed:20847263). The ratio between the highly active tetrameric form and nearly inactive dimeric form determines whether glucose carbons are channeled to biosynthetic processes or used for glycolytic ATP production (PubMed:15996096, PubMed:1854723, PubMed:20847263). The transition between the 2 forms contributes to the control of glycolysis and is important for tumor cell proliferation and survival (PubMed:15996096, PubMed:1854723, PubMed:20847263) Isoform specifically expressed during embryogenesis that has low pyruvate kinase activity by itself and requires allosteric activation by D-fructose 1,6-bisphosphate (FBP) for pyruvate kinase activity (PubMed:18337823, PubMed:20847263). In addition to its pyruvate kinase activity in the cytoplasm, also acts as a regulator of transcription in the nucleus by acting as a protein kinase (PubMed:18191611, PubMed:21620138, PubMed:22056988, PubMed:22306293, PubMed:22901803, PubMed:24120661). Translocates into the nucleus in response to various signals, such as EGF receptor activation, and homodimerizes, leading to its conversion into a protein threonine- and tyrosine-protein kinase (PubMed:22056988, PubMed:22306293, PubMed:22901803, PubMed:24120661, PubMed:26787900). Catalyzes phosphorylation of STAT3 at 'Tyr-705' and histone H3 at 'Thr-11' (H3T11ph), leading to activate transcription (PubMed:22306293, PubMed:22901803, PubMed:24120661). Its ability to activate transcription plays a role in cancer cells by promoting cell proliferation and promote tumorigenesis (PubMed:18337823, PubMed:22901803, PubMed:26787900). Promotes the expression of the immune checkpoint protein CD274 in BMAL1-deficient macrophages (By similarity). May also act as a translation regulator for a subset of mRNAs, independently of its pyruvate kinase activity: associates with subpools of endoplasmic reticulum-associated ribosomes, binds directly to the mRNAs translated at the endoplasmic reticulum and promotes translation of these endoplasmic reticulum-destined mRNAs (By similarity). Plays a role in caspase independent cell death of tumor cells (PubMed:17308100) Pyruvate kinase isoform expressed in adult tissues, which replaces isoform M2 after birth (PubMed:18337823). In contrast to isoform M2, has high pyruvate kinase activity by itself and does not require allosteric activation by D-fructose 1,6-bisphosphate (FBP) for activity (PubMed:20847263)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P14618/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/PKM","classification":"Common Essential","n_dependent_lines":1075,"n_total_lines":1208,"dependency_fraction":0.8899006622516556},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000067225","cell_line_id":"CID000936","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"nucleoplasm","grade":1}],"interactors":[{"gene":"CLIP1","stoichiometry":0.2},{"gene":"FDPS","stoichiometry":0.2},{"gene":"TRUB1","stoichiometry":0.2},{"gene":"PAWR","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000936","total_profiled":1310},"omim":[{"mim_id":"617007","title":"TRIPARTITE MOTIF-CONTAINING PROTEIN 35; TRIM35","url":"https://www.omim.org/entry/617007"},{"mim_id":"610533","title":"WW AND C2 DOMAINS-CONTAINING PROTEIN 1; WWC1","url":"https://www.omim.org/entry/610533"},{"mim_id":"602457","title":"FAS-ASSOCIATED VIA DEATH DOMAIN; FADD","url":"https://www.omim.org/entry/602457"},{"mim_id":"600693","title":"POLYPYRIMIDINE TRACT-BINDING PROTEIN 1; PTBP1","url":"https://www.omim.org/entry/600693"},{"mim_id":"179050","title":"PYRUVATE KINASE, MUSCLE; PKM","url":"https://www.omim.org/entry/179050"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Cytosol","reliability":"Enhanced"},{"location":"Vesicles","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal muscle","ntpm":3777.5},{"tissue":"tongue","ntpm":2492.1}],"url":"https://www.proteinatlas.org/search/PKM"},"hgnc":{"alias_symbol":["THBP1","OIP3","PK3"],"prev_symbol":["PKM2"]},"alphafold":{"accession":"P14618","domains":[{"cath_id":"3.20.20.60","chopping":"45-116_220-385","consensus_level":"high","plddt":98.2647,"start":45,"end":385},{"cath_id":"2.40.33.10","chopping":"118-209","consensus_level":"high","plddt":96.0021,"start":118,"end":209},{"cath_id":"3.40.1380.20","chopping":"391-529","consensus_level":"high","plddt":97.5304,"start":391,"end":529}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14618","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14618-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14618-F1-predicted_aligned_error_v6.png","plddt_mean":96.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PKM","jax_strain_url":"https://www.jax.org/strain/search?query=PKM"},"sequence":{"accession":"P14618","fasta_url":"https://rest.uniprot.org/uniprotkb/P14618.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14618/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14618"}},"corpus_meta":[{"pmid":"22056988","id":"PMC_22056988","title":"Nuclear 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TEM","url":"https://pubmed.ncbi.nlm.nih.gov/22824010","citation_count":308,"is_preprint":false},{"pmid":"24508027","id":"PMC_24508027","title":"PKM2 contributes to cancer metabolism.","date":"2014","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/24508027","citation_count":281,"is_preprint":false},{"pmid":"26998110","id":"PMC_26998110","title":"PKM2 and cancer: The function of PKM2 beyond glycolysis.","date":"2016","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/26998110","citation_count":248,"is_preprint":false},{"pmid":"32078387","id":"PMC_32078387","title":"Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration.","date":"2020","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/32078387","citation_count":242,"is_preprint":false},{"pmid":"32697823","id":"PMC_32697823","title":"PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation.","date":"2020","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32697823","citation_count":238,"is_preprint":false},{"pmid":"33246091","id":"PMC_33246091","title":"Pyruvate kinase M2 (PKM2) in cancer and cancer therapeutics.","date":"2020","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/33246091","citation_count":206,"is_preprint":false},{"pmid":"24316223","id":"PMC_24316223","title":"PKM2 regulates chromosome segregation and mitosis progression of tumor cells.","date":"2013","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/24316223","citation_count":200,"is_preprint":false},{"pmid":"35140065","id":"PMC_35140065","title":"FSTL1 promotes liver fibrosis by reprogramming macrophage function through modulating the intracellular function of PKM2.","date":"2022","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/35140065","citation_count":197,"is_preprint":false},{"pmid":"30887444","id":"PMC_30887444","title":"PKM2 coordinates glycolysis with mitochondrial 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This PKM2–β-catenin interaction is required for recruitment to the CCND1 promoter, HDAC3 removal, histone H3 acetylation, and cyclin D1 expression, thereby promoting tumor cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, nuclear fractionation, site-directed mutagenesis (K433, Y333), gene reporter assays, in vivo brain tumor models\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (Co-IP, ChIP, mutagenesis, in vivo) in a single rigorous study with clear mechanistic dissection\",\n      \"pmids\": [\"22056988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nuclear PKM2 directly binds histone H3 and phosphorylates it at T11 upon EGF receptor activation. This phosphorylation causes dissociation of HDAC3 from the CCND1 and MYC promoters, leading to H3K9 acetylation and transcriptional activation of cyclin D1 and c-Myc, promoting cell-cycle progression and tumorigenesis.