Affinage

NME2

Nucleoside diphosphate kinase B · UniProt P22392

Length
152 aa
Mass
17.3 kDa
Annotated
2026-06-10
95 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1991 High

    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

    PMID:1988104

    Open questions at the time
    • Did not define protein function beyond NDP kinase homology
    • No cellular role assigned
  2. 1993 High

    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

    PMID:8392752

    Open questions at the time
    • Whether DNA binding required catalytic activity was unresolved
    • In vitro only, cellular relevance not yet shown
  3. 1994 High

    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

    PMID:8132589

    Open questions at the time
    • Did not map the DNA-binding surface
    • Mechanism of transcriptional output not defined
  4. 1995 High

    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

    PMID:7658474 PMID:7784082

    Open questions at the time
    • Structure did not show a DNA-bound complex
    • How tumor mutations alter cellular function untested
  5. 1996 High

    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

    PMID:8692914 PMID:8806452

    Open questions at the time
    • DNA-binding mode inferred from crosslinking, not structure
    • Localization study single lab
  6. 2000 High

    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

    PMID:10428867 PMID:11121025 PMID:12009894

    Open questions at the time
    • Physiological substrate for cleavage unknown
    • In vivo cleavage role not established
  7. 1998 Medium

    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

    PMID:9480811

    Open questions at the time
    • In vitro binding only, no in vivo telomere occupancy yet
    • Single lab
  8. 2002 High

    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

    PMID:11919189

    Open questions at the time
    • Functional consequence for adhesion not directly tested
    • Role of catalytic activity unknown
  9. 2008 High

    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

    PMID:19033359

    Open questions at the time
    • Cofactors at the c-MYC G4 not yet identified
    • Distinction between activation and repression contexts unresolved
  10. 2011 High

    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

    PMID:21504894 PMID:22135295

    Open questions at the time
    • How NME2 reduces telomerase activity mechanistically not fully resolved
    • MDM2 study single lab
  11. 2014 High

    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

    PMID:24523290 PMID:25249619

    Open questions at the time
    • Breadth of histidine kinase substrate repertoire unknown
    • Selectivity of NME2 vs NME1 at promoters mechanistically unexplained
  12. 2017 High

    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

    PMID:28717007

    Open questions at the time
    • What dictates activator vs repressor outcome at different G4 promoters unresolved
    • Direct REST-NME2 contact not mapped
  13. 2019 High

    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

    PMID:31311812

    Open questions at the time
    • Whether DNM2 is a direct phosphorylation substrate not established
    • Relevant histidine site on DNM2 unidentified
  14. 2024 Medium

    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

    PMID:39032654

    Open questions at the time
    • Novel substrates not validated by orthogonal methods
    • Physiological relevance of multi-residue phosphorylation untested
  15. 2026 Medium

    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

    PMID:41713665

    Open questions at the time
    • Direct NME2-EPC2 contact interface not mapped
    • Single lab, in one disease model

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003677 DNA binding 5 GO:0140110 transcription regulator activity 5 GO:0016740 transferase activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0140097 catalytic activity, acting on DNA 3 GO:0008289 lipid binding 1 GO:0060089 molecular transducer activity 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005886 plasma membrane 2 GO:0005694 chromosome 1
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-4839726 Chromatin organization 2 R-HSA-5653656 Vesicle-mediated transport 1
Partners
DNM2EPC2ICAP-1ALPHAMDM2PPARDELTATRF1TRF2TRPV5
Complex memberships
NuA4 histone acetyltransferase complex (at NLRP3 promoter)REST-LSD1 co-repressor complex (at hTERT promoter)

