{"gene":"NME2","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1993,"finding":"NME2 (NM23-H2) was identified as identical to the c-myc purine-binding transcription factor PuF; bacterially produced recombinant NM23-H2 bound to the nuclease hypersensitive element (NHE) of the c-myc promoter and activated c-myc transcription in vitro.","method":"cDNA library screening, recombinant protein production in bacteria, in vitro transcription assay, DNA binding assay","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of DNA binding and transcriptional activation, replicated in multiple subsequent studies","pmids":["8392752"],"is_preprint":false},{"year":1991,"finding":"NME2 (nm23-H2) encodes a ~17 kDa protein with 88% identity to NM23-H1 and significant homology to nucleoside diphosphate kinases, establishing it as a distinct second human nm23 gene.","method":"cDNA cloning, DNA sequencing, Southern blot, Northern blot hybridization","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct sequence identification and characterization, foundational paper replicated by multiple subsequent studies","pmids":["1988104"],"is_preprint":false},{"year":1995,"finding":"The crystal structure of NME2 at 2.8 Å resolution revealed it forms a hexamer (unlike the tetrameric Myxococcus xanthus NDP kinase); the fold is identical to other NDP kinases with a hinge-like nucleotide-binding cleft, and tumor-associated mutations destabilize the enzyme without directly affecting the catalytic active site. Ser44 and Ser122 are surface-exposed and likely phosphorylated by exogenous kinases, while Ser120 is buried and likely autophosphorylated via the phosphohistidine intermediate.","method":"X-ray crystallography at 2.8 Å (molecular replacement)","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determination with functional interpretation of active site and mutation sites","pmids":["7658474"],"is_preprint":false},{"year":1995,"finding":"NME2/PuF transactivates the human c-myc gene via the nuclease hypersensitive element (NHE) in a transient transfection assay; deletion of NHE abolished PuF-dependent CAT reporter activation, establishing that NHE is required for NME2-mediated c-myc transactivation in cells.","method":"Transient transfection, CAT reporter assay, deletion mutagenesis of NHE element","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-based reporter assay with deletion control, replicated across multiple labs","pmids":["7784082"],"is_preprint":false},{"year":1994,"finding":"The NDPK enzymatic activity of NME2 is not required for its DNA binding or in vitro transcriptional activation of c-myc; the catalytically inactive H118F mutant (substituting the phosphohistidine intermediate site) retains full DNA binding affinity and transcriptional activity, demonstrating NME2 is a bifunctional protein with separable enzymatic and transcriptional activities.","method":"Site-directed mutagenesis, radioisotopic phosphoenzyme assay, coupled enzyme assay, electrophoretic mobility shift assay (EMSA), in vitro transcription","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis combined with multiple orthogonal biochemical assays in a single rigorous study","pmids":["8132589"],"is_preprint":false},{"year":1996,"finding":"Site-directed mutagenesis identified Arg-34, Asn-69, and Lys-135 as critical residues for NME2 sequence-specific DNA binding to the c-myc regulatory element; these mutants retain NDP kinase activity and form stable hexamers, indicating separate functional domains for enzyme catalysis and DNA binding. Chemical crosslinking supported a dimeric DNA-binding mode.","method":"Site-directed mutagenesis, EMSA, NDP kinase activity assay, chemical crosslinking","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with multiple orthogonal functional assays in one study","pmids":["8692914"],"is_preprint":false},{"year":1999,"finding":"NME2 cleaves double-stranded DNA via formation of a covalent protein-DNA intermediate; cleavage produces staggered ends with 3'-OH groups and protein attached to the 5'-phosphoryl ends, reversible by EDTA. 32P transfer from DNA to NME2 was demonstrated and a covalent polypeptide-DNA complex was isolated and confirmed by Western blotting.","method":"In vitro DNA cleavage assay, 32P radiolabeling, EDTA reversal, Western blot of covalent complex","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — biochemical reconstitution with multiple orthogonal methods (radiolabeling, EDTA reversal, Western blot) in one study","pmids":["10428867"],"is_preprint":false},{"year":2000,"finding":"Lys-12 of NME2 is the nucleophile forming the covalent enzyme-DNA complex during DNA cleavage; its epsilon-amino group is essential for covalent adduct formation (K12Q abolishes, K12R does not rescue), suggesting a DNA glycosylase/lyase-like base excision repair mechanism. Lys-12 is also essential for NDP kinase activity, indicating the two catalytic activities share the nucleotide-binding site.","method":"DNA-linked peptide sequencing, site-directed mutagenesis, in vitro DNA cleavage assay, NDP kinase assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — mutagenesis with multiple orthogonal biochemical readouts identifying the catalytic residue","pmids":["11121025"],"is_preprint":false},{"year":2001,"finding":"NME2 binds single-stranded DNA oligonucleotides competitively at the active site (competitive with NDP kinase substrates); UV crosslinking and MALDI-TOF mass spectrometry identified three specific nucleopeptides as the contact surface with ssDNA, and a guanine at the 3'-end increased binding affinity ~10-fold. A structural model of NME2 bound to ssDNA was proposed.","method":"Competitive enzyme inhibition assay, UV crosslinking, MALDI-TOF mass spectrometry of crosslinked peptides","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assays with crosslinking-MS, single lab","pmids":["11352723"],"is_preprint":false},{"year":2001,"finding":"NME2 represses transcriptional activity of nuclease-hypersensitive elements in the PDGF-A promoter in HepG2 cells; NME2 cleaves within the 5'-portions of both strands of the 5'-SHS, at distinct sites from NME1 (which cleaves 3'-portions), revealing isoform-specific DNA cleavage mechanisms and a role for NME2 in repressing growth factor oncogene transcription.","method":"HeLa cDNA library screening, recombinant protein DNA cleavage assay, transient transfection, CAT/reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro cleavage assay plus cell-based reporter assay, single lab with multiple orthogonal methods","pmids":["11694515"],"is_preprint":false},{"year":2002,"finding":"Structure-based mutagenesis identified Arg88 and Arg105 (in addition to Lys12) as critical for both covalent DNA binding/cleavage and NDP kinase activity; Gln17 is required only for DNA cleavage; Tyr52, Asn115, and His118 are required only for NDP kinase. Nucleoside triphosphates (but not diphosphates) inhibit covalent DNA binding independently of phosphoryl transfer, indicating overlapping but distinct binding modes for nucleotides and duplex DNA in the nucleotide-binding site.","method":"Site-directed mutagenesis, in vitro DNA cleavage assay, NDP kinase assay, nucleotide inhibition assay","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-guided mutagenesis with multiple orthogonal biochemical assays, single lab","pmids":["12009894"],"is_preprint":false},{"year":2002,"finding":"NME2 directly interacts with ICAP-1alpha (integrin cytoplasmic domain-associated protein 1alpha); this interaction was confirmed by yeast two-hybrid, in vitro pulldown with purified recombinant proteins, and co-immunoprecipitation from CHO cells. Both proteins co-localize at lamellipodia during early cell spreading in a beta1-integrin-dependent manner, suggesting NME2 acts on beta1 integrin-mediated cell adhesion through ICAP-1alpha.","method":"Yeast two-hybrid, in vitro pulldown with purified proteins, co-immunoprecipitation, confocal fluorescence microscopy","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal interaction confirmed by three independent methods (Y2H, in vitro pulldown, co-IP) with localization evidence","pmids":["11919189"],"is_preprint":false},{"year":2004,"finding":"NME2 interacts with the C-terminal tail of the thromboxane A2 receptor isoform TPbeta (a GPCR); this interaction is agonist-dependent and was confirmed by co-immunoprecipitation in HEK293 cells. NME2 regulates agonist-induced TPbeta internalization through modulation of Rac1 signaling, and translocates from cytoplasm/nucleus to the plasma membrane upon receptor stimulation.","method":"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence microscopy, endocytosis assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP in cells plus functional endocytosis assay, single lab","pmids":["14976202"],"is_preprint":false},{"year":1996,"finding":"NME2/NDPK-B localizes to the nucleus in cultured cells, associated with chromatin; isoform-specific antibody immunofluorescence showed cytoplasmic and nuclear (fine dot) staining. Sequential nuclear extraction showed DNase I (but not RNase A) removed nuclear NME2 staining, establishing chromatin association. During mitosis, NME2 segregates from condensing chromosomes and reappears in daughter nuclei.","method":"Immunofluorescence with isoform-specific antibodies, sequential nuclear extraction (Triton X-100, RNase A, DNase I), live-cell imaging","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization by multiple extraction methods, single lab","pmids":["8806452"],"is_preprint":false},{"year":1998,"finding":"NME2 interacts with TRF1 (telomere repeat-binding factor 1) identified by yeast two-hybrid; in vitro binding assays showed TRF1 preferentially binds NME2 over NME1. NME2 binds single-stranded telomeric TTAGGG repeats (but not double-stranded) and the template region of telomerase RNA by EMSA. NME2 increased telomerase affinity for its substrate in vitro.","method":"Yeast two-hybrid, in vitro binding assay with recombinant proteins, EMSA, in vitro telomerase activity assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple in vitro binding assays, single lab","pmids":["9480811"],"is_preprint":false},{"year":2008,"finding":"NME2 binds to the G-quadruplex (G4) motif within the c-MYC nuclease hypersensitive element (NHE); NME2-G4 complex formation was shown by FRET (indicating G4 resolution to unfolded state upon binding), and NME2-mediated c-MYC activation requires NME2-G4 binding as demonstrated by luciferase reporter assay and chromatin immunoprecipitation.