\",\n      \"method\": \"In vitro kinase assay with recombinant proteins, Co-IP, ChIP, mass spectrometry, site-directed mutagenesis, in vivo brain tumor models\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of histone kinase activity, mutagenesis, ChIP, and in vivo validation in one rigorous study\",\n      \"pmids\": [\"22901803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"PKM2 (but not PKM1) binds the spindle checkpoint protein Bub3 during mitosis and phosphorylates Bub3 at Y207. This phosphorylation is required for Bub3-Bub1 complex recruitment to kinetochores, correct kinetochore-microtubule attachment, mitotic/spindle-assembly checkpoint fidelity, and accurate chromosome segregation.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (Y207), kinetochore localization imaging, genetic rescue experiments, in vivo tumor models\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay with mutagenesis, Co-IP, and in vivo validation across multiple orthogonal methods in one study\",\n      \"pmids\": [\"24316223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Aurora B phosphorylates PKM2 (but not PKM1) at T45, which is required for PKM2 localization to the contractile ring during cytokinesis. PKM2 then phosphorylates MLC2 at Y118, priming ROCK2 binding to MLC2 and subsequent ROCK2-dependent MLC2 S15 phosphorylation, driving cytokinesis completion and cell proliferation.\",\n      \"method\": \"In vitro kinase assay, Co-IP, site-directed mutagenesis (T45, Y118), live-cell imaging, mass spectrometry, in vivo brain tumor models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assays, mutagenesis at defined sites, Co-IP, and in vivo validation with multiple orthogonal methods\",\n      \"pmids\": [\"25412762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Acetylation of PKM2 at Lys305 decreases its pyruvate kinase activity and targets it for chaperone-mediated autophagy and subsequent lysosomal degradation.\",\n      \"method\": \"In vitro enzymatic activity assay, acetylation mutant analysis, lysosomal degradation assays, chaperone-mediated autophagy pathway analysis\",\n      \"journal\": \"Cold Spring Harbor symposia on quantitative biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity assay and degradation pathway validation, single lab with multiple methods but abstract-level description\",\n      \"pmids\": [\"22096030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Using [32P]-phosphoenolpyruvate (PEP) with recombinant enzyme and PKM2-deleted in vitro systems, no PKM2-dependent protein kinase activity was detected; labeled protein species required ADP and were not PKM2-dependent, and direct phosphate transfer from ATP to protein by PKM2 was not observed. This constitutes a NEGATIVE finding challenging PKM2 protein kinase activity.\",\n      \"method\": \"Radioisotope [32P]-PEP labeling assay with recombinant PKM2, genetic deletion of PKM2 in cell systems, in vitro phosphorylation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro reconstitution with genetic deletion controls, single lab but multiple orthogonal methods; result is explicitly NEGATIVE for PKM2 protein kinase activity\",\n      \"pmids\": [\"26300261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"PKM2-mediated glycolysis promotes NLRP3 and AIM2 inflammasome activation in macrophages by modulating EIF2AK2 phosphorylation. Myeloid cell-specific conditional knockout of PKM2 attenuates inflammasome activation and protects mice from lethal endotoxemia and polymicrobial sepsis.\",\n      \"method\": \"Myeloid-specific PKM2 conditional knockout mice, pharmacological inhibition, inflammasome activation assays, cytokine measurement, in vivo sepsis models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic conditional knockout with clear mechanistic pathway (PKM2→EIF2AK2→inflammasome) validated in vivo with pharmacological corroboration\",\n      \"pmids\": [\"27779186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PKM2 interacts with mitofusin 2 (MFN2) to promote mitochondrial fusion and oxidative phosphorylation while attenuating glycolysis. mTOR modulates this interaction by phosphorylating MFN2, establishing an mTOR-MFN2-PKM2 signaling axis that coordinates glycolysis and OXPHOS.\",\n      \"method\": \"Co-immunoprecipitation, mitochondrial morphology imaging, metabolic flux analysis (Seahorse), mTOR inhibitor experiments, genetic manipulation of MFN2 and PKM2\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and metabolic assays in single lab, mechanistic pathway established with multiple methods but no structural validation\",\n      \"pmids\": [\"30887444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKM2 translocates into the nucleus in Th17 cells and interacts with STAT3, enhancing STAT3 activation and thereby promoting Th17 cell differentiation. T cell-specific PKM2 deletion impairs Th17 differentiation and ameliorates experimental autoimmune encephalomyelitis, independent of effects on metabolic reprogramming or proliferation.\",\n      \"method\": \"T cell-specific PKM2 conditional knockout, Co-immunoprecipitation of PKM2-STAT3, flow cytometry for Th17 markers, EAE mouse model\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic conditional knockout with Co-IP and in vivo disease model, multiple orthogonal methods establishing non-metabolic nuclear function\",\n      \"pmids\": [\"32697823\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lactylation of PKM2 at K62 inhibits its tetramer-to-dimer transition, thereby promoting its pyruvate kinase activity and reducing nuclear distribution, which suppresses the Warburg effect and promotes transition of pro-inflammatory macrophages toward a reparative phenotype.\",\n      \"method\": \"Mass spectrometry identification of lactylation site, K62 mutant analysis, pyruvate kinase activity assay, native PAGE for tetramer/dimer analysis, nuclear fractionation, macrophage polarization assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-identified PTM with activity assay and oligomeric state analysis, single lab with multiple methods\",\n      \"pmids\": [\"36439872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PKM2 regulates the cardiomyocyte cell cycle and reduces oxidative stress through anabolic pathways and β-catenin. Cardiomyocyte-specific Pkm2 deletion during cardiac development reduces cardiomyocyte cell cycle activity, cardiomyocyte numbers, and myocardial size.