NME2

Summary

NME2 (NME/NM23 nucleoside diphosphate kinase 2, HGNC:7850) is a protein-coding gene on chromosome 17q21.33, encoding Nucleoside diphosphate kinase B (P22392). 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. It is a selective cancer dependency (DepMap: 24.4% of cell lines).

Nucleoside diphosphate kinase (NDK) exists as a hexamer composed of ‘A’ (encoded by NME1) and ‘B’ (encoded by this gene) isoforms. Multiple alternatively spliced transcript variants have been found for this gene. Read-through transcription from the neighboring upstream gene (NME1) generates naturally-occurring transcripts (NME1-NME2) that encode a fusion protein comprised of sequence sharing identity with each individual gene product.

Source: NCBI Gene 4831 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 24.4% of screened cell lines
• MANE Select transcript: NM_002512

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7850
Approved symbol	NME2
Name	NME/NM23 nucleoside diphosphate kinase 2
Location	17q21.33
Locus type	gene with protein product
Status	Approved
Aliases	NM23-H2, NDPKB
Ensembl gene	ENSG00000243678
Ensembl biotype	protein_coding
OMIM	156491
Entrez	4831

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 24 protein_coding, 3 retained_intron

ENST00000393183, ENST00000393190, ENST00000485076, ENST00000503064, ENST00000512737, ENST00000513177, ENST00000514264, ENST00000570801, ENST00000573262, ENST00000861527, ENST00000861528, ENST00000861529, ENST00000926696, ENST00000926697, ENST00000926698, ENST00000926699, ENST00000926700, ENST00000926701, ENST00000926702, ENST00000926703, ENST00000926704, ENST00000926705, ENST00000926706, ENST00000926707, ENST00000941167, ENST00000941168, ENST00000941169

RefSeq mRNA: 5 — MANE Select: NM_002512 NM_001018137, NM_001018138, NM_001018139, NM_001198682, NM_002512

CCDS: CCDS11580, CCDS74107

Canonical transcript exons

ENST00000512737 — 5 exons

Exon	Start	End
ENSE00003460413	51171487	51171744
ENSE00003651397	51166411	51166497
ENSE00003705710	51169937	51170049
ENSE00003721718	51166827	51166956
ENSE00003781211	51168242	51168343

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 555.0081 / max 2562.4250, expressed in 1827 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161742	398.4006	1827
161743	155.1590	1818
161740	1.2380	446
161741	0.2105	83

Top tissues by expression

134 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	99.56	gold quality
skin of abdomen	UBERON:0001416	99.55	gold quality
zone of skin	UBERON:0000014	99.54	gold quality
skin of leg	UBERON:0001511	99.54	gold quality
ovary	UBERON:0000992	99.53	gold quality
metanephros cortex	UBERON:0010533	99.53	gold quality
endocervix	UBERON:0000458	99.52	gold quality
left coronary artery	UBERON:0001626	99.52	gold quality
esophagus mucosa	UBERON:0002469	99.52	gold quality
mucosa of transverse colon	UBERON:0004991	99.52	gold quality
lower esophagus	UBERON:0013473	99.52	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.52	gold quality
esophagus	UBERON:0001043	99.51	gold quality
thoracic mammary gland	UBERON:0005200	99.51	gold quality
body of pancreas	UBERON:0001150	99.50	gold quality
right ovary	UBERON:0002118	99.50	gold quality
stromal cell of endometrium	CL:0002255	99.49	gold quality
vagina	UBERON:0000996	99.49	gold quality
adipose tissue	UBERON:0001013	99.49	gold quality
subcutaneous adipose tissue	UBERON:0002190	99.49	gold quality
body of uterus	UBERON:0009853	99.49	gold quality
omental fat pad	UBERON:0010414	99.49	gold quality
myometrium	UBERON:0001296	99.48	gold quality
ectocervix	UBERON:0012249	99.48	gold quality
left adrenal gland	UBERON:0001234	99.47	gold quality
left adrenal gland cortex	UBERON:0035825	99.47	gold quality
saliva-secreting gland	UBERON:0001044	99.46	gold quality
body of stomach	UBERON:0001161	99.46	gold quality
minor salivary gland	UBERON:0001830	99.46	gold quality
right lobe of thyroid gland	UBERON:0001119	99.45	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-MTAB-6653	yes	1446.34
E-GEOD-149689	yes	1352.18
E-HCAD-4	yes	86.02
E-GEOD-125970	yes	53.64
E-MTAB-8410	yes	48.77
E-MTAB-10553	yes	35.65
E-CURD-46	yes	33.98
E-CURD-112	yes	33.77
E-CURD-122	yes	23.19
E-HCAD-9	yes	19.88
E-HCAD-1	yes	19.01
E-MTAB-10042	yes	17.45
E-ANND-3	yes	15.89
E-MTAB-9467	yes	11.69
E-MTAB-9067	yes	10.43