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), FRET with recombinant NME2","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — three orthogonal methods (luciferase, ChIP, FRET) in one study supporting the same mechanistic conclusion","pmids":["19033359"],"is_preprint":false},{"year":2011,"finding":"NME2 associates with telomere ends in vivo (identified by ChIP-seq reads mapping to telomeres, validated by independent ChIP methods); NME2 associates with TRF2 intranuclearly; NME2 associates with telomerase and reduces telomerase activity in vitro and in vivo; sustained NME2 expression leads to reduced telomere length in aggressive cancer cells.","method":"ChIP-seq, independent ChIP validation, co-immunoprecipitation (NME2-TRF2), in vitro and in vivo telomerase activity assays, telomere length measurement","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent methods (ChIP-seq, ChIP, co-IP, telomerase activity assay) in one study","pmids":["22135295"],"is_preprint":false},{"year":2014,"finding":"NME2 acts as a histidine kinase to activate the epithelial Ca2+ channel TRPV5; NME2 (NDPK-B) phosphorylates His711 in the C-terminal tail of TRPV5, increasing channel activity and Ca2+ flux; PHPT1 (histidine phosphatase) reverses this activation in inside-out patch experiments. NDPK-B knockdown decreases TRPV5 activity, and NDPK-B knockout mice show increased urinary Ca2+ excretion on high-Ca2+ diet.","method":"Inside-out patch clamp electrophysiology, site-directed mutagenesis of TRPV5 His711, shRNA knockdown, NDPK-B knockout mouse model, Ca2+ flux assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with mutagenesis plus KO mouse model providing in vivo validation","pmids":["24523290"],"is_preprint":false},{"year":2014,"finding":"NME2 suppresses lung cancer metastasis by directly binding to the promoter of vinculin (a focal adhesion factor) and transcriptionally repressing its expression; ChIP-chip showed NME2 binds vinculin promoter; NME2 depletion increased vinculin transcription; selective siRNA knockdown of vinculin diminished metastatic potential of NME2-depleted lung cancer cells in zebrafish and mouse xenograft models. NME1 did not bind the vinculin promoter.","method":"ChIP-chip (promoter-wide binding map), transcriptome profiling, siRNA knockdown, zebrafish and nude mice metastasis assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP-chip plus in vivo rescue experiment with multiple model systems in one study","pmids":["25249619"],"is_preprint":false},{"year":2017,"finding":"NME2 epigenetically represses hTERT transcription in a G-quadruplex-dependent manner; NME2 occupies the hTERT core promoter G4 motif (shown by ChIP); NME2 recruits the REST-LSD1 co-repressor complex to maintain repressive chromatin at the hTERT promoter; loss of NME2 upregulates hTERT expression; the G4 motif is required for NME2 and REST complex occupancy.","method":"ChIP, luciferase reporter assay, siRNA knockdown, G-quadruplex ligand treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assay, KD) establishing G4-dependent epigenetic repression mechanism","pmids":["28717007"],"is_preprint":false},{"year":2019,"finding":"NME2 promotes dynamin-2 (DNM2) oligomerization and increases its GTPase activity, stimulating endocytosis of transferrin receptor and EGFR, suppressing tumor cell motility and metastasis; NME2-DNM2 interaction was confirmed by co-immunoprecipitation; the histidine protein kinase activity (but not NDP kinase activity) of NME1 was required for endocytosis enhancement; NME-dependent metastasis suppression was abrogated by DNM2 knockdown.","method":"Co-immunoprecipitation, in vitro DNM2 oligomerization/GTPase assay, shRNA knockdown, endocytosis assay, lung metastasis assay, NME1 histidine kinase-inactive mutant transfection","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, in vitro GTPase assay, in vivo metastasis model, and domain mutagenesis in one study","pmids":["31311812"],"is_preprint":false},{"year":2010,"finding":"Plakoglobin (gamma-catenin) interacts with NME2 (primary isoform) and increases NME2 protein levels; co-immunoprecipitation and confocal microscopy showed NME2 interacts with plakoglobin, cadherins, and alpha-catenin in the cytoskeleton-associated protein pool; this interaction requires the N-terminal (alpha-catenin interacting) domain of plakoglobin.","method":"Co-immunoprecipitation, confocal microscopy, domain-deletion mutagenesis of plakoglobin","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP and localization with domain mapping, single lab","pmids":["20101217"],"is_preprint":false},{"year":2004,"finding":"NME2 binds the amino-terminal region (containing Dof domain) of Lbc proto-oncogene (a Rho-type GEF); identified by yeast two-hybrid and confirmed in cells; NME2 expression reduces GTP-bound Rho and suppresses Lbc-stimulated stress fiber formation; binding is independent of NME2 kinase activity; NME1 does not bind Lbc.","method":"Yeast two-hybrid, co-immunoprecipitation (implied by cell-based interaction), GTP-Rho pulldown assay, stress fiber imaging","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus functional Rho-GTP assay, single lab","pmids":["15249197"],"is_preprint":false},{"year":2011,"finding":"MDM2 directly interacts with NME2 (but not the 87.5% identical NME1) identified by affinity chromatography/MS and yeast two-hybrid; MDM2 upregulation in renal cell carcinoma abolishes NME2's ability to suppress cell motility; siRNA knockdown of MDM2 rescues NME2-mediated motility suppression.","method":"Affinity chromatography, tandem mass spectrometry, yeast two-hybrid, siRNA knockdown, cell motility assay","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by two orthogonal methods (proteomics + Y2H), functional rescue by siRNA, single lab","pmids":["21504894"],"is_preprint":false},{"year":2007,"finding":"NME2 interacts with Diva (Boo/Bcl2L10) in cells, requiring the transmembrane domain of Diva; both proteins co-localize in the cytoplasm. NME2 overexpression reduces Diva protein levels and induces apoptosis; NME2 knockdown restores Diva expression; NME2 depletion increases Diva-mediated apoptotic activity.","method":"Yeast two-hybrid, co-immunoprecipitation, co-localization, overexpression and siRNA knockdown, apoptosis assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional KD/OE rescue, single lab","pmids":["17532299"],"is_preprint":false},{"year":2007,"finding":"NME2 associates specifically with estrogen receptor beta (ERbeta) but not ERalpha; identified by yeast two-hybrid and confirmed by co-localization in human tissues; co-overexpression of NME2 and ERbeta increased estrogen response element-mediated transcription by ~97%; NME2 overexpression synergistically with estrogen reduced MCF-7 cell migration.","method":"Yeast two-hybrid, immunofluorescence co-localization, ERE-luciferase reporter assay, cell migration assay","journal":"The Journal of steroid biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H with cell-based reporter assay and functional migration assay, single lab","pmids":["17964137"],"is_preprint":false},{"year":1999,"finding":"The S122P tumor-associated mutation in NME2 reduces steady-state NDP kinase activity ~5-fold; transient kinetics showed the rate-limiting step shifts to dephosphorylation (phosphoryl transfer from phospho-enzyme to NDP), with 5-fold reduced phosphorylation and 40-200-fold reduced dephosphorylation rates; S122P also destabilizes the protein toward heat and urea, similar to 'killer of prune' mutations in other NDP kinases.","method":"Steady-state enzyme kinetics, stopped-flow transient kinetics, intrinsic fluorescence kinetics, thermal/urea stability assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous transient kinetics dissecting individual half-reactions, single lab","pmids":["10400630"],"is_preprint":false},{"year":2014,"finding":"PIWIL2 promotes c-Myc transcription by interacting with NME2 and facilitating NME2 binding to the G4-motif region within the c-Myc promoter; co-immunoprecipitation demonstrated PIWIL2-NME2 interaction; NME2 was shown to upregulate RhoA and F-actin formation in a c-Myc-dependent manner downstream of PIWIL2.","method":"Co-immunoprecipitation, ChIP, luciferase reporter assay, siRNA knockdown, F-actin imaging","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus ChIP and reporter assay, single lab","pmids":["25193865"],"is_preprint":false},{"year":2020,"finding":"After gamma irradiation (DNA damage), NME1 and NME2 co-localize in the cytoplasm of non-irradiated cells and translocate simultaneously to the nucleus; FRET/FLIM shows a slight shift in homomer/heteromer balance between nucleus and cytoplasm after DNA damage, suggesting nuclear NME1-NME2 functional cooperation in DNA damage response.","method":"Live-cell imaging, FRET/FLIM, gamma irradiation","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET/FLIM with live imaging, single lab","pmids":["32235358"],"is_preprint":false},{"year":2016,"finding":"NME2 (NDPK-B) binds lipid membranes in a two-step process: first via electrostatic adsorption to anionic phospholipids, then shallow hydrophobic penetration; membrane binding leads to decreased membrane fluidity and formation of protein patches/microdomains.","method":"Liposome binding assay, lipid monolayer, supported lipid bilayer, biophysical measurements of membrane fluidity","journal":"Langmuir","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biophysical characterization with multiple membrane model systems, single lab","pmids":["27934520"],"is_preprint":false},{"year":2012,"finding":"Diva/BclB inhibits NME2-mediated neuronal differentiation by sequestering NME2 in the cytoplasm and preventing its nuclear translocation; overexpression of Diva/BclB increases Diva-NME2 complexes and Diva-beta-tubulin complexes while decreasing NME2-beta-tubulin complexes, blocking neurite outgrowth; overexpression of NME2 promotes PC-12 neuronal differentiation, neurite outgrowth, and cell cycle arrest.","method":"Overexpression and co-immunoprecipitation, immunofluorescence, neurite outgrowth assay, cell cycle analysis in PC-12 cells","journal":"BMC neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with functional overexpression rescue, single lab","pmids":["23057762"],"is_preprint":false},{"year":2016,"finding":"NME2 interacts with PTPsigma (protein tyrosine phosphatase receptor type S) intracellular domain; identified by mass spectrometry screening and confirmed by co-immunoprecipitation in HEK-293T cells; NME2 knockdown in cortical neurons completely rescued CSPG-induced neurite outgrowth inhibition, placing NME2 downstream of PTPsigma in CSPG signaling.","method":"Mass spectrometry, co-immunoprecipitation, siRNA knockdown, neurite outgrowth assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS plus co-IP plus functional KD rescue, single