\",\n      \"method\": \"Cardiomyocyte-specific Pkm2 conditional knockout, modified mRNA overexpression, cardiac morphometry, cell cycle marker analysis, myocardial infarction models\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic conditional KO with clear phenotypic readout, mechanistic link to β-catenin stated but limited orthogonal biochemical validation described in abstract\",\n      \"pmids\": [\"32078387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PHGDH prevents PKM2 K305 acetylation (catalyzed by PCAF) and subsequent autophagic degradation by directly interacting with PKM2. PHGDH also facilitates p300-catalyzed PKM2 K433 acetylation, which promotes PKM2 nuclear translocation and enables it to phosphorylate H3T11, regulating transcription of senescence-associated genes.\",\n      \"method\": \"Co-immunoprecipitation, acetylation mutant analysis (K305, K433), in vitro kinase assay (H3T11 phosphorylation), autophagy inhibition assays, ChIP, endothelial senescence models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including in vitro kinase assay, mutagenesis at defined sites, Co-IP, ChIP in a single rigorous study\",\n      \"pmids\": [\"36899022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Jmjd4 interacts with Hsp70 to mediate degradation of Pkm2 through chaperone-mediated autophagy, dependent on Jmjd4-catalyzed hydroxylation of K66 of Pkm2. Loss of Jmjd4 in cardiomyocytes leads to Pkm2 accumulation, impaired mitochondrial respiration, and spontaneous dilated cardiomyopathy.\",\n      \"method\": \"Cardiomyocyte-specific Jmjd4 conditional knockout, Co-IP of Jmjd4-Hsp70-Pkm2, mass spectrometry, chaperone-mediated autophagy assays, metabolite profiling, RNA-seq\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — genetic KO, biochemical Co-IP establishing ternary complex, defined PTM site (K66 hydroxylation), and multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"37066795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SIRT1 interacts with and deacetylates PKM2 at K135 and K206, leading to reduced PKM2 enzymatic activity and lactate production, which decreases glial activation in the brain and ameliorates Parkinson's disease phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, deacetylation site mapping (K135, K206), pyruvate kinase activity assay, lactate measurement, PD mouse models with SIRT1 knockdown/overexpression and PKM2 inhibition\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and enzymatic activity assay with defined PTM sites and in vivo disease model, single lab\",\n      \"pmids\": [\"39128469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PKM2 moonlights as a histidine kinase in a phosphoenolpyruvate (PEP)-dependent manner to catalyze PGAM1 H11 phosphorylation, which is essential for PGAM1 activity. Monomeric and dimeric PKM2 (but not tetrameric) efficiently phosphorylate PGAM1. Src-catalyzed PGAM1 Y119 phosphorylation is a prerequisite for PKM2 binding and subsequent H11 phosphorylation.\",\n      \"method\": \"In vitro histidine kinase assay, mass spectrometry, Co-IP, site-directed mutagenesis (H11, Y119), cell-permeable peptide disruption of PKM2-PGAM1 interaction, tumor xenograft models\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution with defined substrates, mutagenesis at phosphorylation sites, peptide disruption validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38750259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Nuclear PKM2 functions as a non-canonical RNA-binding protein that specifically interacts with folded RNA G-quadruplex (rG4) structures in precursor mRNAs. PKM2 occupancy at rG4s prevents binding of repressive RBPs (e.g., HNRNPF) and promotes expression of rG4-containing pre-mRNAs. Preventing nuclear PKM2 accumulation represses the rG4ome and reduces cancer cell migration and invasion.\",\n      \"method\": \"eCLIP-seq, ribosome footprinting, nuclear fractionation, RNA-binding assays, in vitro G-quadruplex binding, xenograft mouse models, competitive displacement with HNRNPF\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — eCLIP-seq identifies genome-wide binding sites, biochemical in vitro binding, functional xenograft validation; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"39153475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PKM binds ribosomes in a poly-ADP ribosylation (PARylation)-dependent manner. PKM crosslinks to mRNA sequences downstream of lysine- and glutamate-encoding regions and causes translational stalling near these sequences. PKM-polysome interaction is regulated by ADP levels, linking carbohydrate metabolism to mRNA translation regulation.\",\n      \"method\": \"Proteomic polysome survey, eCLIP-seq, ribosome footprint protection sequencing, ADP titration assays, PARylation inhibition experiments\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal genome-wide and biochemical methods (eCLIP-seq, ribosome profiling, biochemical assays) in single rigorous study establishing novel function\",\n      \"pmids\": [\"37224531\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FSTL1 binds directly to PKM2 through its FK domain, promotes PKM2 phosphorylation and nuclear translocation, and reduces PKM2 ubiquitination, thereby enhancing PKM2-dependent glycolysis and macrophage M1 polarization, promoting liver fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, ubiquitination assay, myeloid-specific FSTL1 knockout mice, pharmacological PKM2 activation (DASA-58)\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with defined domain, genetic KO, and pharmacological validation; single lab with multiple methods\",\n      \"pmids\": [\"35140065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Annexin A5 directly interacts with PKM2 at ASP101, LEU104, and ARG106, inhibits phosphorylation of Y105, and promotes PKM2 tetramer formation, thereby switching macrophage metabolism from glycolysis to oxidative phosphorylation and promoting M2 polarization.\",\n      \"method\": \"Pull-down assay, molecular docking, site-directed mutagenesis (D101, L104, R106), PKM2 Y105E phosphomimetic mutant, native PAGE for oligomeric state, metabolic flux analysis\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding with defined residues, mutant validation, oligomeric state assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32863213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PKM2 regulates post-ischemic inflammation in peripheral neutrophils by promoting STAT3 phosphorylation. Myeloid cell-specific PKM2 deletion reduced neutrophil extracellular traps, cerebral thrombo-inflammation, and infarct volume after stroke. Inhibiting PKM2 nuclear translocation pharmacologically reduced neutrophil hyperactivation.