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
MYC	Activation

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

6 targeting NME2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-1301-5P	98.09	66.62	495
HSA-MIR-6502-5P	98.09	66.73	495
HSA-MIR-3152-5P	96.98	66.88	819
HSA-MIR-4423-5P	95.24	64.42	454

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 24.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• The N-myc and c-myc downstream pathways include the chromosome 17q genes nm23-H1 and nm23-H2. (PMID:11960382)
• NM23-H2 protein expression in human leukemia cell lines is related to cellular lineage and differentiation stages. (PMID:12007505)
• The nucleotide-binding site of NM23-H2 plays a critical role in not only the NDP kinase reaction but also the reactions involving covalent DNA binding and DNA cleavage catalysis. (PMID:12009894)
• expression of nucleoside diphosphate kinase in Alzheimer disease and Down syndrome brains (PMID:12200143)
• found that Nm23-H5 and NDP kinases A and B are differently distributed in spermatids and mature spermatozoa and could therefore be involved at various levels of sperm differentiation and function (PMID:14499630)
• Nm23-H2 had a cytoplasmic and nuclear localization but was induced to translocate to the plasma membrane upon stimulation of thromboxane A2 receptor beta to show extensive co-localization with the receptor. (PMID:14976202)
• Novel roles of NM23 proteins in skin homeostasis, repair and disease. (PMID:16862176)
• novel association of NM23-H2 with ERbeta and show for the first time its expression in vascular cells and demonstrate regulation of its expression and localization by estrogen (PMID:17272673)
• Thus, these results indicate the existence of a previously undiscovered mechanism by which NM23-H2 involves in the regulation of Diva-mediated apoptosis. (PMID:17532299)
• NM23-H2 as an estrogen receptor beta-associated protein may play an important role in modulating the response to endogenous and exogenous estrogens. (PMID:17964137)
• describe the identification of NM23-H2 as a novel HLA-A32-restricted TAA of CML cells and demonstrate the presence of specifically reactive T cells in a patient 5 years after transplantation (PMID:18496563)
• While hPLIC proteins are not ubiquitinated by HERC3, HERC5 plays an important role in ubiquitination of Nm23B. (PMID:18535780)
• data indicate that NM23H2 is a negative regulator of cellular proliferation stimulated by EGF- and Ras-mediated activation of the ERK pathway (PMID:19022560)
• Role of NM23-H2 in the regulation of cell shape and migration via Rho family GTPase signals is reported. (PMID:19381785)
• Data suggest that transglutaminase 2 is overexpressed in cystic fibrosis and affects nucleoside diphosphate kinase function (PMID:19619546)
• Data support the hypothesis that exogenous pDNA binds to cytoplasmic shuttle proteins NM23-H2 and Chx10, and is then translocated to the nucleus using the minimal import machinery. (PMID:19638341)
• further demonstrate that shNDPK-B is released into the circulation in immunocompromized mice carrying the human breast carcinoma cell MDA-MB- (PMID:20830314)
• Studies indicate that most of the proteins known to interact with human NME proteins were also found in starlet sea anemone. (PMID:21085602)
• NM23-H2 expression enhances tumorigenicity. (PMID:22192927)
• post-transcriptional up-regulation of the tumor antigen NME2 is a common and specific property of CML closely associated with Bcr-Abl activity (PMID:22251158)
• NME mRNA and high NME2 mRNA are strong indicator of increased event-free survival independent of FLT3-internal tandem duplication in cytogenetically normal acute myeloid leukemia (PMID:22421058)
• PuF may regulate the APP gene promoter (PMID:23368879)
• nucleoside diphosphate kinase B (NDPK-B), activates TRPV5 channel activity and Ca(2+) flux, and this activation requires histidine 711 in the carboxy-terminal tail of TRPV5. (PMID:24523290)
• findings show NDPKs (NM23-H1/H2/H4) interact with and provide GTP to dynamins, allowing these motor proteins to work with high thermodynamic efficiency for membrane remodeling (PMID:24970086)
• NDPK-B and NDPK-D were shown to bind efficiently to liposomes mimicking plasma membrane and mitochondrial inner membrane (PMID:25010650)