lab","pmids":["26896769"],"is_preprint":false},{"year":2019,"finding":"NME2 promotes transcription of antiapoptotic genes (including miR-100, RIPK1, STARD5, LIMS1) by interacting with RNA polymerase II and RNA polymerase II-associated protein 2, mediating phosphorylation of the RNA Pol II C-terminal domain at Ser5, thereby suppressing apoptosis of gastric cancer cells in vitro and in vivo.","method":"Co-immunoprecipitation (NME2-RNA Pol II), ChIP, luciferase reporter assay, siRNA knockdown, mouse xenograft model","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with ChIP and in vivo model, single lab","pmids":["31694930"],"is_preprint":false},{"year":2020,"finding":"NDPK-B (NME2) deficiency in endothelial cells elevates UDP-GlcNAc, reduces NDPK activity, induces GFAT expression, and suppresses OGA activity, leading to increased protein O-GlcNAcylation and elevated Ang-2. The NTP/NDP transphosphorylase and histidine kinase activities of NDPK-B were dispensable for O-GlcNAcylation effects, identifying a novel regulatory axis.","method":"siRNA knockdown, in vitro NDPK and OGA activity assays, UPLC-PDA nucleotide measurement, immunoblot for O-GlcNAcylation, adenoviral re-expression","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic assays plus domain function tests, single lab","pmids":["33086728"],"is_preprint":false},{"year":2020,"finding":"NME2 histidine kinase activity is involved in TGF-beta1-induced hepatic stellate cell (HSC) activation and CCl4-induced liver fibrosis; NME2 silencing decreased TGF-beta1-induced histidine phosphorylation and reduced alpha-SMA and COL1A1 expression; the inhibitory effect on HSC activation was mediated through reduced phosphorylation of Smad2 and Smad3.","method":"siRNA knockdown, pHis antibody detection, immunoblot (alpha-SMA, COL1A1, pSmad2/3), CCl4 mouse model","journal":"Journal of molecular histology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined downstream pathway (Smad phosphorylation), in vivo and in vitro models, single lab","pmids":["32860079"],"is_preprint":false},{"year":2015,"finding":"CARMA3 represses NME2 expression through the NF-kappaB/miR-182 pathway; NF-kappaB drives miR-182 transcription and miR-182 reduces NME2 levels; CARMA3-driven reduction of NME2 promotes lung cancer cell motility, stemness, and metastasis; ChIP and luciferase reporter assays confirmed NF-kappaB binding to the miR-182 promoter.","method":"ChIP, luciferase reporter assay, miRNA overexpression/inhibition, in vitro motility assay, in vivo metastasis model","journal":"American journal of respiratory and critical care medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo model, single lab","pmids":["25906011"],"is_preprint":false},{"year":2006,"finding":"Protein kinase CK2alpha (catalytic subunit) acts as a signal switch: under basal conditions CK2alpha is part of the NDPK-A/AMPKalpha1 complex; upon AMPK-dependent phosphorylation of S122 on NDPK-A (NME1), CK2alpha dissociates and translocates to bind NDPK-B (NME2), representing the first described phosphorylation-dependent linkage between NME1 and NME2.","method":"Co-immunoprecipitation, in vivo AMPK activation (metformin/phenformin), protein binding assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP in cells with pharmacological AMPK activation, single lab","pmids":["17135357"],"is_preprint":false},{"year":2024,"finding":"Using ATP-biotin as a cosubstrate for phosphorylbiotinylation, kinase-catalyzed biotinylation methodology identified three novel substrates of NME2 (in addition to validation of known substrates); NME2 phosphorylates serine, threonine, histidine, and aspartic acid residues on substrate proteins.","method":"Kinase-catalyzed biotinylation with ATP-biotin cosubstrate, mass spectrometry substrate identification","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro kinase assay with novel ATP analog, single lab, substrates not yet validated by orthogonal methods","pmids":["39032654"],"is_preprint":false},{"year":2025,"finding":"NME2 modulates 4EBP1 phosphorylation at Thr37/46 independently of mTOR, regulates eIF4F complex formation, and controls autophagy flux in hepatocellular carcinoma cells; site-specific mutation of 4EBP1 confirmed this mTOR-independent NME2-4EBP1 axis.","method":"Knockdown/overexpression, site mutation analysis, immunoblot for pThr37/46-4EBP1, autophagy flux assay","journal":"Hepatology communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single paper, mechanistic follow-up limited in abstracts","pmids":["40489759"],"is_preprint":false},{"year":2014,"finding":"NME2 binds PPARdelta via its C-terminal region; identified by yeast two-hybrid and confirmed by co-immunoprecipitation; NME2 overexpression inhibits PPARdelta promoter activity and reduces PPARdelta expression and AKT phosphorylation; NME2 siRNA activated PPARdelta activity and increased GW501516-stimulated cholangiocarcinoma growth.","method":"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay, siRNA knockdown, cell proliferation assay","journal":"Digestive and liver disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H plus co-IP plus functional reporter, single lab","pmids":["25277864"],"is_preprint":false},{"year":2001,"finding":"Fragile X mental retardation protein (FMRP) directly binds NME2 (NDK/Nm23-H2) in a yeast two-hybrid screen of human fetal hippocampus cDNA library; the interaction site on FMRP was mapped to exons 1-11.","method":"Yeast two-hybrid, FMRP domain mapping","journal":"Acta Academiae Medicinae Sinicae","confidence":"Low","confidence_rationale":"Tier 3 / Weak — yeast two-hybrid only, no in vitro or cell-based confirmation reported in abstract","pmids":["12901102"],"is_preprint":false},{"year":2024,"finding":"Sanguinarine (SG) enhances NME2 binding to the c-MYC G-quadruplex promoter element both in vitro and in cells, leading to c-MYC transcriptional repression and cancer cell growth inhibition in an NME2-dependent manner; mechanistic studies and molecular modeling suggest SG binds the c-MYC G4/NME2 interface as an orthosteric stabilizer.","method":"In vitro binding assay (G4-NME2 interaction), cellular transcription assay, NME2-dependent growth inhibition assay, molecular modeling","journal":"Bioorganic chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro binding plus cell-based NME2-dependence assay, single lab","pmids":["39342890"],"is_preprint":false},{"year":2026,"finding":"NME2 directly binds the Nlrp3 promoter in microglia and recruits EPC2 (a component of the NuA4 histone acetyltransferase complex), inducing H2AK5 acetylation and chromatin remodeling to enhance Nlrp3 transcription; conditional knockout of Nme2 in microglia or pharmacological inhibition with stauprimide decreases CSF IL-1beta and attenuates neuronal death and cognitive impairment in septic mice.","method":"ChIP, scRNA-seq, conditional Nme2 knockout, pharmacological inhibition, IL-1beta measurement, cognitive behavioral assays","journal":"Brain, behavior, and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus in vivo KO with functional readouts, single lab, preprint not yet peer-reviewed at time of corpus assembly","pmids":["41713665"],"is_preprint":false}],"current_model":"NME2 (NM23-H2/NDPK-B) is a hexameric, bifunctional enzyme that catalyzes nucleoside diphosphate kinase (NDP kinase) phosphoryl transfer via a phosphohistidine (His118) intermediate and, through a separate Lys12-mediated active site, cleaves DNA by a DNA glycosylase/lyase-like covalent mechanism; it also acts as a sequence-specific transcription factor (PuF) that binds G-quadruplex and single-stranded DNA elements in the c-MYC promoter NHE to activate transcription (or recruit REST-LSD1 to repress hTERT), functions as a protein histidine kinase that activates TRPV5 channels and modulates Smad and 4EBP1 phosphorylation, and suppresses metastasis through interactions with multiple partners including ICAP-1alpha/beta1-integrin, dynamin-2 (promoting endocytosis), Lbc-RhoGEF, MDM2, PPARdelta, TRF1/TRF2/telomerase, and the NuA4 histone acetyltransferase complex at the NLRP3 promoter."},"narrative":{"mechanistic_narrative":"NME2 (NM23-H2/NDPK-B) is a hexameric, bifunctional protein that couples nucleoside diphosphate kinase chemistry to sequence-specific gene regulation and acts as a metastasis suppressor [PMID:1988104, PMID:7658474, PMID:25249619]. It catalyzes phosphoryl transfer through a phosphohistidine (His118) intermediate, and its tumor-associated S122P mutation shifts the rate-limiting step to dephosphorylation while destabilizing the enzyme [PMID:7658474, PMID:10400630]. NME2 was identified as the c-myc purine-binding factor PuF, binding the nuclease-hypersensitive element (NHE) to activate transcription; this DNA-binding and transcriptional activity is genetically separable from catalysis, since the catalytically dead H118F mutant retains full DNA binding and transactivation while DNA-binding-dead mutants (Arg34, Asn69, Lys135) retain NDP kinase activity [PMID:8392752, PMID:7784082, PMID:8132589, PMID:8692914]. NME2 binds and resolves the G-quadruplex within the c-MYC NHE to activate transcription, while at the hTERT promoter it occupies a G4 motif and recruits the REST-LSD1 co-repressor complex to enforce repression, and at the NLRP3 promoter it recruits the NuA4 component EPC2 to deposit H2AK5 acetylation and drive transcription [PMID:19033359, PMID:28717007, PMID:41713665]. Beyond duplex recognition, NME2 cleaves DNA via a covalent protein-DNA intermediate using Lys12 as the nucleophile in a glycosylase/lyase-like reaction whose active site overlaps the nucleotide-binding pocket [PMID:10428867, PMID:11121025, PMID:12009894]. As a protein histidine kinase, NME2 phosphorylates His711 of the Ca2+ channel TRPV5 to increase channel activity (reversed by PHPT1), and its histidine kinase activity feeds into TGF-beta/Smad2/3 signaling and 4EBP1 phosphorylation [PMID:24523290, PMID:32860079, PMID:40489759]. NME2 suppresses metastasis through transcriptional repression of vinculin and through promotion of dynamin-2 oligomerization and GTPase activity to drive receptor endocytosis, the latter requiring histidine kinase rather than NDP kinase activity [PMID:25249619, PMID:31311812]. It engages numerous partners coordinating adhesion, cytoskeletal, and telomere biology, including ICAP-1alpha/beta1-integrin, Lbc-RhoGEF, MDM2, and TRF1/TRF2/telomerase, at which last it associates with telomere ends and reduces telomerase activity [PMID:11919189, PMID:22135295, PMID:15249197, PMID:21504894].","teleology":[{"year":1991,"claim":"Establishing that nm23-H2 is a distinct second human nm23 gene defined NME2 as a separate gene product highly related to the metastasis-associated