\",\n      \"method\": \"Myeloid-specific PKM2 conditional knockout mice, STAT3 phosphorylation assay, neutrophil extracellular trap quantification, stroke models (filament/clot), laser speckle imaging, small-molecule nuclear translocation inhibitor\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic conditional KO with defined signaling readout (STAT3 phosphorylation), corroborated by pharmacological inhibition with multiple in vivo models\",\n      \"pmids\": [\"34529778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"GTPBP4 facilitates SUMO1-mediated sumoylation of PKM2, which promotes PKM2 dimer formation and aerobic glycolysis. Sumoylated PKM2 relocates from cytoplasm to nucleus, activating EMT and STAT3 signaling in hepatocellular carcinoma.\",\n      \"method\": \"Co-immunoprecipitation, sumoylation assay, nuclear fractionation, UBA2 activation assay, gain/loss-of-function studies, in vitro and in vivo tumor models\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and sumoylation assay with defined pathway components; single lab, multiple methods\",\n      \"pmids\": [\"36116159\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Extracellular PKM2 (EcPKM2) secreted by myofibroblasts interacts with integrin αvβ3 on myofibroblast surfaces to activate FAK-PI3K signaling, which activates NF-κB survival pathway (preventing apoptosis) and suppresses PTEN to upregulate arginase-1, facilitating proline biosynthesis and collagen production in organ fibrosis.\",\n      \"method\": \"Co-immunoprecipitation of EcPKM2-integrin αvβ3, FAK-PI3K phosphorylation assays, NF-κB reporter, arginase-1 assay, antibody blocking experiments, in vivo fibrosis models\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing extracellular binding partner, signaling pathway validation, antibody disruption in vivo; single lab\",\n      \"pmids\": [\"34693222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Celastrol binds covalently to Cys424 of PKM2, inhibiting its enzymatic activity and suppressing aerobic glycolysis (Warburg effect) in macrophages, thereby attenuating inflammatory responses in sepsis.\",\n      \"method\": \"Activity-based protein profiling (ABPP), cellular thermal shift assay (CETSA), surface plasmon resonance (SPR), point mutagenesis (Cys424), gene knockdown\",\n      \"journal\": \"Military Medical Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — biophysical binding assays (SPR, CETSA), defined covalent binding site via mutagenesis; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"35596191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PKM2-C31 palmitoylation (mediated by palmitoyl acyltransferase zDHHC13) impairs PKM2 tetramerization, inhibits its pyruvate kinase activity and endothelial glycolysis, causing palmitic acid-induced endothelial injury and cardiovascular dysfunction. PKM2-C31S mutation prevents these effects.\",\n      \"method\": \"Palmitoyl-proteomics, site-directed mutagenesis (C31S), endothelial-specific AAV-mediated expression, pyruvate kinase activity assay, native PAGE for tetramerization, palmitoyl-transferase inhibitor/activator experiments, ApoE-/- mouse model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — defined palmitoylation site with mutagenesis rescue, enzymatic activity assay, oligomeric state analysis, and in vivo validation; multiple orthogonal methods\",\n      \"pmids\": [\"39665133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Prohibitin 2 (PHB2), through its C-terminus, directly interacts with hnRNPA1 (a key modulator of PKM alternative splicing) to counteract hnRNPA1-mediated PKM2 expression and glycolysis, thereby maintaining the contractile VSMC phenotype.\",\n      \"method\": \"Co-immunoprecipitation, mammalian two-hybrid assay, protein interactome analysis, PKM splicing analysis (RT-PCR), metabolic flux analysis, PHB2-deficient mouse model, neointima formation model\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and mammalian two-hybrid with defined domain, splicing and metabolic phenotype validation; single lab\",\n      \"pmids\": [\"36200440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PINK1 phosphorylates PKM2 at Ser127, preserving its active tetrameric form and inhibiting its nuclear translocation and interaction with β-catenin, resulting in a metabolic shift toward energy production. SIRT3 deacetylates PINK1 to promote this pathway (SIRT3-PINK1-PKM2 axis) protecting against osteoarthritis.\",\n      \"method\": \"PINK1 knockout/overexpression mouse models, Co-immunoprecipitation, phosphorylation site analysis (S127), native PAGE for tetramer confirmation, nuclear fractionation, double-knockout mouse model\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic models with Co-IP and phosphorylation site identification; single lab with multiple orthogonal methods but abstract-level detail\",\n      \"pmids\": [\"40087281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DEUBIQUITINASE JOSD2 interacts with PKM2 and reduces its K433 acetylation, thereby blocking PKM2 nuclear localization and downstream non-glycolytic gene expression in acute myeloid leukemia, without affecting PKM2 protein stability.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, co-immunofluorescence, K433 acetylation assay, nuclear fractionation, gene expression analysis, in vivo AML progression model\",\n      \"journal\": \"Experimental hematology & oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mass spectrometry, defined PTM site, nuclear fractionation; single lab, multiple methods\",\n      \"pmids\": [\"35836282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"March2 promotes K33-linked polyubiquitination of PKM2, facilitating PKM2 dimer-to-tetramer conversion. Deficiency of March2 lessens PKM2 tetramerization, promotes glycolysis-derived H3K18 lactylation, and drives p53-dependent apoptotic transcription, accelerating aortic aneurysm/dissection pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination type analysis (K33-linkage specific), native PAGE for oligomeric state, ChIP for H3K18 lactylation (CUT&TAG), smooth muscle cell-specific March2 knockout mice, PKM2 activator (TEPP-46) rescue\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, defined ubiquitin linkage, oligomeric state assay, genetic KO and pharmacological rescue; single lab, multiple methods\",\n      \"pmids\": [\"40079144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PKM2-derived pyruvate is converted to lactate, which lactylates histone H3 at K9 (H3K9la), upregulating Sox family transcription factors through epigenetic modification to control cochlear development. PKM2 deletion causes a metabolic switch from glycolysis to OXPHOS and impairs cochlear sensory epithelium morphogenesis.\",\n      \"method\": \"Conditional PKM2 knockout in cochlear progenitors, cochlear organoids, H3K9la ChIP, metabolic flux analysis, gene expression (Sox factors), human and mouse cochlear explants with PKM2 overexpression\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined epigenetic mechanism (H3K9la ChIP), multiple model systems; single lab\",\n      \"pmids\": [\"39773029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Tetrameric PKM2 (promoted by TEPP-46) increases ATP production from glycolysis; extracellular ATP is converted to adenosine via ectonucleotidases, activating adenosine receptor A2a (A2aR) to enhance IL-10 production in macrophages. This effect is abolished in PKM2-deficient macrophages.