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 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. cDNA library screening, recombinant protein production in bacteria, in vitro transcription assay, DNA binding assay Science High 8392752
1991 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. cDNA cloning, DNA sequencing, Southern blot, Northern blot hybridization Cancer research High 1988104
1995 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. X-ray crystallography at 2.8 Å (molecular replacement) Journal of molecular biology High 7658474
1995 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. Transient transfection, CAT reporter assay, deletion mutagenesis of NHE element Oncogene High 7784082
1994 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. Site-directed mutagenesis, radioisotopic phosphoenzyme assay, coupled enzyme assay, electrophoretic mobility shift assay (EMSA), in vitro transcription The Journal of biological chemistry High 8132589
1996 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. Site-directed mutagenesis, EMSA, NDP kinase activity assay, chemical crosslinking Proceedings of the National Academy of Sciences of the United States of America High 8692914
1999 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. In vitro DNA cleavage assay, 32P radiolabeling, EDTA reversal, Western blot of covalent complex The Journal of biological chemistry High 10428867
2000 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. DNA-linked peptide sequencing, site-directed mutagenesis, in vitro DNA cleavage assay, NDP kinase assay Proceedings of the National Academy of Sciences of the United States of America High 11121025
2001 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. Competitive enzyme inhibition assay, UV crosslinking, MALDI-TOF mass spectrometry of crosslinked peptides Biochemistry Medium 11352723
2001 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. HeLa cDNA library screening, recombinant protein DNA cleavage assay, transient transfection, CAT/reporter assay The Journal of biological chemistry High 11694515
2002 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. Site-directed mutagenesis, in vitro DNA cleavage assay, NDP kinase assay, nucleotide inhibition assay Biochemistry High 12009894
2002 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. Yeast two-hybrid, in vitro pulldown with purified proteins, co-immunoprecipitation, confocal fluorescence microscopy The Journal of biological chemistry High 11919189
2004 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. Yeast two-hybrid, co-immunoprecipitation, immunofluorescence microscopy, endocytosis assay The Journal of biological chemistry Medium 14976202
1996 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. Immunofluorescence with isoform-specific antibodies, sequential nuclear extraction (Triton X-100, RNase A, DNase I), live-cell imaging Experimental cell research Medium 8806452
1998 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. Yeast two-hybrid, in vitro binding assay with recombinant proteins, EMSA, in vitro telomerase activity assay Biochemical and biophysical research communications Medium 9480811
2008 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. Luciferase reporter assay, chromatin immunoprecipitation (ChIP), FRET with recombinant NME2 Nucleic acids research High 19033359
2011 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. ChIP-seq, independent ChIP validation, co-immunoprecipitation (NME2-TRF2), in vitro and in vivo telomerase activity assays, telomere length measurement Nucleic acids research High 22135295
2014 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. Inside-out patch clamp electrophysiology, site-directed mutagenesis of TRPV5 His711, shRNA knockdown, NDPK-B knockout mouse model, Ca2+ flux assay Molecular biology of the cell High 24523290
2014 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. ChIP-chip (promoter-wide binding map), transcriptome profiling, siRNA knockdown, zebrafish and nude mice metastasis assays Nucleic acids research High 25249619
2017 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. ChIP, luciferase reporter assay, siRNA knockdown, G-quadruplex ligand treatment The Journal of biological chemistry High 28717007
2019 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. Co-immunoprecipitation, in vitro DNM2 oligomerization/GTPase assay, shRNA knockdown, endocytosis assay, lung metastasis assay, NME1 histidine kinase-inactive mutant transfection Cancer research High 31311812