NME1.","evidence":"cDNA cloning and sequencing with Southern/Northern blots","pmids":["1988104"],"confidence":"High","gaps":["Did not define protein function beyond NDP kinase homology","No cellular role assigned"]},{"year":1993,"claim":"Identifying NME2 as the c-myc transcription factor PuF answered whether an NDP kinase could function in gene regulation, revealing a moonlighting transcriptional role.","evidence":"Recombinant protein DNA binding and in vitro transcription on the c-myc NHE","pmids":["8392752"],"confidence":"High","gaps":["Whether DNA binding required catalytic activity was unresolved","In vitro only, cellular relevance not yet shown"]},{"year":1994,"claim":"Demonstrating that the H118F catalytic mutant retains DNA binding and transactivation separated the enzymatic and transcriptional functions, establishing NME2 as genuinely bifunctional.","evidence":"Site-directed mutagenesis with EMSA, in vitro transcription, and phosphoenzyme assays","pmids":["8132589"],"confidence":"High","gaps":["Did not map the DNA-binding surface","Mechanism of transcriptional output not defined"]},{"year":1995,"claim":"The hexameric crystal structure and cell-based NHE-deletion assays placed NME2's fold, mutation sites, and the required cis-element on a structural and cellular footing.","evidence":"X-ray crystallography at 2.8 A and transient transfection CAT reporter with NHE deletion","pmids":["7658474","7784082"],"confidence":"High","gaps":["Structure did not show a DNA-bound complex","How tumor mutations alter cellular function untested"]},{"year":1996,"claim":"Mapping DNA-binding residues (Arg34, Asn69, Lys135) distinct from catalytic residues, and showing chromatin association, localized two separable functional modules within the hexamer in the nucleus.","evidence":"Mutagenesis with EMSA and NDP kinase assays; sequential nuclear extraction and immunofluorescence","pmids":["8692914","8806452"],"confidence":"High","gaps":["DNA-binding mode inferred from crosslinking, not structure","Localization study single lab"]},{"year":2000,"claim":"Identifying Lys12 as the covalent nucleophile and the shared nucleotide-binding pocket defined the DNA cleavage chemistry and its relationship to NDP kinase activity.","evidence":"DNA-linked peptide sequencing, mutagenesis, and parallel cleavage/kinase assays","pmids":["11121025","10428867","12009894"],"confidence":"High","gaps":["Physiological substrate for cleavage unknown","In vivo cleavage role not established"]},{"year":1998,"claim":"Linking NME2 to TRF1 and telomeric/telomerase RNA opened a telomere-associated function distinct from c-myc regulation.","evidence":"Yeast two-hybrid, in vitro binding, EMSA, and telomerase activity assay","pmids":["9480811"],"confidence":"Medium","gaps":["In vitro binding only, no in vivo telomere occupancy yet","Single lab"]},{"year":2002,"claim":"Demonstrating direct binding to ICAP-1alpha and co-localization at lamellipodia connected NME2 to beta1-integrin adhesion machinery, suggesting a cytoskeletal/motility function.","evidence":"Yeast two-hybrid, in vitro pulldown, co-IP, and confocal microscopy in CHO cells","pmids":["11919189"],"confidence":"High","gaps":["Functional consequence for adhesion not directly tested","Role of catalytic activity unknown"]},{"year":2008,"claim":"Showing NME2 binds and unfolds the c-MYC G-quadruplex defined the structural DNA element underlying its transcriptional activation, refining the PuF mechanism.","evidence":"Luciferase reporter, ChIP, and FRET with recombinant NME2","pmids":["19033359"],"confidence":"High","gaps":["Cofactors at the c-MYC G4 not yet identified","Distinction between activation and repression contexts unresolved"]},{"year":2011,"claim":"Confirming NME2 occupancy of telomere ends and association with TRF2/telomerase in vivo, alongside discovery of the MDM2 interaction, advanced both telomere and metastasis-suppressor mechanisms.","evidence":"ChIP-seq, co-IP, telomerase assays, telomere length; affinity-MS and Y2H plus motility rescue","pmids":["22135295","21504894"],"confidence":"High","gaps":["How NME2 reduces telomerase activity mechanistically not fully resolved","MDM2 study single lab"]},{"year":2014,"claim":"Identifying NME2 as a histidine kinase for TRPV5 His711 and as a direct transcriptional repressor of vinculin gave concrete molecular mechanisms for its signaling and metastasis-suppressor roles.","evidence":"Inside-out patch clamp with TRPV5 mutagenesis and NDPK-B KO mice; ChIP-chip with zebrafish/mouse metastasis rescue","pmids":["24523290","25249619"],"confidence":"High","gaps":["Breadth of histidine kinase substrate repertoire unknown","Selectivity of NME2 vs NME1 at promoters mechanistically unexplained"]},{"year":2017,"claim":"Showing G4-dependent recruitment of REST-LSD1 to the hTERT promoter explained how the same G4-binding protein can repress rather than activate, defining a context-dependent epigenetic mechanism.","evidence":"ChIP, luciferase reporter, siRNA, and G4-ligand treatment","pmids":["28717007"],"confidence":"High","gaps":["What dictates activator vs repressor outcome at different G4 promoters unresolved","Direct REST-NME2 contact not mapped"]},{"year":2019,"claim":"Demonstrating that NME2 promotes dynamin-2 oligomerization and GTPase activity to drive receptor endocytosis, requiring histidine kinase activity, mechanistically linked NME2 enzymology to metastasis suppression.","evidence":"Reciprocal co-IP, in vitro DNM2 oligomerization/GTPase assays, endocytosis and lung metastasis assays with kinase-dead mutant","pmids":["31311812"],"confidence":"High","gaps":["Whether DNM2 is a direct phosphorylation substrate not established","Relevant histidine site on DNM2 unidentified"]},{"year":2024,"claim":"Kinase-catalyzed biotinylation expanded the substrate repertoire and showed NME2 phosphorylates Ser, Thr, His, and Asp residues, broadening its potential signaling reach.","evidence":"ATP-biotin kinase-catalyzed biotinylation with mass spectrometry","pmids":["39032654"],"confidence":"Medium","gaps":["Novel substrates not validated by orthogonal methods","Physiological relevance of multi-residue phosphorylation untested"]},{"year":2026,"claim":"Showing NME2 recruits the NuA4 component EPC2 to the Nlrp3 promoter to drive H2AK5 acetylation and neuroinflammation extended its transcriptional activation mechanism to chromatin remodeling and a disease context.","evidence":"ChIP, scRNA-seq, conditional microglial Nme2 knockout, pharmacological inhibition, and behavioral assays in septic mice","pmids":["41713665"],"confidence":"Medium","gaps":["Direct NME2-EPC2 contact interface not mapped","Single lab, in one disease model"]},{"year":null,"claim":"How NME2 selects between transcriptional activation and repression at distinct G4 promoters, and whether its DNA cleavage and multi-residue protein kinase activities operate physiologically, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of NME2 bound to G-quadruplex or duplex DNA","Physiological substrate of covalent DNA cleavage unknown","Determinants of co-repressor vs co-activator recruitment undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[2,17,26,37]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[17,34,37]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[0,4,5,6,15]},{"term_id":"GO:0140097","term_label":"catalytic activity, acting on DNA","supporting_discovery_ids":[6,7,10]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,3,15,18,19]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[17]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[29]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[13,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[13,28,30]},{"term_id":"GO:0005694","term_label":"chromosome","supporting_discovery_ids":[13]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[16,19,42]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[11,12]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,3,15,18,19,42]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[19,42]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[20]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[18,26]}],"complexes":["NuA4 histone acetyltransferase complex (at NLRP3 promoter)","REST-LSD1 co-repressor complex (at hTERT promoter)"],"partners":["ICAP-1ALPHA","TRF1","TRF2","DNM2","MDM2","TRPV5","PPARDELTA","EPC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P22392","full_name":"Nucleoside diphosphate kinase B","aliases":["C-myc purine-binding transcription factor PUF","Histidine protein kinase NDKB","Nucleoside diphoshate kinase 2","NDK2","nm23-H2"],"length_aa":152,"mass_kda":17.3,"function":"Catalyzes the transfer of a gamma-phosphoryl group from a nucleoside triphosphate, mainly ATP, to a nucleoside diphosphate via a ping-pong mechanism involving a phosphohistidine intermediate, therefore contributing to the nucleoside triphosphate homeostasis (PubMed:11121025, PubMed:16313181, PubMed:1851158, PubMed:25679041). Also functions as a histidine protein kinase by transferring the phosphoryl group from the phosphohistidine intermediate to a histidine residue in target proteins (PubMed:17157250, PubMed:20946858). Phosphorylates the GNB1 subunit of heterotrimeric G proteins at 'His-266', generating a high-energy phosphate group that promotes GTP formation and enables receptor-independent activation of heterotrimeric G proteins (By similarity). Also phosphorylates KCNN4 at 'His-358', leading to activation of its intermediate conductance calcium-activated potassium channel activity, Ca(2+) influx, and subsequent activation of B and T cells (PubMed:17157250). Additionally involved in transcriptional regulation through direct DNA binding and chromatin remodeling (PubMed:11121025, PubMed:11694515, PubMed:19033359, PubMed:19435876, PubMed:25679041, PubMed:8392752). In this context, functions as a single-stranded DNA binding protein that binds and stabilizes the G-quadruplex (G4) structures within the nuclease hypersensitive element (NHE) III(1) region of the MYC gene promoter, facilitating recruitment of additional single-strand DNA binding proteins and activation of MYC transcription (PubMed:19033359, PubMed:19435876, PubMed:25679041, PubMed:8392752). G4 DNA-binding activity is independent of its nucleoside diphosphate kinase function and recognizes both folded and unfolded G4 structures (PubMed:25679041). With NME1, may regulate acetyl-CoA (AcCoA) usage between histone acetylation and fatty acid synthesis by targeting AcCoA release at ATP-rich, HAT-associated chromatin regions (By similarity). Also negatively regulates Rho activity by interacting with AKAP13/LBC (PubMed:15249197)","subcellular_location":"Cytoplasm; Cytoplasm, perinuclear region; Nucleus","url":"https://www.uniprot.org/uniprotkb/P22392/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/NME2","classification":"Common Essential","n_dependent_lines":414,"n_total_lines":1208,"dependency_fraction":0.34271523178807944},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ACTR2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/NME2","total_profiled":1310},"omim":[{"mim_id":"608294","title":"NME/NM23 NUCLEOSIDE DIPHOSPHATE KINASE 6; NME6","url":"https://www.omim.org/entry/608294"},{"mim_id":"601818","title":"NME/NM23 NUCLEOSIDE DIPHOSPHATE KINASE 4; NME4","url":"https://www.omim.org/entry/601818"},{"mim_id":"601817","title":"NME/NM23 NUCLEOSIDE DIPHOSPHATE KINASE 3; NME3","url":"https://www.omim.org/entry/601817"},{"mim_id":"156491","title":"NME/NM23 NUCLEOSIDE DIPHOSPHATE KINASE 2; NME2","url":"https://www.omim.org/entry/156491"},{"mim_id":"156490","title":"NME/NM23 NUCLEOSIDE DIPHOSPHATE KINASE 1; NME1","url":"https://www.omim.org/entry/156490"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/NME2"},"hgnc":{"alias_symbol":["NM23-H2","NDPKB"],"prev_symbol":[]},"alphafold":{"accession":"P22392","domains":[{"cath_id":"3.30.70.141","chopping":"5-140","consensus_level":"high","plddt":98.0771,"start":5,"end":140}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22392","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22392-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22392-F1-predicted_aligned_error_v6.png","plddt_mean":97.