• NDPKB is required for VEGF-induced angiogenesis and contributes to the correct localization of VEGF receptor type 2 and VE-cadherin at the endothelial adherens junctions. (PMID:25147336)
• PIWIL2 modulates tumor cell proliferation and F-actin filaments by interacting with NME2 and regulating c-Myc expression. (PMID:25193865)
• The results demonstrate that reduced NME2 levels lead to transcriptional de-repression of vinculin and regulate lung cancer metastasis. (PMID:25249619)
• Regulatory functions of Nm23-H2 in tumorigenesis: insights from biochemical to clinical perspectives (PMID:25413836)
• Recent findings demonstrate NME2 presence at telomere ends, association with telomerase, and NME2’s role in inhibition of telomerase activity in cancer cells (PMID:25547372)
• NME2 may have an inhibitory activity on the propagation and invasion of gastric cancer cells. (PMID:25700270)
• Overexpression of Nm23H1 did not affect tumorigenesis in nude mice assays, while overexpression of Nm23H2 enhanced tumor growth with elevated expression of the c-Myc proto-oncogene. (PMID:25748386)
• Patients whose MPM tissues expressed elevated mRNA levels of BIRC5, DSP, NME2, and THBS2 showed a statistically significant shorter overall survival. (PMID:25771974)
• A novel mechanism of CARMA3 in lung cancer stemness and metastasis through the negative regulation of NME2 was identified. (PMID:25906011)
• Role of Interaction and Nucleoside Diphosphate Kinase B in Regulation of the Cystic Fibrosis Transmembrane Conductance Regulator Function by cAMP-Dependent Protein Kinase A (PMID:26950439)
• Data suggest that NME2 participates in epigenetic repression of TERT expression via a mechanism that is dependent on interactions with G-quadruplex DNA; NME2 appears to interact with TERT promoter as NME2/REST/LSD1 complex. (NME2 = metastasis suppressor protein 2; TERT = telomerase reverse transcriptase; REST = RE1-silencing transcription factor; LSD1 = lysine specific demethylase 1) (PMID:28717007)
• The data presented suggest an important role for cytoplasmic IRF6 in regulating the availability or localization of the NME1/2 complex and thus the dynamic behavior of epithelia during lip/palate development. (PMID:28767310)
• interacts with nucleotide-binding site NBD1 in CFTR via a motif involving amino acid residues 36-56 on the surface of NDPK-B [review] (PMID:29251738)
• NME2 mediates chemoresistance to 5-FU in CRC (PMID:29475390)
• Study reports that NME2 is an oncogene in osteosarcoma (OS) that is associated with its clinicopathologic features. Downregulation of NME2 could reduce the proliferation of OS cells and arrest the OS cell cycle in the G2/M phase. The deregulation of NME2 enhanced the expression of c-Myc and affected the proliferation of osteosarcoma. (PMID:29630434)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Nme2	ENSMUSG00000020857
rattus_norvegicus	Nme2	ENSRNOG00000002671

Paralogs (8): NME8 (ENSG00000086288), NME3 (ENSG00000103024), NME4 (ENSG00000103202), NME5 (ENSG00000112981), NME7 (ENSG00000143156), NME6 (ENSG00000172113), NME9 (ENSG00000181322), NME1 (ENSG00000239672)

Protein

Protein identifiers

Nucleoside diphosphate kinase B — P22392 (reviewed: P22392)

Alternative names: C-myc purine-binding transcription factor PUF, Histidine protein kinase NDKB, Nucleoside diphoshate kinase 2, nm23-H2

All UniProt accessions (3): P22392, F6XY72, Q6FHN3

UniProt curated annotations — full annotation on UniProt →

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. Also functions as a histidine protein kinase by transferring the phosphoryl group from the phosphohistidine intermediate to a histidine residue in target proteins. 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. 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. Additionally involved in transcriptional regulation through direct DNA binding and chromatin remodeling. 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. G4 DNA-binding activity is independent of its nucleoside diphosphate kinase function and recognizes both folded and unfolded G4 structures. 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. Also negatively regulates Rho activity by interacting with AKAP13/LBC.