\",\n      \"method\": \"PKM2-deficient macrophages, TEPP-46 pharmacological activation, extracellular ATP/adenosine measurement, A2aR antagonist, ectonucleotidase inhibition, IL-10 ELISA, metabolic flux analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PKM2 KO abolishment of effect, defined metabolic-signaling pathway with pharmacological dissection; single lab, multiple methods\",\n      \"pmids\": [\"39772395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"PKM2 dimerization is induced by PKM2 sumoylation (via GTPBP4-SUMO1-UBA2 axis), and dimeric PKM2 promotes aerobic glycolysis and nuclear translocation. Separately, PKM2 nuclear translocation is required for complex formation with STAT3, HIF1α-mediated angiogenesis, and tumor maintenance in bladder cancer.\",\n      \"method\": \"PKM2 knockout, PKM2 overexpression (PKM2 vs PKM1), Co-IP of PKM2-STAT3, nuclear fractionation, VEGF/HIF1α pathway analysis, inducible PKM2 expression mouse models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation comparing PKM1 vs PKM2, Co-IP, nuclear fractionation; single lab with multiple in vivo and in vitro methods\",\n      \"pmids\": [\"34903602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dimeric/monomeric PKM2 nuclear translocation is promoted by ROS-induced oxidation at Cys423/Cys424, leading to glutathionylation of PKM2. Nuclear PKM2 then acts as a co-factor to promote HIF-1α-dependent gene induction, contributing to cardioprotective adaptive responses.\",\n      \"method\": \"Cys423/424 mutagenesis, glutathionylation assay, nuclear fractionation, HIF-1α reporter, cardiac-specific Pkm2 knockdown, ROS measurement, ischemia mouse model\",\n      \"journal\": \"Acta pharmaceutica Sinica. B\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis at defined Cys sites with glutathionylation assay and nuclear fractionation; single lab, in vitro and in vivo validation\",\n      \"pmids\": [\"36815040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PKM2 aggregates form in senescent cells and organs from aged mice, impairing PKM2 enzymatic activity and glycolytic flux, thereby driving cells into senescence. Small molecules capable of dissolving PKM2 aggregates alleviate senescence and extend lifespan in mouse models.\",\n      \"method\": \"PKM2 aggregate detection (biochemical fractionation, imaging), pyruvate kinase activity assay in senescent vs non-senescent cells, small molecule library screening, senescence marker analysis (SA-β-Gal, p16), lifespan measurement in aging mouse models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical aggregate characterization, enzymatic activity impairment, small molecule rescue; single lab with multiple methods including in vivo lifespan\",\n      \"pmids\": [\"38982055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKM2 interacts with NF-κB and induces nuclear translocation of both PKM2 and NF-κB with assistance of importin 4. In the nucleus, PKM2-NF-κB complexes augment VEGFA transcription, promoting tumor angiogenesis. FBP promotes assembly of a FOXM1D-PKM2 heterooctamer that reduces PKM2 metabolic activity.\",\n      \"method\": \"Co-immunoprecipitation, nuclear fractionation, importin 4 knockdown, VEGFA promoter reporter, exosome-mediated VEGFA secretion assay, metabolic activity assay, tumor angiogenesis model\",\n      \"journal\": \"Molecular oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for multiple complexes, nuclear translocation assay, reporter assay; single lab with multiple methods\",\n      \"pmids\": [\"33314660\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CXCL12 signaling through CXCR4 and ACKR3 stimulates protein interactions among β-arrestin 2, PKM2, and ERK2, leading to dissociation of PKM2 from β-arrestin 2, reduced PKM2 oligomerization (tetramers to dimers/monomers), and increased glycolytic intermediates and pentose phosphate pathway metabolites.\",\n      \"method\": \"Luciferase protein complementation assays for protein-protein interactions, mass spectrometry of metabolites with isotopically labeled glucose, PKM2 oligomerization assay, tumor xenograft model\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative protein interaction assay, isotopic metabolite tracing, oligomerization measurement; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"35681470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKM2 interacts with Oct4 in glioma stem cells, and this interaction is implicated in the regulation of glioma stemness. Silencing PKM2 enhances apoptosis and differentiation of glioma spheroids. DCA (a PDK inhibitor) increases PKM2/Oct4 complex formation and inhibits Oct4-dependent gene expression.\",\n      \"method\": \"Co-immunoprecipitation of PKM2-Oct4, PKM2 siRNA knockdown, apoptosis assays, differentiation markers, DCA treatment and Oct4 reporter\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing PKM2-Oct4 interaction, loss-of-function with defined phenotypic readouts; single lab\",\n      \"pmids\": [\"24481450\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKM2 promotes IL-10 production via tetramerization-dependent ATP release and adenosine signaling, and PKM2 mediates autophagic activation by increasing phosphorylation of Beclin-1 in NPM1-mutated AML cells, contributing to cell survival.\",\n      \"method\": \"PKM2 knockdown, Beclin-1 phosphorylation assay, autophagy flux assay, cell viability assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single method for Beclin-1 phosphorylation; limited mechanistic biochemical detail in abstract\",\n      \"pmids\": [\"30906218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PKM2 regulates lipid homeostasis through an ER transmembrane protein TMEM33. Loss of PKM2 upregulates TMEM33, which recruits E3 ligase RNF5 to promote SCAP degradation. TMEM33 is transcriptionally regulated by NRF1, whose cleavage is controlled by PKM2 levels.\",\n      \"method\": \"Co-immunoprecipitation, SCAP degradation assay, NRF1 cleavage assay, TMEM33 promoter analysis, PKM2 global knockout mice (cholesterol measurement), allograft tumor model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, defined degradation pathway with biochemical assays, genetic KO with physiological readout; single lab\",\n      \"pmids\": [\"34487377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Vitamin B5 (pantothenate) is catabolized to coenzyme A (CoA) in a PANK-dependent manner, and CoA binds directly to PKM2, impeding its phosphorylation and nuclear translocation, thus inhibiting glycolysis and STAT3 phosphorylation, and suppressing Th17 cell differentiation.