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=NME2","jax_strain_url":"https://www.jax.org/strain/search?query=NME2"},"sequence":{"accession":"P22392","fasta_url":"https://rest.uniprot.org/uniprotkb/P22392.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22392/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22392"}},"corpus_meta":[{"pmid":"8392752","id":"PMC_8392752","title":"Human c-myc transcription factor 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Ser44 and Ser122 are surface-exposed and likely phosphorylated by exogenous kinases, while Ser120 is buried and likely autophosphorylated via the phosphohistidine intermediate.\",\n      \"method\": \"X-ray crystallography at 2.8 Å (molecular replacement)\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determination with functional interpretation of active site and mutation sites\",\n      \"pmids\": [\"7658474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"NME2/PuF transactivates the human c-myc gene via the nuclease hypersensitive element (NHE) in a transient transfection assay; deletion of NHE abolished PuF-dependent CAT reporter activation, establishing that NHE is required for NME2-mediated c-myc transactivation in cells.\",\n      \"method\": \"Transient transfection, CAT reporter assay, deletion mutagenesis of NHE element\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-based reporter assay with deletion control, replicated across multiple labs\",\n      \"pmids\": [\"7784082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"The NDPK enzymatic activity of NME2 is not required for its DNA binding or in vitro transcriptional activation of c-myc; the catalytically inactive H118F mutant (substituting the phosphohistidine intermediate site) retains full DNA binding affinity and transcriptional activity, demonstrating NME2 is a bifunctional protein with separable enzymatic and transcriptional activities.\",\n      \"method\": \"Site-directed mutagenesis, radioisotopic phosphoenzyme assay, coupled enzyme assay, electrophoretic mobility shift assay (EMSA), in vitro transcription\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis combined with multiple orthogonal biochemical assays in a single rigorous study\",\n      \"pmids\": [\"8132589\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Site-directed mutagenesis identified Arg-34, Asn-69, and Lys-135 as critical residues for NME2 sequence-specific DNA binding to the c-myc regulatory element; these mutants retain NDP kinase activity and form stable hexamers, indicating separate functional domains for enzyme catalysis and DNA binding. Chemical crosslinking supported a dimeric DNA-binding mode.\",\n      \"method\": \"Site-directed mutagenesis, EMSA, NDP kinase activity assay, chemical crosslinking\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with multiple orthogonal functional assays in one study\",\n      \"pmids\": [\"8692914\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"NME2 cleaves double-stranded DNA via formation of a covalent protein-DNA intermediate; cleavage produces staggered ends with 3'-OH groups and protein attached to the 5'-phosphoryl ends, reversible by EDTA. 32P transfer from DNA to NME2 was demonstrated and a covalent polypeptide-DNA complex was isolated and confirmed by Western blotting.\",\n      \"method\": \"In vitro DNA cleavage assay, 32P radiolabeling, EDTA reversal, Western blot of covalent complex\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biochemical reconstitution with multiple orthogonal methods (radiolabeling, EDTA reversal, Western blot) in one study\",\n      \"pmids\": [\"10428867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Lys-12 of NME2 is the nucleophile forming the covalent enzyme-DNA complex during DNA cleavage; its epsilon-amino group is essential for covalent adduct formation (K12Q abolishes, K12R does not rescue), suggesting a DNA glycosylase/lyase-like base excision repair mechanism. Lys-12 is also essential for NDP kinase activity, indicating the two catalytic activities share the nucleotide-binding site.\",\n      \"method\": \"DNA-linked peptide sequencing, site-directed mutagenesis, in vitro DNA cleavage assay, NDP kinase assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — mutagenesis with multiple orthogonal biochemical readouts identifying the catalytic residue\",\n      \"pmids\": [\"11121025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NME2 binds single-stranded DNA oligonucleotides competitively at the active site (competitive with NDP kinase substrates); UV crosslinking and MALDI-TOF mass spectrometry identified three specific nucleopeptides as the contact surface with ssDNA, and a guanine at the 3'-end increased binding affinity ~10-fold. A structural model of NME2 bound to ssDNA was proposed.\",\n      \"method\": \"Competitive enzyme inhibition assay, UV crosslinking, MALDI-TOF mass spectrometry of crosslinked peptides\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assays with crosslinking-MS, single lab\",\n      \"pmids\": [\"11352723\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NME2 represses transcriptional activity of nuclease-hypersensitive elements in the PDGF-A promoter in HepG2 cells; NME2 cleaves within the 5'-portions of both strands of the 5'-SHS, at distinct sites from NME1 (which cleaves 3'-portions), revealing isoform-specific DNA cleavage mechanisms and a role for NME2 in repressing growth factor oncogene transcription.\",\n      \"method\": \"HeLa cDNA library screening, recombinant protein DNA cleavage assay, transient transfection, CAT/reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro cleavage assay plus cell-based reporter assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"11694515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Structure-based mutagenesis identified Arg88 and Arg105 (in addition to Lys12) as critical for both covalent DNA binding/cleavage and NDP kinase activity; Gln17 is required only for DNA cleavage; Tyr52, Asn115, and His118 are required only for NDP kinase. Nucleoside triphosphates (but not diphosphates) inhibit covalent DNA binding independently of phosphoryl transfer, indicating overlapping but distinct binding modes for nucleotides and duplex DNA in the nucleotide-binding site.\",\n      \"method\": \"Site-directed mutagenesis, in vitro DNA cleavage assay, NDP kinase assay, nucleotide inhibition assay\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-guided mutagenesis with multiple orthogonal biochemical assays, single lab\",\n      \"pmids\": [\"12009894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"NME2 directly interacts with ICAP-1alpha (integrin cytoplasmic domain-associated protein 1alpha); this interaction was confirmed by yeast two-hybrid, in vitro pulldown with purified recombinant proteins, and co-immunoprecipitation from CHO cells. Both proteins co-localize at lamellipodia during early cell spreading in a beta1-integrin-dependent manner, suggesting NME2 acts on beta1 integrin-mediated cell adhesion through ICAP-1alpha.\",\n      \"method\": \"Yeast two-hybrid, in vitro pulldown with purified proteins, co-immunoprecipitation, confocal fluorescence microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal interaction confirmed by three independent methods (Y2H, in vitro pulldown, co-IP) with localization evidence\",\n      \"pmids\": [\"11919189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NME2 interacts with the C-terminal tail of the thromboxane A2 receptor isoform TPbeta (a GPCR); this interaction is agonist-dependent and was confirmed by co-immunoprecipitation in HEK293 cells. NME2 regulates agonist-induced TPbeta internalization through modulation of Rac1 signaling, and translocates from cytoplasm/nucleus to the plasma membrane upon receptor stimulation.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, immunofluorescence microscopy, endocytosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP in cells plus functional endocytosis assay, single lab\",\n      \"pmids\": [\"14976202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"NME2/NDPK-B localizes to the nucleus in cultured cells, associated with chromatin; isoform-specific antibody immunofluorescence showed cytoplasmic and nuclear (fine dot) staining. Sequential nuclear extraction showed DNase I (but not RNase A) removed nuclear NME2 staining, establishing chromatin association. During mitosis, NME2 segregates from condensing chromosomes and reappears in daughter nuclei.\",\n      \"method\": \"Immunofluorescence with isoform-specific antibodies, sequential nuclear extraction (Triton X-100, RNase A, DNase I), live-cell imaging\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization by multiple extraction methods, single lab\",\n      \"pmids\": [\"8806452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"NME2 interacts with TRF1 (telomere repeat-binding factor 1) identified by yeast two-hybrid; in vitro binding assays showed TRF1 preferentially binds NME2 over NME1. NME2 binds single-stranded telomeric TTAGGG repeats (but not double-stranded) and the template region of telomerase RNA by EMSA. NME2 increased telomerase affinity for its substrate in vitro.