2010 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. Co-immunoprecipitation, confocal microscopy, domain-deletion mutagenesis of plakoglobin Oncogene Medium 20101217
2004 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. Yeast two-hybrid, co-immunoprecipitation (implied by cell-based interaction), GTP-Rho pulldown assay, stress fiber imaging Biochemical and biophysical research communications Medium 15249197
2011 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. Affinity chromatography, tandem mass spectrometry, yeast two-hybrid, siRNA knockdown, cell motility assay Carcinogenesis Medium 21504894
2007 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. Yeast two-hybrid, co-immunoprecipitation, co-localization, overexpression and siRNA knockdown, apoptosis assay Biochemical and biophysical research communications Medium 17532299
2007 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. Yeast two-hybrid, immunofluorescence co-localization, ERE-luciferase reporter assay, cell migration assay The Journal of steroid biochemistry and molecular biology Medium 17964137
1999 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. Steady-state enzyme kinetics, stopped-flow transient kinetics, intrinsic fluorescence kinetics, thermal/urea stability assays The Journal of biological chemistry High 10400630
2014 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. Co-immunoprecipitation, ChIP, luciferase reporter assay, siRNA knockdown, F-actin imaging Oncotarget Medium 25193865
2020 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. Live-cell imaging, FRET/FLIM, gamma irradiation International journal of molecular sciences Medium 32235358
2016 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. Liposome binding assay, lipid monolayer, supported lipid bilayer, biophysical measurements of membrane fluidity Langmuir Medium 27934520
2012 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. Overexpression and co-immunoprecipitation, immunofluorescence, neurite outgrowth assay, cell cycle analysis in PC-12 cells BMC neuroscience Medium 23057762
2016 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. Mass spectrometry, co-immunoprecipitation, siRNA knockdown, neurite outgrowth assay Biochemical and biophysical research communications Medium 26896769
2019 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. Co-immunoprecipitation (NME2-RNA Pol II), ChIP, luciferase reporter assay, siRNA knockdown, mouse xenograft model Molecular cancer research Medium 31694930
2020 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. siRNA knockdown, in vitro NDPK and OGA activity assays, UPLC-PDA nucleotide measurement, immunoblot for O-GlcNAcylation, adenoviral re-expression Cells Medium 33086728
2020 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. siRNA knockdown, pHis antibody detection, immunoblot (alpha-SMA, COL1A1, pSmad2/3), CCl4 mouse model Journal of molecular histology Medium 32860079
2015 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. ChIP, luciferase reporter assay, miRNA overexpression/inhibition, in vitro motility assay, in vivo metastasis model American journal of respiratory and critical care medicine Medium 25906011
2006 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. Co-immunoprecipitation, in vivo AMPK activation (metformin/phenformin), protein binding assays FASEB journal Medium 17135357
2024 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. Kinase-catalyzed biotinylation with ATP-biotin cosubstrate, mass spectrometry substrate identification The Journal of biological chemistry Medium 39032654
2025 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. Knockdown/overexpression, site mutation analysis, immunoblot for pThr37/46-4EBP1, autophagy flux assay Hepatology communications Low 40489759
2014 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. Yeast two-hybrid, co-immunoprecipitation, luciferase reporter assay, siRNA knockdown, cell proliferation assay Digestive and liver disease Medium 25277864
2001 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. Yeast two-hybrid, FMRP domain mapping Acta Academiae Medicinae Sinicae Low 12901102
2024 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. In vitro binding assay (G4-NME2 interaction), cellular transcription assay, NME2-dependent growth inhibition assay, molecular modeling Bioorganic chemistry Medium 39342890
2026 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. ChIP, scRNA-seq, conditional Nme2 knockout, pharmacological inhibition, IL-1beta measurement, cognitive behavioral assays Brain, behavior, and immunity Medium 41713665