\",\n      \"method\": \"PKM2-CoA binding assay, PKM2 phosphorylation assay, nuclear fractionation, STAT3 phosphorylation assay, Th17 differentiation assay, EAE and colitis mouse models\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay for CoA-PKM2, nuclear translocation assay, defined signaling readout; single lab, multiple methods\",\n      \"pmids\": [\"36450257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Mannose directly binds PKM2, inhibiting its enzymatic activity and reducing lactate production, leading to decreased PKM2 lactylation and increased PKM2 acetylation, which causes nuclear translocation of PKM2 and NF-κB pathway activation, inducing NLRP1/Caspase-1/GSDMD/IL-1β-dependent pyroptosis in bladder cancer.\",\n      \"method\": \"Direct binding assay (mannose-PKM2), pyruvate kinase activity assay, lactate measurement, lactylation/acetylation assays on PKM2, nuclear fractionation, NF-κB pathway assay, pyroptosis markers, xenograft and organoid models\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding assay, PTM characterization, nuclear translocation, downstream pathway; single lab, multiple methods\",\n      \"pmids\": [\"40312519\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PKM2 is a multifunctional glycolytic enzyme that, in its cytoplasmic tetrameric form, catalyzes the conversion of PEP to pyruvate; its dimer/monomer forms can translocate to the nucleus where it acts as a protein kinase (phosphorylating histone H3-T11, Bub3-Y207, MLC2-Y118, and PGAM1-H11 via PEP-dependent mechanisms), a co-transcriptional activator (binding β-catenin, STAT3, NF-κB, and Oct4 to regulate gene expression), and a non-canonical RNA-binding protein (interacting with RNA G-quadruplex structures to regulate pre-mRNA expression); its oligomeric state, subcellular localization, and activities are tightly regulated by post-translational modifications including phosphorylation (Aurora B at T45, PINK1 at S127, Src at Y105), acetylation (PCAF at K305 targeting it for autophagy; p300 at K433 promoting nuclear entry), sumoylation, glutathionylation (Cys423/424), lactylation (K62 promoting tetramerization), palmitoylation (C31 impairing tetramerization), and hydroxylation (Jmjd4 at K66 promoting CMA degradation), as well as allosteric regulators and interactions with binding partners such as MFN2, PHGDH, Annexin A5, FSTL1, CoA, and integrin αvβ3.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PKM (PKM2 isoform) is a multifunctional glycolytic pyruvate kinase whose tetrameric form drives metabolic flux but whose dimeric/monomeric forms acquire non-canonical activities upon translocation to the nucleus, coordinating metabolism with gene expression, cell-cycle control, and inflammation [#0, #2]. The interconversion between oligomeric states is the central regulatory switch: tetramerization favors enzymatic pyruvate kinase activity, whereas dimer/monomer formation favors nuclear functions, and this balance is tuned by an extensive set of post-translational modifications including lactylation at K62 [#9], palmitoylation at C31 [#23], glutathionylation at Cys423/424 [#31], sumoylation [#20], and several ubiquitin linkages [#27]. In the nucleus, PKM2 acts as a co-transcriptional activator that binds c-Src-phosphorylated \\u03b2-catenin to drive CCND1 transcription [#0], and phosphorylates histone H3 at T11 to evict HDAC3 and activate cyclin D1 and c-Myc [#1, #11]. During mitosis it phosphorylates the spindle-checkpoint protein Bub3 at Y207 to ensure correct kinetochore-microtubule attachment [#2], and during cytokinesis Aurora-B-primed PKM2 phosphorylates MLC2 at Y118 at the contractile ring [#3]; it also moonlights as a PEP-dependent histidine kinase phosphorylating PGAM1 at H11 [#14]. Nuclear PKM2 additionally functions as a non-canonical RNA-binding protein that occupies RNA G-quadruplex structures in pre-mRNAs to promote their expression and cancer cell invasion [#15], and binds ribosomes in a PARylation- and ADP-dependent manner to stall translation [#16]. Through nuclear partnership with STAT3 and NF-\\u03baB, PKM2 controls Th17 differentiation, macrophage and neutrophil inflammatory programs, and tumor angiogenesis [#8, #19, #33]. PKM2 abundance is governed by chaperone-mediated autophagy following K305 acetylation or Jmjd4-catalyzed K66 hydroxylation [#4, #12]. An in vitro reconstitution study using [32P]-PEP failed to detect PKM2-dependent protein kinase activity, defining a point of contention over the protein-kinase model [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established that PKM2, unlike PKM1, has a nuclear non-metabolic role by showing growth-signal-induced nuclear translocation and a direct interaction with \\u03b2-catenin required for oncogenic transcription, reframing a metabolic enzyme as a transcriptional coactivator.\",\n      \"evidence\": \"Co-IP, ChIP, nuclear fractionation, K433/Y333 mutagenesis, and in vivo brain tumor models\",\n      \"pmids\": [\"22056988\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how PKM2 oligomeric state controls nuclear entry\", \"Structural basis of the PKM2-\\u03b2-catenin interface not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Linked a specific PTM to PKM2 turnover by showing K305 acetylation lowers enzymatic activity and routes PKM2 to chaperone-mediated autophagy, connecting acetylation status to enzyme abundance.\",\n      \"evidence\": \"In vitro activity assay, acetylation mutant analysis, lysosomal/CMA degradation assays\",\n      \"pmids\": [\"22096030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Abstract-level detail only\", \"Acetyltransferase and deacetylase not defined in this study\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided the first proposed protein-kinase mechanism for nuclear PKM2 by demonstrating direct histone H3-T11 phosphorylation that evicts HDAC3 to activate cyclin D1 and c-Myc, defining an epigenetic output of PKM2.\",\n      \"evidence\": \"In vitro kinase assay with recombinant proteins, Co-IP, ChIP, mass spectrometry, mutagenesis, in vivo tumor models\",\n      \"pmids\": [\"22901803\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphate-donor mechanism (PEP vs ATP) not definitively resolved\", \"Later challenged by negative reconstitution data\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended the PKM2 protein-kinase model to mitosis by showing isoform-specific phosphorylation of Bub3 at Y207 controls kinetochore attachment and spindle-checkpoint fidelity, implicating PKM2 in chromosome segregation.\",\n      \"evidence\": \"Co-IP, in vitro kinase assay, Y207 mutagenesis, kinetochore imaging, rescue and in vivo tumor models\",\n      \"pmids\": [\"24316223\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphotransfer chemistry not independently confirmed\", \"How mitotic PKM2 is targeted to kinetochores unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected upstream mitotic kinase signaling to PKM2 localization, showing Aurora B phosphorylation at T45 directs PKM2 to the contractile ring where it primes MLC2 for ROCK2, integrating PKM2 into cytokinesis.