\",\n      \"method\": \"Yeast two-hybrid, in vitro binding assay with recombinant proteins, EMSA, in vitro telomerase activity assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple in vitro binding assays, single lab\",\n      \"pmids\": [\"9480811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NME2 binds to the G-quadruplex (G4) motif within the c-MYC nuclease hypersensitive element (NHE); NME2-G4 complex formation was shown by FRET (indicating G4 resolution to unfolded state upon binding), and NME2-mediated c-MYC activation requires NME2-G4 binding as demonstrated by luciferase reporter assay and chromatin immunoprecipitation.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), FRET with recombinant NME2\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three orthogonal methods (luciferase, ChIP, FRET) in one study supporting the same mechanistic conclusion\",\n      \"pmids\": [\"19033359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"NME2 associates with telomere ends in vivo (identified by ChIP-seq reads mapping to telomeres, validated by independent ChIP methods); NME2 associates with TRF2 intranuclearly; NME2 associates with telomerase and reduces telomerase activity in vitro and in vivo; sustained NME2 expression leads to reduced telomere length in aggressive cancer cells.\",\n      \"method\": \"ChIP-seq, independent ChIP validation, co-immunoprecipitation (NME2-TRF2), in vitro and in vivo telomerase activity assays, telomere length measurement\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent methods (ChIP-seq, ChIP, co-IP, telomerase activity assay) in one study\",\n      \"pmids\": [\"22135295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NME2 acts as a histidine kinase to activate the epithelial Ca2+ channel TRPV5; NME2 (NDPK-B) phosphorylates His711 in the C-terminal tail of TRPV5, increasing channel activity and Ca2+ flux; PHPT1 (histidine phosphatase) reverses this activation in inside-out patch experiments. NDPK-B knockdown decreases TRPV5 activity, and NDPK-B knockout mice show increased urinary Ca2+ excretion on high-Ca2+ diet.\",\n      \"method\": \"Inside-out patch clamp electrophysiology, site-directed mutagenesis of TRPV5 His711, shRNA knockdown, NDPK-B knockout mouse model, Ca2+ flux assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with mutagenesis plus KO mouse model providing in vivo validation\",\n      \"pmids\": [\"24523290\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NME2 suppresses lung cancer metastasis by directly binding to the promoter of vinculin (a focal adhesion factor) and transcriptionally repressing its expression; ChIP-chip showed NME2 binds vinculin promoter; NME2 depletion increased vinculin transcription; selective siRNA knockdown of vinculin diminished metastatic potential of NME2-depleted lung cancer cells in zebrafish and mouse xenograft models. NME1 did not bind the vinculin promoter.\",\n      \"method\": \"ChIP-chip (promoter-wide binding map), transcriptome profiling, siRNA knockdown, zebrafish and nude mice metastasis assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP-chip plus in vivo rescue experiment with multiple model systems in one study\",\n      \"pmids\": [\"25249619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NME2 epigenetically represses hTERT transcription in a G-quadruplex-dependent manner; NME2 occupies the hTERT core promoter G4 motif (shown by ChIP); NME2 recruits the REST-LSD1 co-repressor complex to maintain repressive chromatin at the hTERT promoter; loss of NME2 upregulates hTERT expression; the G4 motif is required for NME2 and REST complex occupancy.\",\n      \"method\": \"ChIP, luciferase reporter assay, siRNA knockdown, G-quadruplex ligand treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (ChIP, reporter assay, KD) establishing G4-dependent epigenetic repression mechanism\",\n      \"pmids\": [\"28717007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NME2 promotes dynamin-2 (DNM2) oligomerization and increases its GTPase activity, stimulating endocytosis of transferrin receptor and EGFR, suppressing tumor cell motility and metastasis; NME2-DNM2 interaction was confirmed by co-immunoprecipitation; the histidine protein kinase activity (but not NDP kinase activity) of NME1 was required for endocytosis enhancement; NME-dependent metastasis suppression was abrogated by DNM2 knockdown.\",\n      \"method\": \"Co-immunoprecipitation, in vitro DNM2 oligomerization/GTPase assay, shRNA knockdown, endocytosis assay, lung metastasis assay, NME1 histidine kinase-inactive mutant transfection\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, in vitro GTPase assay, in vivo metastasis model, and domain mutagenesis in one study\",\n      \"pmids\": [\"31311812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Plakoglobin (gamma-catenin) interacts with NME2 (primary isoform) and increases NME2 protein levels; co-immunoprecipitation and confocal microscopy showed NME2 interacts with plakoglobin, cadherins, and alpha-catenin in the cytoskeleton-associated protein pool; this interaction requires the N-terminal (alpha-catenin interacting) domain of plakoglobin.\",\n      \"method\": \"Co-immunoprecipitation, confocal microscopy, domain-deletion mutagenesis of plakoglobin\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP and localization with domain mapping, single lab\",\n      \"pmids\": [\"20101217\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"NME2 binds the amino-terminal region (containing Dof domain) of Lbc proto-oncogene (a Rho-type GEF); identified by yeast two-hybrid and confirmed in cells; NME2 expression reduces GTP-bound Rho and suppresses Lbc-stimulated stress fiber formation; binding is independent of NME2 kinase activity; NME1 does not bind Lbc.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation (implied by cell-based interaction), GTP-Rho pulldown assay, stress fiber imaging\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus functional Rho-GTP assay, single lab\",\n      \"pmids\": [\"15249197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"MDM2 directly interacts with NME2 (but not the 87.5% identical NME1) identified by affinity chromatography/MS and yeast two-hybrid; MDM2 upregulation in renal cell carcinoma abolishes NME2's ability to suppress cell motility; siRNA knockdown of MDM2 rescues NME2-mediated motility suppression.\",\n      \"method\": \"Affinity chromatography, tandem mass spectrometry, yeast two-hybrid, siRNA knockdown, cell motility assay\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by two orthogonal methods (proteomics + Y2H), functional rescue by siRNA, single lab\",\n      \"pmids\": [\"21504894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NME2 interacts with Diva (Boo/Bcl2L10) in cells, requiring the transmembrane domain of Diva; both proteins co-localize in the cytoplasm. NME2 overexpression reduces Diva protein levels and induces apoptosis; NME2 knockdown restores Diva expression; NME2 depletion increases Diva-mediated apoptotic activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, co-localization, overexpression and siRNA knockdown, apoptosis assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional KD/OE rescue, single lab\",\n      \"pmids\": [\"17532299\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"NME2 associates specifically with estrogen receptor beta (ERbeta) but not ERalpha; identified by yeast two-hybrid and confirmed by co-localization in human tissues; co-overexpression of NME2 and ERbeta increased estrogen response element-mediated transcription by ~97%; NME2 overexpression synergistically with estrogen reduced MCF-7 cell migration.\",\n      \"method\": \"Yeast two-hybrid, immunofluorescence co-localization, ERE-luciferase reporter assay, cell migration assay\",\n      \"journal\": \"The Journal of steroid biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H with cell-based reporter assay and functional migration assay, single lab\",\n      \"pmids\": [\"17964137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"The S122P tumor-associated mutation in NME2 reduces steady-state NDP kinase activity ~5-fold; transient kinetics showed the rate-limiting step shifts to dephosphorylation (phosphoryl transfer from phospho-enzyme to NDP), with 5-fold reduced phosphorylation and 40-200-fold reduced dephosphorylation rates; S122P also destabilizes the protein toward heat and urea, similar to 'killer of prune' mutations in other NDP kinases.\",\n      \"method\": \"Steady-state enzyme kinetics, stopped-flow transient kinetics, intrinsic fluorescence kinetics, thermal/urea stability assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous transient kinetics dissecting individual half-reactions, single lab\",\n      \"pmids\": [\"10400630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIWIL2 promotes c-Myc transcription by interacting with NME2 and facilitating NME2 binding to the G4-motif region within the c-Myc promoter; co-immunoprecipitation demonstrated PIWIL2-NME2 interaction; NME2 was shown to upregulate RhoA and F-actin formation in a c-Myc-dependent manner downstream of PIWIL2.\",\n      \"method\": \"Co-immunoprecipitation, ChIP, luciferase reporter assay, siRNA knockdown, F-actin imaging\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus ChIP and reporter assay, single lab\",\n      \"pmids\": [\"25193865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"After gamma irradiation (DNA damage), NME1 and NME2 co-localize in the cytoplasm of non-irradiated cells and translocate simultaneously to the nucleus; FRET/FLIM shows a slight shift in homomer/heteromer balance between nucleus and cytoplasm after DNA damage, suggesting nuclear NME1-NME2 functional cooperation in DNA damage response.\",\n      \"method\": \"Live-cell imaging, FRET/FLIM, gamma irradiation\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET/FLIM with live imaging, single lab\",\n      \"pmids\": [\"32235358\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NME2 (NDPK-B) binds lipid membranes in a two-step process: first via electrostatic adsorption to anionic phospholipids, then shallow hydrophobic penetration; membrane binding leads to decreased membrane fluidity and formation of protein patches/microdomains.\",\n      \"method\": \"Liposome binding assay, lipid monolayer, supported lipid bilayer, biophysical measurements of membrane fluidity\",\n      \"journal\": \"Langmuir\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biophysical characterization with multiple membrane model systems, single lab\",\n      \"pmids\": [\"27934520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Diva/BclB inhibits NME2-mediated neuronal differentiation by sequestering NME2 in the cytoplasm and preventing its nuclear translocation; overexpression of Diva/BclB increases Diva-NME2 complexes and Diva-beta-tubulin complexes while decreasing NME2-beta-tubulin complexes, blocking neurite outgrowth; overexpression of NME2 promotes PC-12 neuronal differentiation, neurite outgrowth, and cell cycle arrest.