Source papers

Stage 0 corpus · 95 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1993 Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science (New York, N.Y.) 484 8392752
1991 Identification of a second human nm23 gene, nm23-H2. Cancer research 412 1988104
2008 Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression. Nucleic acids research 157 19033359
1993 Reduced expression of nm23-H1, but not of nm23-H2, is concordant with the frequency of lymph-node metastasis of human breast cancer. International journal of cancer 149 8102131
1995 The crystal structure of a human nucleoside diphosphate kinase, NM23-H2. Journal of molecular biology 127 7658474
1995 PuF/NM23-H2/NDPK-B transactivates a human c-myc promoter-CAT gene via a functional nuclease hypersensitive element. Oncogene 125 7784082
1994 Expression of metastasis-related nm23-H1 and nm23-H2 genes in ovarian carcinomas: correlation with clinicopathology, EGFR, c-erbB-2, and c-erbB-3 genes, and sex steroid receptor expression. Cancer research 123 7907945
1994 Nucleoside diphosphate kinase enzyme activity of NM23-H2/PuF is not required for its DNA binding and in vitro transcriptional functions. The Journal of biological chemistry 114 8132589
1993 High levels of nm23-H1 and nm23-H2 messenger RNA in human squamous-cell lung carcinoma are associated with poor differentiation and advanced tumor stages. International journal of cancer 104 8375920
2005 Identification of ATF-3, caveolin-1, DLC-1, and NM23-H2 as putative antitumorigenic, progesterone-regulated genes for ovarian cancer cells by gene profiling. Oncogene 99 15674352
2001 NM23-H1 and NM23-H2 repress transcriptional activities of nuclease-hypersensitive elements in the platelet-derived growth factor-A promoter. The Journal of biological chemistry 99 11694515
2002 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-1alpha ) interacts directly with the metastasis suppressor nm23-H2, and both proteins are targeted to newly formed cell adhesion sites upon integrin engagement. The Journal of biological chemistry 91 11919189
1994 Expression of human nm23-H1 and nm23-H2 proteins in hepatocellular carcinoma. Cancer 86 8168032
2000 Catalysis of DNA cleavage and nucleoside triphosphate synthesis by NM23-H2/NDP kinase share an active site that implies a DNA repair function. Proceedings of the National Academy of Sciences of the United States of America 83 11121025
1999 Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. Clinical cancer research : an official journal of the American Association for Cancer Research 79 10632374
1993 Increased nm23-H1 and nm23-H2 messenger RNA expression and absence of mutations in colon carcinomas of low and high metastatic potential. Journal of the National Cancer Institute 77 8418304
1996 Mutational analysis of NM23-H2/NDP kinase identifies the structural domains critical to recognition of a c-myc regulatory element. Proceedings of the National Academy of Sciences of the United States of America 75 8692914
1995 Overexpression of nm23-H1 and nm23-H2 genes in colorectal carcinomas and loss of nm23-H1 expression in advanced tumour stages. Gut 72 8549951
1995 NM23-H1 and NM23-H2 messenger RNA abundance in human hepatocellular carcinoma. Cancer research 69 7530600
2011 [Ir(PCy3)2(H)2(H2B-NMe2)]+ as a latent source of aminoborane: probing the role of metal in the dehydrocoupling of H3B⋅NMe2H and retrodimerisation of [H2BNMe2]2. Chemistry (Weinheim an der Bergstrasse, Germany) 68 21322070
1993 Expression of nm23-H1 and nm23-H2 proteins in prostate carcinoma. Japanese journal of cancer research : Gann 67 7693635
1996 Decreased expression of nucleoside diphosphate kinase alpha isoform, an nm23-H2 gene homolog, is associated with metastatic potential of rat mammary-adenocarcinoma cells. International journal of cancer 66 8621239
1999 Cleavage of DNA by human NM23-H2/nucleoside diphosphate kinase involves formation of a covalent protein-DNA complex. The Journal of biological chemistry 65 10428867
2014 Regulation of the epithelial Ca²⁺ channel TRPV5 by reversible histidine phosphorylation mediated by NDPK-B and PHPT1. Molecular biology of the cell 63 24523290
2002 The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. Oncogene 63 11960382
1998 Association of nucleoside diphosphate kinase nm23-H2 with human telomeres. Biochemical and biophysical research communications 56 9480811
2017 Epigenetic suppression of human telomerase (hTERT) is mediated by the metastasis suppressor NME2 in a G-quadruplex-dependent fashion. The Journal of biological chemistry 51 28717007
1996 Nuclear localization of nucleoside diphosphate kinase type B (nm23-H2) in cultured cells. Experimental cell research 51 8806452
2004 Nm23-H2 interacts with a G protein-coupled receptor to regulate its endocytosis through an Rac1-dependent mechanism. The Journal of biological chemistry 50 14976202
2010 Plakoglobin interacts with and increases the protein levels of metastasis suppressor Nm23-H2 and regulates the expression of Nm23-H1. Oncogene 48 20101217
2017 The actions of NME1/NDPK-A and NME2/NDPK-B as protein kinases. Laboratory investigation; a journal of technical methods and pathology 46 29200201