\",\n      \"evidence\": \"In vitro kinase assays, Co-IP, T45/Y118 mutagenesis, live-cell imaging, in vivo tumor models\",\n      \"pmids\": [\"25412762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality beyond tumor models not established\", \"Does not resolve the broader controversy over PKM2 kinase activity\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Directly challenged the PKM2 protein-kinase paradigm by failing to detect PKM2-dependent protein phosphorylation in reconstituted [32P]-PEP assays with genetic deletion controls, defining a methodological dispute central to the field.\",\n      \"evidence\": \"Radioisotope [32P]-PEP labeling with recombinant PKM2 and PKM2-deleted cell systems\",\n      \"pmids\": [\"26300261\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Negative result does not exclude context-dependent kinase activity in cells\", \"Does not reconcile with positive reconstitution reports\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established a metabolism-driven role for PKM2 in innate immunity, showing glycolytic PKM2 promotes inflammasome activation via EIF2AK2 and that myeloid PKM2 loss protects against sepsis.\",\n      \"evidence\": \"Myeloid-specific conditional knockout, pharmacological inhibition, inflammasome and cytokine assays, in vivo sepsis models\",\n      \"pmids\": [\"27779186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the effect is purely metabolic or involves nuclear PKM2 not dissected\", \"Direct PKM2-EIF2AK2 biochemistry not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified a direct mitochondrial partner, showing PKM2-MFN2 interaction promotes fusion and OXPHOS while restraining glycolysis under mTOR control, establishing PKM2 as a node balancing glycolysis and respiration.\",\n      \"evidence\": \"Co-IP, mitochondrial imaging, Seahorse flux, mTOR inhibitor and genetic manipulation\",\n      \"pmids\": [\"30887444\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural validation of the interaction\", \"Single lab; reciprocal validation limited\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated a metabolism-independent nuclear function in adaptive immunity, where PKM2-STAT3 interaction drives Th17 differentiation independent of metabolic reprogramming.\",\n      \"evidence\": \"T cell-specific conditional knockout, PKM2-STAT3 Co-IP, flow cytometry, EAE model\",\n      \"pmids\": [\"32697823\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs indirect enhancement of STAT3 not fully separated\", \"Oligomeric state required for STAT3 binding not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended PKM2 cell-cycle and redox functions to developmental physiology, showing cardiomyocyte PKM2 supports proliferation and limits oxidative stress via \\u03b2-catenin during heart development.\",\n      \"evidence\": \"Cardiomyocyte-specific conditional knockout, modified mRNA overexpression, morphometry, MI models\",\n      \"pmids\": [\"32078387\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited orthogonal biochemical validation of the \\u03b2-catenin link\", \"Mechanism of oxidative-stress reduction not detailed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined an extracellular, receptor-mediated PKM2 function, where secreted PKM2 engages integrin \\u03b1v\\u03b23 to activate FAK-PI3K-NF-\\u03baB survival and pro-fibrotic collagen synthesis.\",\n      \"evidence\": \"Co-IP of EcPKM2-integrin, FAK-PI3K assays, NF-\\u03baB reporter, antibody blocking, in vivo fibrosis models\",\n      \"pmids\": [\"34693222\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of PKM2 secretion not defined\", \"Single lab; structural basis of integrin binding unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Broadened nuclear partner repertoire by showing PKM2-NF-\\u03baB complexes (importin-4-dependent) drive VEGFA transcription and that an FBP-induced FOXM1D-PKM2 heterooctamer suppresses metabolic activity, linking oligomerization to angiogenesis.\",\n      \"evidence\": \"Co-IP, nuclear fractionation, importin-4 knockdown, VEGFA reporter, metabolic assays, angiogenesis model\",\n      \"pmids\": [\"33314660\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Heterooctamer stoichiometry not structurally resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified lactylation at K62 as a PTM that locks PKM2 in its tetramer, raising enzymatic activity and reducing nuclear distribution to reprogram macrophage phenotype, formalizing a PTM-oligomer-function axis.\",\n      \"evidence\": \"Mass spectrometry, K62 mutagenesis, activity assay, native PAGE, nuclear fractionation, polarization assays\",\n      \"pmids\": [\"36439872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme catalyzing K62 lactylation not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed multiple PTM and binding-partner routes converge on the tetramer-dimer equilibrium: sumoylation (GTPBP4-SUMO1) and CXCL12-driven \\u03b2-arrestin-2/ERK2 interactions favor dimers/nuclear PKM2, while Annexin A5 binding and CoA binding favor tetramers and block nuclear translocation.\",\n      \"evidence\": \"Co-IP, sumoylation and oligomerization assays, pull-down with residue mapping, metabolite tracing, binding assays, immune/tumor models\",\n      \"pmids\": [\"36116159\", \"35681470\", \"32863213\", \"36450257\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"These regulators were studied in separate systems and not integrated\", \"Quantitative hierarchy of competing inputs unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined pharmacological and lipid-based covalent control of PKM2 activity, with celastrol binding Cys424 and zDHHC13-mediated C31 palmitoylation both impairing tetramerization and activity in inflammatory and vascular disease contexts.\",\n      \"evidence\": \"ABPP, CETSA, SPR, palmitoyl-proteomics, C31S/Cys424 mutagenesis, activity and native PAGE assays, in vivo models\",\n      \"pmids\": [\"35596191\", \"39665133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Off-target effects of celastrol not fully excluded\", \"Interplay between palmitoylation and other C31-proximal modifications unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Linked PKM2 abundance and isoform choice to vascular and fibrotic disease through ubiquitin regulation (JOSD2 deubiquitinase blocks K433 acetylation/nuclear entry; FSTL1 reduces ubiquitination to enhance nuclear PKM2) and splicing control (PHB2-hnRNPA1 axis sets PKM2 expression).\",\n      \"evidence\": \"Co-IP, mass spectrometry, ubiquitination and acetylation assays, mammalian two-hybrid, splicing RT-PCR, genetic KO models\",\n      \"pmids\": [\"35836282\", \"35140065\", \"36200440\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of some interactions limited\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed a redox-sensing nuclear function in which ROS-induced Cys423/424 glutathionylation drives dimer/monomer nuclear translocation where PKM2 acts as a HIF-1\\u03b1 cofactor for cardioprotective gene induction.