\",\n      \"method\": \"Overexpression and co-immunoprecipitation, immunofluorescence, neurite outgrowth assay, cell cycle analysis in PC-12 cells\",\n      \"journal\": \"BMC neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with functional overexpression rescue, single lab\",\n      \"pmids\": [\"23057762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"NME2 interacts with PTPsigma (protein tyrosine phosphatase receptor type S) intracellular domain; identified by mass spectrometry screening and confirmed by co-immunoprecipitation in HEK-293T cells; NME2 knockdown in cortical neurons completely rescued CSPG-induced neurite outgrowth inhibition, placing NME2 downstream of PTPsigma in CSPG signaling.\",\n      \"method\": \"Mass spectrometry, co-immunoprecipitation, siRNA knockdown, neurite outgrowth assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS plus co-IP plus functional KD rescue, single lab\",\n      \"pmids\": [\"26896769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"NME2 promotes transcription of antiapoptotic genes (including miR-100, RIPK1, STARD5, LIMS1) by interacting with RNA polymerase II and RNA polymerase II-associated protein 2, mediating phosphorylation of the RNA Pol II C-terminal domain at Ser5, thereby suppressing apoptosis of gastric cancer cells in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (NME2-RNA Pol II), ChIP, luciferase reporter assay, siRNA knockdown, mouse xenograft model\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with ChIP and in vivo model, single lab\",\n      \"pmids\": [\"31694930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NDPK-B (NME2) deficiency in endothelial cells elevates UDP-GlcNAc, reduces NDPK activity, induces GFAT expression, and suppresses OGA activity, leading to increased protein O-GlcNAcylation and elevated Ang-2. The NTP/NDP transphosphorylase and histidine kinase activities of NDPK-B were dispensable for O-GlcNAcylation effects, identifying a novel regulatory axis.\",\n      \"method\": \"siRNA knockdown, in vitro NDPK and OGA activity assays, UPLC-PDA nucleotide measurement, immunoblot for O-GlcNAcylation, adenoviral re-expression\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic assays plus domain function tests, single lab\",\n      \"pmids\": [\"33086728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"NME2 histidine kinase activity is involved in TGF-beta1-induced hepatic stellate cell (HSC) activation and CCl4-induced liver fibrosis; NME2 silencing decreased TGF-beta1-induced histidine phosphorylation and reduced alpha-SMA and COL1A1 expression; the inhibitory effect on HSC activation was mediated through reduced phosphorylation of Smad2 and Smad3.\",\n      \"method\": \"siRNA knockdown, pHis antibody detection, immunoblot (alpha-SMA, COL1A1, pSmad2/3), CCl4 mouse model\",\n      \"journal\": \"Journal of molecular histology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined downstream pathway (Smad phosphorylation), in vivo and in vitro models, single lab\",\n      \"pmids\": [\"32860079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"CARMA3 represses NME2 expression through the NF-kappaB/miR-182 pathway; NF-kappaB drives miR-182 transcription and miR-182 reduces NME2 levels; CARMA3-driven reduction of NME2 promotes lung cancer cell motility, stemness, and metastasis; ChIP and luciferase reporter assays confirmed NF-kappaB binding to the miR-182 promoter.\",\n      \"method\": \"ChIP, luciferase reporter assay, miRNA overexpression/inhibition, in vitro motility assay, in vivo metastasis model\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus reporter assay plus in vivo model, single lab\",\n      \"pmids\": [\"25906011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Protein kinase CK2alpha (catalytic subunit) acts as a signal switch: under basal conditions CK2alpha is part of the NDPK-A/AMPKalpha1 complex; upon AMPK-dependent phosphorylation of S122 on NDPK-A (NME1), CK2alpha dissociates and translocates to bind NDPK-B (NME2), representing the first described phosphorylation-dependent linkage between NME1 and NME2.\",\n      \"method\": \"Co-immunoprecipitation, in vivo AMPK activation (metformin/phenformin), protein binding assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP in cells with pharmacological AMPK activation, single lab\",\n      \"pmids\": [\"17135357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Using ATP-biotin as a cosubstrate for phosphorylbiotinylation, kinase-catalyzed biotinylation methodology identified three novel substrates of NME2 (in addition to validation of known substrates); NME2 phosphorylates serine, threonine, histidine, and aspartic acid residues on substrate proteins.\",\n      \"method\": \"Kinase-catalyzed biotinylation with ATP-biotin cosubstrate, mass spectrometry substrate identification\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro kinase assay with novel ATP analog, single lab, substrates not yet validated by orthogonal methods\",\n      \"pmids\": [\"39032654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NME2 modulates 4EBP1 phosphorylation at Thr37/46 independently of mTOR, regulates eIF4F complex formation, and controls autophagy flux in hepatocellular carcinoma cells; site-specific mutation of 4EBP1 confirmed this mTOR-independent NME2-4EBP1 axis.\",\n      \"method\": \"Knockdown/overexpression, site mutation analysis, immunoblot for pThr37/46-4EBP1, autophagy flux assay\",\n      \"journal\": \"Hepatology communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single paper, mechanistic follow-up limited in abstracts\",\n      \"pmids\": [\"40489759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"NME2 binds PPARdelta via its C-terminal region; identified by yeast two-hybrid and confirmed by co-immunoprecipitation; NME2 overexpression inhibits PPARdelta promoter activity and reduces PPARdelta expression and AKT phosphorylation; NME2 siRNA activated PPARdelta activity and increased GW501516-stimulated cholangiocarcinoma growth.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay, siRNA knockdown, cell proliferation assay\",\n      \"journal\": \"Digestive and liver disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H plus co-IP plus functional reporter, single lab\",\n      \"pmids\": [\"25277864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Fragile X mental retardation protein (FMRP) directly binds NME2 (NDK/Nm23-H2) in a yeast two-hybrid screen of human fetal hippocampus cDNA library; the interaction site on FMRP was mapped to exons 1-11.\",\n      \"method\": \"Yeast two-hybrid, FMRP domain mapping\",\n      \"journal\": \"Acta Academiae Medicinae Sinicae\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — yeast two-hybrid only, no in vitro or cell-based confirmation reported in abstract\",\n      \"pmids\": [\"12901102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Sanguinarine (SG) enhances NME2 binding to the c-MYC G-quadruplex promoter element both in vitro and in cells, leading to c-MYC transcriptional repression and cancer cell growth inhibition in an NME2-dependent manner; mechanistic studies and molecular modeling suggest SG binds the c-MYC G4/NME2 interface as an orthosteric stabilizer.\",\n      \"method\": \"In vitro binding assay (G4-NME2 interaction), cellular transcription assay, NME2-dependent growth inhibition assay, molecular modeling\",\n      \"journal\": \"Bioorganic chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro binding plus cell-based NME2-dependence assay, single lab\",\n      \"pmids\": [\"39342890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NME2 directly binds the Nlrp3 promoter in microglia and recruits EPC2 (a component of the NuA4 histone acetyltransferase complex), inducing H2AK5 acetylation and chromatin remodeling to enhance Nlrp3 transcription; conditional knockout of Nme2 in microglia or pharmacological inhibition with stauprimide decreases CSF IL-1beta and attenuates neuronal death and cognitive impairment in septic mice.\",\n      \"method\": \"ChIP, scRNA-seq, conditional Nme2 knockout, pharmacological inhibition, IL-1beta measurement, cognitive behavioral assays\",\n      \"journal\": \"Brain, behavior, and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus in vivo KO with functional readouts, single lab, preprint not yet peer-reviewed at time of corpus assembly\",\n      \"pmids\": [\"41713665\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"NME2 (NM23-H2/NDPK-B) is a hexameric, bifunctional enzyme that catalyzes nucleoside diphosphate kinase (NDP kinase) phosphoryl transfer via a phosphohistidine (His118) intermediate and, through a separate Lys12-mediated active site, cleaves DNA by a DNA glycosylase/lyase-like covalent mechanism; it also acts as a sequence-specific transcription factor (PuF) that binds G-quadruplex and single-stranded DNA elements in the c-MYC promoter NHE to activate transcription (or recruit REST-LSD1 to repress hTERT), functions as a protein histidine kinase that activates TRPV5 channels and modulates Smad and 4EBP1 phosphorylation, and suppresses metastasis through interactions with multiple partners including ICAP-1alpha/beta1-integrin, dynamin-2 (promoting endocytosis), Lbc-RhoGEF, MDM2, PPARdelta, TRF1/TRF2/telomerase, and the NuA4 histone acetyltransferase complex at the NLRP3 promoter.