Subunit / interactions. Homohexamer. Heterohexamer of two different chains: A/NME1 and B/NME2 (A5B or A4B2 or A3B3 or A2B4 or AB5). Interacts with CAPN8. Interacts with AKAP13. Interacts with ITGB1BP1 (via C-terminal domain region); this interaction leads to their recruitment to ITGB1-rich cell adhesion sites in cell spreading on FN1. Interacts with BCL2L10.

Subcellular location. Cytoplasm. Nucleus. Cell projection. Lamellipodium. Ruffle Cytoplasm. Perinuclear region. Nucleus Cytoplasm.

Tissue specificity. Ubiquitously expressed. Ubiquitously expressed.

Post-translational modifications. Autophosphorylated.

Miscellaneous. Involved in the activation pathway of bemnifosbuvir (AT-527) and its epimer, AT-752. AT-527 and AT-752 are two guanosine analogs tested in clinical trials against several RNA viruses, which are activated into their common 5’-triphosphate AT-9010 in human cells. Mediates the last activation step by catalyzing transformation of AT-8500 into AT-9010. Based on a naturally occurring readthrough transcript which produces an NME1-NME2 fusion protein.

Similarity. Belongs to the NDK family.

Isoforms (2)

UniProt ID	Names	Canonical?
P22392-1	1, NM23-H2	yes
P22392-2	3, NM23-LV

RefSeq proteins (5): NP_001018147, NP_001018148, NP_001018149, NP_001185611, NP_002503* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001564	Nucleoside_diP_kinase	Family
IPR023005	Nucleoside_diP_kinase_AS	Active_site
IPR034907	NDK-like_dom	Domain
IPR036850	NDK-like_dom_sf	Homologous_superfamily

Pfam: PF00334

Enzyme classification (BRENDA):

• EC 2.7.4.6 — nucleoside-diphosphate kinase (BRENDA: 102 organisms, 269 substrates, 41 inhibitors, 131 Km, 29 kcat entries)

Substrate kinetics (BRENDA)

20 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.07–5.5	22
ADP	0.024–1.26	17
ATP	0.005–4.6	14
DTDP	0.001–1.1	11
CTP	0.04–12	8
UTP	0.11–27	8
DCDP	0.01–0.56	6
GDP	0.02–0.049	5
UDP	0.1–0.28	5
TTP	0.89–5.28	4
8-BROMO-IDP	0.033–0.06	2
CDP	0.05–0.69	2
DGDP	0.14–0.25	2
DCTP	0.02	1
DGTP	0.041	1

Catalyzed reactions (Rhea), 8 shown:

• a ribonucleoside 5’-diphosphate + ATP = a ribonucleoside 5’-triphosphate + ADP (RHEA:18113)
• UDP + ATP = UTP + ADP (RHEA:25098)
• CDP + ATP = CTP + ADP (RHEA:25237)
• dTDP + ATP = dTTP + ADP (RHEA:27682)
• GDP + ATP = GTP + ADP (RHEA:27686)
• IDP + ATP = ITP + ADP (RHEA:30347)
• a 2’-deoxyribonucleoside 5’-diphosphate + ATP = a 2’-deoxyribonucleoside 5’-triphosphate + ADP (RHEA:44640)
• ADP + ATP = ADP + ATP (RHEA:84315)

UniProt features (33 total): helix 13, binding site 10, strand 4, mutagenesis site 2, chain 1, region of interest 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
3BBB	X-RAY DIFFRACTION	1.3
8PYW	X-RAY DIFFRACTION	1.55
3BBC	X-RAY DIFFRACTION	1.7
3BBF	X-RAY DIFFRACTION	1.7
8PIE	X-RAY DIFFRACTION	1.9
1NUE	X-RAY DIFFRACTION	2
7KPF	X-RAY DIFFRACTION	2.23
1NSK	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22392-F1	97.65	0.99