\",\n      \"evidence\": \"Cys423/424 mutagenesis, glutathionylation assay, nuclear fractionation, HIF-1\\u03b1 reporter, cardiac knockdown, ischemia model\",\n      \"pmids\": [\"36815040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct HIF-1\\u03b1 cofactor mechanism not biochemically detailed\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved a degradation mechanism by showing Jmjd4-catalyzed K66 hydroxylation, together with Hsp70, routes PKM2 to chaperone-mediated autophagy, with loss causing PKM2 accumulation and dilated cardiomyopathy.\",\n      \"evidence\": \"Cardiomyocyte-specific Jmjd4 knockout, Jmjd4-Hsp70-PKM2 Co-IP, mass spectrometry, CMA assays, metabolite profiling\",\n      \"pmids\": [\"37066795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How hydroxylation creates a CMA-targeting signal not structurally defined\", \"Generality beyond cardiomyocytes untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected serine-pathway metabolism to PKM2 stability and nuclear function, showing PHGDH binding blocks K305 acetylation/autophagy while promoting p300-mediated K433 acetylation, nuclear entry, and H3T11 phosphorylation governing senescence genes.\",\n      \"evidence\": \"Co-IP, K305/K433 mutagenesis, in vitro H3T11 kinase assay, autophagy inhibition, ChIP, endothelial senescence models\",\n      \"pmids\": [\"36899022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation with negative protein-kinase data not addressed\", \"Direct PHGDH-PKM2 interface not structurally mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established PKM2 as a metabolism-responsive translational regulator, showing PARylation- and ADP-dependent ribosome binding and crosslinking to codon-specific mRNA regions that stall translation, coupling carbohydrate metabolism to protein synthesis.\",\n      \"evidence\": \"Polysome proteomics, eCLIP-seq, ribosome footprint profiling, ADP titration, PARylation inhibition\",\n      \"pmids\": [\"37224531\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct RNA-binding interface on PKM2 not defined\", \"Physiological consequences of stalling not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a moonlighting histidine-kinase activity in which monomeric/dimeric PKM2 phosphorylates PGAM1 H11 (PEP-dependent, primed by Src Y119 phosphorylation), tying PKM2 oligomeric state to a specific glycolytic substrate.\",\n      \"evidence\": \"In vitro histidine kinase assay, mass spectrometry, Co-IP, H11/Y119 mutagenesis, peptide disruption, xenografts\",\n      \"pmids\": [\"38750259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Independent reconstitution in light of prior negative kinase data lacking\", \"Chemistry of histidine phosphotransfer not structurally resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a sequence-specific non-canonical RNA function, showing nuclear PKM2 binds RNA G-quadruplexes in pre-mRNAs to exclude repressive RBPs like HNRNPF and promote rG4-containing transcript expression and invasion.\",\n      \"evidence\": \"eCLIP-seq, ribosome footprinting, in vitro G-quadruplex binding, nuclear fractionation, HNRNPF competition, xenografts\",\n      \"pmids\": [\"39153475\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"RNA-binding domain/residues of PKM2 not mapped\", \"Relationship to PKM2 kinase activity unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed SIRT1 deacetylates PKM2 at K135/K206 to lower enzymatic activity and lactate, reducing glial activation in Parkinson's disease models, adding a deacetylation node to PKM2 regulation.\",\n      \"evidence\": \"Co-IP, K135/K206 site mapping, activity and lactate assays, PD mouse models with SIRT1 and PKM2 manipulation\",\n      \"pmids\": [\"39128469\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether deacetylation affects oligomeric state not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated that PKM2 aggregation in senescent and aged tissues impairs its enzymatic activity and glycolysis to drive senescence, and that dissolving aggregates extends lifespan, linking PKM2 conformational state to aging.\",\n      \"evidence\": \"Aggregate detection, activity assays, small-molecule screening, senescence markers, lifespan measurement\",\n      \"pmids\": [\"38982055\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural nature of aggregates undefined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified additional ubiquitin- and phospho-based tetramer-promoting inputs (PINK1 S127 phosphorylation; March2 K33-linked ubiquitination) that block nuclear translocation and constrain glycolysis-derived histone lactylation in osteoarthritis and aortic disease.\",\n      \"evidence\": \"Genetic KO/overexpression models, Co-IP, S127 phosphorylation and K33-ubiquitination analysis, native PAGE, CUT&TAG, pharmacological rescue\",\n      \"pmids\": [\"40087281\", \"40079144\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab studies\", \"How distinct ubiquitin linkages mechanistically alter oligomerization not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PKM2-derived lactate to developmental epigenetics and immune metabolite signaling, with H3K9 lactylation controlling Sox factors in cochlear development and tetramer-driven ATP/adenosine-A2aR signaling enhancing macrophage IL-10.\",\n      \"evidence\": \"Conditional KO, organoids, H3K9la ChIP, metabolic flux, TEPP-46 activation, ATP/adenosine measurement, A2aR antagonism, IL-10 ELISA\",\n      \"pmids\": [\"39773029\", \"39772395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs metabolite-mediated effects not fully separated in all contexts\", \"Single-lab studies\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The central unresolved question remains whether PKM2's reported protein/histidine kinase activities reflect a genuine intrinsic catalytic mechanism or are artifacts/indirect effects, and how a single quaternary-structure equilibrium is quantitatively partitioned among its glycolytic, kinase, transcriptional, RNA-binding, and translational roles in a given cell.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Positive (H3T11, Bub3, MLC2, PGAM1) and negative reconstitution results not reconciled\", \"No unified structural model linking oligomeric state to each non-canonical activity\", \"Quantitative flux partitioning among competing functions unmeasured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 14]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 8, 33]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [1, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 1, 8, 15, 30, 33]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 18, 34]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"GO:0005840\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 9, 18, 23, 29]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 8, 33]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 8, 19, 29]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [2, 3, 10]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [4, 12, 36]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [31, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CTNNB1\", \"STAT3\", \"MFN2\", \"PHGDH\", \"PGAM1\", \"MARCH2\", \"ANXA5\", \"FSTL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}