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"NME2 (NM23-H2/NDPK-B) is a hexameric, bifunctional protein that couples nucleoside diphosphate kinase chemistry to sequence-specific gene regulation and acts as a metastasis suppressor [#1, #2, #18]. It catalyzes phosphoryl transfer through a phosphohistidine (His118) intermediate, and its tumor-associated S122P mutation shifts the rate-limiting step to dephosphorylation while destabilizing the enzyme [#2, #26]. NME2 was identified as the c-myc purine-binding factor PuF, binding the nuclease-hypersensitive element (NHE) to activate transcription; this DNA-binding and transcriptional activity is genetically separable from catalysis, since the catalytically dead H118F mutant retains full DNA binding and transactivation while DNA-binding-dead mutants (Arg34, Asn69, Lys135) retain NDP kinase activity [#0, #3, #4, #5]. NME2 binds and resolves the G-quadruplex within the c-MYC NHE to activate transcription, while at the hTERT promoter it occupies a G4 motif and recruits the REST-LSD1 co-repressor complex to enforce repression, and at the NLRP3 promoter it recruits the NuA4 component EPC2 to deposit H2AK5 acetylation and drive transcription [#15, #19, #42]. Beyond duplex recognition, NME2 cleaves DNA via a covalent protein-DNA intermediate using Lys12 as the nucleophile in a glycosylase/lyase-like reaction whose active site overlaps the nucleotide-binding pocket [#6, #7, #10]. As a protein histidine kinase, NME2 phosphorylates His711 of the Ca2+ channel TRPV5 to increase channel activity (reversed by PHPT1), and its histidine kinase activity feeds into TGF-beta/Smad2/3 signaling and 4EBP1 phosphorylation [#17, #34, #38]. NME2 suppresses metastasis through transcriptional repression of vinculin and through promotion of dynamin-2 oligomerization and GTPase activity to drive receptor endocytosis, the latter requiring histidine kinase rather than NDP kinase activity [#18, #20]. It engages numerous partners coordinating adhesion, cytoskeletal, and telomere biology, including ICAP-1alpha/beta1-integrin, Lbc-RhoGEF, MDM2, and TRF1/TRF2/telomerase, at which last it associates with telomere ends and reduces telomerase activity [#11, #16, #22, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Establishing that nm23-H2 is a distinct second human nm23 gene defined NME2 as a separate gene product highly related to the metastasis-associated NME1.\",\n      \"evidence\": \"cDNA cloning and sequencing with Southern/Northern blots\",\n      \"pmids\": [\"1988104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define protein function beyond NDP kinase homology\", \"No cellular role assigned\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Identifying NME2 as the c-myc transcription factor PuF answered whether an NDP kinase could function in gene regulation, revealing a moonlighting transcriptional role.\",\n      \"evidence\": \"Recombinant protein DNA binding and in vitro transcription on the c-myc NHE\",\n      \"pmids\": [\"8392752\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DNA binding required catalytic activity was unresolved\", \"In vitro only, cellular relevance not yet shown\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Demonstrating that the H118F catalytic mutant retains DNA binding and transactivation separated the enzymatic and transcriptional functions, establishing NME2 as genuinely bifunctional.\",\n      \"evidence\": \"Site-directed mutagenesis with EMSA, in vitro transcription, and phosphoenzyme assays\",\n      \"pmids\": [\"8132589\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the DNA-binding surface\", \"Mechanism of transcriptional output not defined\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"The hexameric crystal structure and cell-based NHE-deletion assays placed NME2's fold, mutation sites, and the required cis-element on a structural and cellular footing.\",\n      \"evidence\": \"X-ray crystallography at 2.8 A and transient transfection CAT reporter with NHE deletion\",\n      \"pmids\": [\"7658474\", \"7784082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure did not show a DNA-bound complex\", \"How tumor mutations alter cellular function untested\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapping DNA-binding residues (Arg34, Asn69, Lys135) distinct from catalytic residues, and showing chromatin association, localized two separable functional modules within the hexamer in the nucleus.\",\n      \"evidence\": \"Mutagenesis with EMSA and NDP kinase assays; sequential nuclear extraction and immunofluorescence\",\n      \"pmids\": [\"8692914\", \"8806452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DNA-binding mode inferred from crosslinking, not structure\", \"Localization study single lab\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identifying Lys12 as the covalent nucleophile and the shared nucleotide-binding pocket defined the DNA cleavage chemistry and its relationship to NDP kinase activity.\",\n      \"evidence\": \"DNA-linked peptide sequencing, mutagenesis, and parallel cleavage/kinase assays\",\n      \"pmids\": [\"11121025\", \"10428867\", \"12009894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate for cleavage unknown\", \"In vivo cleavage role not established\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Linking NME2 to TRF1 and telomeric/telomerase RNA opened a telomere-associated function distinct from c-myc regulation.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, EMSA, and telomerase activity assay\",\n      \"pmids\": [\"9480811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro binding only, no in vivo telomere occupancy yet\", \"Single lab\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Demonstrating direct binding to ICAP-1alpha and co-localization at lamellipodia connected NME2 to beta1-integrin adhesion machinery, suggesting a cytoskeletal/motility function.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro pulldown, co-IP, and confocal microscopy in CHO cells\",\n      \"pmids\": [\"11919189\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for adhesion not directly tested\", \"Role of catalytic activity unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showing NME2 binds and unfolds the c-MYC G-quadruplex defined the structural DNA element underlying its transcriptional activation, refining the PuF mechanism.\",\n      \"evidence\": \"Luciferase reporter, ChIP, and FRET with recombinant NME2\",\n      \"pmids\": [\"19033359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cofactors at the c-MYC G4 not yet identified\", \"Distinction between activation and repression contexts unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Confirming NME2 occupancy of telomere ends and association with TRF2/telomerase in vivo, alongside discovery of the MDM2 interaction, advanced both telomere and metastasis-suppressor mechanisms.\",\n      \"evidence\": \"ChIP-seq, co-IP, telomerase assays, telomere length; affinity-MS and Y2H plus motility rescue\",\n      \"pmids\": [\"22135295\", \"21504894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How NME2 reduces telomerase activity mechanistically not fully resolved\", \"MDM2 study single lab\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying NME2 as a histidine kinase for TRPV5 His711 and as a direct transcriptional repressor of vinculin gave concrete molecular mechanisms for its signaling and metastasis-suppressor roles.\",\n      \"evidence\": \"Inside-out patch clamp with TRPV5 mutagenesis and NDPK-B KO mice; ChIP-chip with zebrafish/mouse metastasis rescue\",\n      \"pmids\": [\"24523290\", \"25249619\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Breadth of histidine kinase substrate repertoire unknown\", \"Selectivity of NME2 vs NME1 at promoters mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing G4-dependent recruitment of REST-LSD1 to the hTERT promoter explained how the same G4-binding protein can repress rather than activate, defining a context-dependent epigenetic mechanism.\",\n      \"evidence\": \"ChIP, luciferase reporter, siRNA, and G4-ligand treatment\",\n      \"pmids\": [\"28717007\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"What dictates activator vs repressor outcome at different G4 promoters unresolved\", \"Direct REST-NME2 contact not mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating that NME2 promotes dynamin-2 oligomerization and GTPase activity to drive receptor endocytosis, requiring histidine kinase activity, mechanistically linked NME2 enzymology to metastasis suppression.\",\n      \"evidence\": \"Reciprocal co-IP, in vitro DNM2 oligomerization/GTPase assays, endocytosis and lung metastasis assays with kinase-dead mutant\",\n      \"pmids\": [\"31311812\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether DNM2 is a direct phosphorylation substrate not established\", \"Relevant histidine site on DNM2 unidentified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Kinase-catalyzed biotinylation expanded the substrate repertoire and showed NME2 phosphorylates Ser, Thr, His, and Asp residues, broadening its potential signaling reach.\",\n      \"evidence\": \"ATP-biotin kinase-catalyzed biotinylation with mass spectrometry\",\n      \"pmids\": [\"39032654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Novel substrates not validated by orthogonal methods\", \"Physiological relevance of multi-residue phosphorylation untested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Showing NME2 recruits the NuA4 component EPC2 to the Nlrp3 promoter to drive H2AK5 acetylation and neuroinflammation extended its transcriptional activation mechanism to chromatin remodeling and a disease context.\",\n      \"evidence\": \"ChIP, scRNA-seq, conditional microglial Nme2 knockout, pharmacological inhibition, and behavioral assays in septic mice\",\n      \"pmids\": [\"41713665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NME2-EPC2 contact interface not mapped\", \"Single lab, in one disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How NME2 selects between transcriptional activation and repression at distinct G4 promoters, and whether its DNA cleavage and multi-residue protein kinase activities operate physiologically, remain unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of NME2 bound to G-quadruplex or duplex DNA\", \"Physiological substrate of covalent DNA cleavage unknown\", \"Determinants of co-repressor vs co-activator recruitment undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [2, 17, 26, 37]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [17, 34, 37]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [0, 4, 5, 6, 15]},\n      {\"term_id\": \"GO:0140097\", \"supporting_discovery_ids\": [6, 7, 10]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 3, 15, 18, 19]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [13, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [13, 28, 30]},\n      {\"term_id\": \"GO:0005694\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [16, 19, 42]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 12]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 3, 15, 18, 19, 42]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [19, 42]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [18, 26]}\n    ],\n    \"complexes\": [\"NuA4 histone acetyltransferase complex (at NLRP3 promoter)\", \"REST-LSD1 co-repressor complex (at hTERT promoter)\"],\n    \"partners\": [\"ICAP-1alpha\", \"TRF1\", \"TRF2\", \"DNM2\", \"MDM2\", \"TRPV5\", \"PPARdelta\", \"EPC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}