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 118 (pros-phosphohistidine intermediate)

Ligand- & substrate-binding residues (10): 115; 118; 152; 12; 12; 52; 88; 94; 94; 115

Mutagenesis-validated functional residues (2):

Position	Phenotype
88	decreased single-stranded dna-binding and nucleotide-binding activity. no effect on 3d-structure.
118	loss of histidine kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-499943	Interconversion of nucleotide di- and triphosphates
R-HSA-6798695	Neutrophil degranulation
R-HSA-9748787	Azathioprine ADME
R-HSA-9755088	Ribavirin ADME
R-HSA-1430728	Metabolism
R-HSA-15869	Metabolism of nucleotides
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-9748784	Drug ADME

MSigDB gene sets: 256 (showing top): GOBP_POSITIVE_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_POSITIVE_REGULATION_OF_KERATINOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, GOCC_SECRETORY_GRANULE, GOMF_NUCLEASE_ACTIVITY, MODULE_151, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_POSITIVE_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, MORF_UBE2I, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_PYRIMIDINE_NUCLEOSIDE_TRIPHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (17): GTP biosynthetic process (GO:0006183), UTP biosynthetic process (GO:0006228), CTP biosynthetic process (GO:0006241), cell adhesion (GO:0007155), integrin-mediated signaling pathway (GO:0007229), nucleoside triphosphate biosynthetic process (GO:0009142), regulation of fatty acid biosynthetic process (GO:0042304), regulation of apoptotic process (GO:0042981), negative regulation of apoptotic process (GO:0043066), positive regulation of keratinocyte differentiation (GO:0045618), regulation of epidermis development (GO:0045682), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), ITP biosynthetic process (GO:0046042), positive regulation of epithelial cell proliferation (GO:0050679), positive regulation of DNA-templated transcription initiation (GO:2000144), nucleotide metabolic process (GO:0009117)

GO Molecular Function (14): DNA-binding transcription activator activity (GO:0001216), DNA binding (GO:0003677), nucleoside diphosphate kinase activity (GO:0004550), protein histidine kinase activity (GO:0004673), ATP binding (GO:0005524), kinase activity (GO:0016301), GDP binding (GO:0019003), identical protein binding (GO:0042802), metal ion binding (GO:0046872), G-quadruplex DNA binding (GO:0051880), coenzyme A binding (GO:0120225), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (12): ruffle (GO:0001726), extracellular region (GO:0005576), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), lamellipodium (GO:0030027), secretory granule lumen (GO:0034774), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cell periphery (GO:0071944), ficolin-1-rich granule lumen (GO:1904813), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Drug ADME	2
Metabolism of nucleotides	1
Innate Immune System	1
Metabolism	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
positive regulation of DNA-templated transcription	3
purine ribonucleotide biosynthetic process	2
purine ribonucleoside triphosphate biosynthetic process	2
pyrimidine ribonucleoside triphosphate biosynthetic process	2
pyrimidine ribonucleotide biosynthetic process	2
apoptotic process	2
anion binding	2
nucleoside phosphate binding	2
heterocyclic compound binding	2
cell leading edge	2
plasma membrane bounded cell projection	2
cytoplasm	2
GTP metabolic process	1
UTP metabolic process	1
CTP metabolic process	1
cellular process	1
cell surface receptor signaling pathway	1
nucleoside triphosphate metabolic process	1
nucleoside phosphate biosynthetic process	1
fatty acid biosynthetic process	1
regulation of fatty acid metabolic process	1
regulation of lipid biosynthetic process	1
regulation of programmed cell death	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
keratinocyte differentiation	1
positive regulation of epidermal cell differentiation	1
regulation of keratinocyte differentiation	1
positive regulation of multicellular organismal process	1
epidermis development	1
regulation of developmental process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
ITP metabolic process	1
positive regulation of cell population proliferation	1
epithelial cell proliferation	1