2014 Non-metastatic 2 (NME2)-mediated suppression of lung cancer metastasis involves transcriptional regulation of key cell adhesion factor vinculin. Nucleic acids research 45 25249619
2019 Metastasis Suppressors NME1 and NME2 Promote Dynamin 2 Oligomerization and Regulate Tumor Cell Endocytosis, Motility, and Metastasis. Cancer research 44 31311812
2014 PIWIL2 induces c-Myc expression by interacting with NME2 and regulates c-Myc-mediated tumor cell proliferation. Oncotarget 44 25193865
2002 Structure-based mutational and functional analysis identify human NM23-H2 as a multifunctional enzyme. Biochemistry 42 12009894
2007 NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling. Biochemical and biophysical research communications 35 17532299
2017 Design, Synthesis, and Evaluation of New Selective NM23-H2 Binders as c-MYC Transcription Inhibitors via Disruption of the NM23-H2/G-Quadruplex Interaction. Journal of medicinal chemistry 34 28714689
2015 NME2 reduces proliferation, migration and invasion of gastric cancer cells to limit metastasis. PloS one 34 25700270
2004 Lbc proto-oncogene product binds to and could be negatively regulated by metastasis suppressor nm23-H2. Biochemical and biophysical research communications 33 15249197
1996 Down regulation of NM23.H1, NM23.H2 and c-myc genes during differentiation induced by 1,25 dihydroxyvitamin D3. Leukemia research 32 8628015
2017 Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate c-myc Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex. Journal of medicinal chemistry 31 28128954
2015 CARMA3 Represses Metastasis Suppressor NME2 to Promote Lung Cancer Stemness and Metastasis. American journal of respiratory and critical care medicine 30 25906011
2015 Chemical intervention of the NM23-H2 transcriptional programme on c-MYC via a novel small molecule. Nucleic acids research 30 26117539
2007 Discovery of NM23-H2 as an estrogen receptor beta-associated protein: role in estrogen-induced gene transcription and cell migration. The Journal of steroid biochemistry and molecular biology 30 17964137
2011 Metastases suppressor NME2 associates with telomere ends and telomerase and reduces telomerase activity within cells. Nucleic acids research 28 22135295
2018 Identification of CRKII, CFL1, CNTN1, NME2, and TKT as Novel and Frequent T-Cell Targets in Human IDH-Mutant Glioma. Clinical cancer research : an official journal of the American Association for Cancer Research 26 29563135
2009 Double knockout Nme1/Nme2 mouse model suggests a critical role for NDP kinases in erythroid development. Molecular and cellular biochemistry 26 19381783
2012 Pro-oncogenic potential of NM23-H2 in hepatocellular carcinoma. Experimental & molecular medicine 25 22192927
2011 MDM2 interacts with NME2 (non-metastatic cells 2, protein) and suppresses the ability of NME2 to negatively regulate cell motility. Carcinogenesis 24 21504894
2011 Mechanisms of non-metastatic 2 (NME2)-mediated control of metastasis across tumor types. Naunyn-Schmiedeberg's archives of pharmacology 23 21556888
2008 Inhibition of Nm23H2 gene product (NDPK-B) by angiostatin, polyphenols and nucleoside analogs. Proceedings of the Western Pharmacology Society 23 19544670
2006 Read-through transcript from NM23-H1 into the neighboring NM23-H2 gene encodes a novel protein, NM23-LV. Genomics 23 16442775
2019 NME2 Is a Master Suppressor of Apoptosis in Gastric Cancer Cells via Transcriptional Regulation of miR-100 and Other Survival Factors. Molecular cancer research : MCR 22 31694930
2000 Expression of a catalytically inactive H118Y mutant of nm23-H2 suppresses the metastatic potential of line IV Cl 1 human melanoma cells. International journal of cancer 22 11058869
1993 The human NME2 gene lies within 18kb of NME1 in chromosome 17. Genes, chromosomes & cancer 22 7685630
2021 Requirement of transcription factor NME2 for the maintenance of the stemness of gastric cancer stem-like cells. Cell death & disease 20 34628473
2008 Identification of NM23-H2 as a tumour-associated antigen in chronic myeloid leukaemia. Leukemia 16 18496563
1995 Characterization of the human nm23-H2 promoter region and localization of the microsatellite D17S396. Biochemical and biophysical research communications 16 7488060
2024 Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC. Nature communications 15 38191557
2020 Involvement of NDPK-B in Glucose Metabolism-Mediated Endothelial Damage via Activation of the Hexosamine Biosynthesis Pathway and Suppression of O-GlcNAcase Activity. Cells 15 33086728
2016 Nicotine induces Nme2-mediated apoptosis in mouse testes. Biochemical and biophysical research communications 15 26972251
2006 NDPK-A (but not NDPK-B) and AMPK alpha1 (but not AMPK alpha2) bind the cystic fibrosis transmembrane conductance regulator in epithelial cell membranes. Cellular signalling 15 16466905
2006 NM23-H2, an estrogen receptor beta-associated protein, shows diminished expression with progression of atherosclerosis. American journal of physiology. Regulatory, integrative and comparative physiology 15 17272673
2020 The Subcellular Localization and Oligomerization Preferences of NME1/NME2 upon Radiation-Induced DNA Damage. International journal of molecular sciences 14 32235358
2014 Regulatory functions of Nm23-H2 in tumorigenesis: insights from biochemical to clinical perspectives. Naunyn-Schmiedeberg's archives of pharmacology 14 25413836
1999 Human nucleoside diphosphate kinase B (Nm23-H2) from melanoma cells shows altered phosphoryl transfer activity due to the S122P mutation. The Journal of biological chemistry 14 10400630
1993 Localization of a second NM23 gene, NME2, to chromosome 17q21-q22. Genomics 13 8406509
2001 Peptidic determinants and structural model of human NDP kinase B (Nm23-H2) bound to single-stranded DNA. Biochemistry 12 11352723
2012 Bcr-Abl dependent post-transcriptional activation of NME2 expression is a specific and common feature of chronic myeloid leukemia. Leukemia & lymphoma 11 22251158
2020 CircPSMC3 Suppresses Migration and Invasion of Non-Small Cell Lung Cancer Cells via miR-182-5p/NME2 Axis. Medical science monitor : international medical journal of experimental and clinical research 10 32386284
2020 Nme1 and Nme2 genes exert metastasis-suppressor activities in a genetically engineered mouse model of UV-induced melanoma. British journal of cancer 10 33024267
1997 Isolation and characterization of new microsatellites at the nm23-H1 and nm23-H2 gene loci and application for loss of heterozygosity (LOH) analysis. Human genetics 10 9341864
1995 Expression of nm23-H1 and nm23-H2 protein in endometrial carcinoma. British journal of cancer 10 8519661
2021 Loss of the Metastasis Suppressor NME1, But Not of Its Highly Related Isoform NME2, Induces a Hybrid Epithelial-Mesenchymal State in Cancer Cells. International journal of molecular sciences 9 33918324
2003 Method to express and purify nm23-H2 protein from baculovirus-infected cells. BioTechniques 9 12951781
2022 Extracellular Vesicle-Mediated Metastasis Suppressors NME1 and NME2 Modify Lipid Metabolism in Fibroblasts. Cancers 8 36010906
2021 Comprehensive molecular profiling of UV-induced metastatic melanoma in Nme1/Nme2-deficient mice reveals novel markers of survival in human patients. Oncogene 8 34433909
2020 Histidine kinase NME1 and NME2 are involved in TGF-β1-induced HSC activation and CCl4-induced liver fibrosis. Journal of molecular histology 8 32860079
2016 Two-Step Membrane Binding of NDPK-B Induces Membrane Fluidity Decrease and Changes in Lipid Lateral Organization and Protein Cluster Formation. Langmuir : the ACS journal of surfaces and colloids 8 27934520
2003 Analysis of both NM23-h1 and NM23-H2 expression identifies "at-risk" patients with colorectal cancer. The American surgeon 8 12678475
2014 Recruited metastasis suppressor NM23-H2 attenuates expression and activity of peroxisome proliferator-activated receptor δ (PPARδ) in human cholangiocarcinoma. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver 7 25277864
2012 Diva/BclB regulates differentiation by inhibiting NDPKB/Nm23H2-mediated neuronal differentiation in PC-12 cells. BMC neuroscience 7 23057762
1996 Different expression of nm23-H1 and nm23-H2 protein with proliferative activities in various sizes of human renal cell carcinoma. Oncology 7 8570138
2024 Identification of sanguinarine as c-MYC transcription inhibitor through enhancing the G-quadruplex-NM23-H2 interactions. Bioorganic chemistry 5 39342890
2023 Nme2 Cas9-mediated therapeutic editing in inhibiting angiogenesis after wet age-related macular degeneration onset. Clinical and translational medicine 5 37598400
2006 Protein kinase CK2 acts as a signal molecule switching between the NDPK-A/AMPK alpha1 complex and NDPK-B. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 17135357
2016 NME2 associates with PTPσ to transduce signals from chondroitin sulfate proteoglycans. Biochemical and biophysical research communications 3 26896769
2024 Kinase-catalyzed biotinylation for discovery and validation of substrates to multispecificity kinases NME1 and NME2. The Journal of biological chemistry 1 39032654
1997 [Amplification, clone and identification of the specific fragments of tumor metastasis-suppressor gene nm23-H1 and nm23-H2]. Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology 1 11479979
2026 NME2-driven epigenetic control of inflammasome-activated microglial lineage dynamics promotes sepsis-associated encephalopathy. Brain, behavior, and immunity 0 41713665
2025 Effect of NME2 and SAMHD1 genetic polymorphisms involved in Ara-C metabolism on the response to induction chemotherapy in adult acute myeloid leukemia. Journal of the Egyptian National Cancer Institute 0 40289230
2025 NME2 modulates HCC progression through 4EBP1 phosphorylation and autophagy regulation independent of mTOR. Hepatology communications 0 40489759
2024 Rational Design of Enhanced Nme2Cas9 and Nme2SmuCas9 Nucleases and Base Editors. bioRxiv : the preprint server for biology 0 39554198
2014 Towards a comprehensive understanding of the chemical vapor deposition of titanium nitride using Ti(NMe2)4: a density functional theory approach. Dalton transactions (Cambridge, England : 2003) 0 24788479
2001 [Fragile X mental retardation protein interacts with human NDK/Nm23-H2]. Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae 0 12901102

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