Protein interactions and networks

STRING

6420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NME2	KCNN4	O15554	931
NME2	ITGB1BP1	O14713	833
NME2	PHPT1	Q9NRX4	781
NME2	CSN3	P07498	721
NME2	PGAM5	Q96HS1	702
NME2	MYC	P01106	671
NME2	LHPP	Q9H008	633
NME2	CNBP	P20694	631
NME2	PUM3	Q15397	621
NME2	EEF1A2	P54266	583
NME2	RP2	O75695	571
NME2	HNRNPK	P61978	551
NME2	PIK3C2B	O00750	546
NME2	HNRNPA1	P09651	530
NME2	LDHA	P00338	530

IntAct

189 interactions, top by confidence:

A	B	Type	Score
NME1	NME4	psi-mi:“MI:0914”(association)	0.900
NME2	NME1	psi-mi:“MI:0915”(physical association)	0.750
NME1	NME2	psi-mi:“MI:0915”(physical association)	0.750
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
PRELID3B	TRIAP1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ITGB1BP1	NME2	psi-mi:“MI:0915”(physical association)	0.670
ITGB1BP1	NME2	psi-mi:“MI:0407”(direct interaction)	0.670
NME2	ITGB1BP1	psi-mi:“MI:0407”(direct interaction)	0.670
NME2	ITGB1BP1	psi-mi:“MI:0915”(physical association)	0.670
ITGB1BP1	NME2	psi-mi:“MI:0403”(colocalization)	0.670
NME2	NME4	psi-mi:“MI:0915”(physical association)	0.660
NME2	NME4	psi-mi:“MI:0914”(association)	0.660
NME3	NME4	psi-mi:“MI:0914”(association)	0.640
SLC17A5	LGALS8	psi-mi:“MI:0914”(association)	0.640
HSF1	KPNA3	psi-mi:“MI:0914”(association)	0.640
VDAC1	HK1	psi-mi:“MI:0914”(association)	0.560
WWOX	DVL2	psi-mi:“MI:0914”(association)	0.560
MAPT	DENR	psi-mi:“MI:0914”(association)	0.560
NME2	NME2	psi-mi:“MI:0915”(physical association)	0.550
RPS6	IPO7	psi-mi:“MI:0914”(association)	0.530
NME1	NME2P1	psi-mi:“MI:0914”(association)	0.530
TRABD	FCN1	psi-mi:“MI:0914”(association)	0.530
NPC2	NME2P1	psi-mi:“MI:0914”(association)	0.530

BioGRID (379): NME2 (Affinity Capture-MS), AHCY (Co-fractionation), AHCY (Co-fractionation), AKR1A1 (Co-fractionation), AKR1A1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B1 (Co-fractionation), AKR1B15 (Co-fractionation), ENO1 (Co-fractionation), ENO1 (Co-fractionation), ENO2 (Co-fractionation), ENO2 (Co-fractionation), ENO3 (Co-fractionation), ENO3 (Co-fractionation), FKBP1A (Co-fractionation)

ESM2 similar proteins: A2BZG4, A4J0S4, A6N0M9, B0C4I0, B0JHT4, B0TBN6, B1WQB7, B2IX22, B4FK49, B8HUM7, O57535, O81372, P08879, P15531, P15532, P19804, P22392, P27950, P39207, P47922, P48817, P49740, P52174, P52175, P70010, P70011, P74494, Q01768, Q02254, Q05982, Q07661, Q0W8X1, Q2EN76, Q2JPL4, Q39839, Q3AFJ7, Q3M7K5, Q3T0Q4, Q50KA8, Q50KA9

Diamond homologs: A0A3Q0KJ78, A2BNH4, A2BU01, A2CDK0, A2VD68, A4J0S4, A5D5U8, A6N0M9, A8G244, B0C4I0, B0JHT4, B0TBN6, B1I1P4, B1WQB7, B2IX22, B4FK49, B8DBZ7, B8FZD1, B8HUM7, B9E6K9, C0ZCD6, C1KWM9, O00746, O29491, O49203, O57535, O60361, O64903, O81372, P08879, P15531, P15532, P19804, P22392, P22887, P27950, P31103, P36010, P39207, P47919

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
NME2	up-regulates	KCNN4	phosphorylation
NME2	“up-regulates activity”	NME2	phosphorylation
HERC5	“up-regulates quantity by stabilization”	NME2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 206 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Negative regulation of NOTCH4 signaling	8	12.5×	2e-04
Vpu mediated degradation of CD4	7	12.2×	2e-04
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	7	11.4×	2e-04
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	7	11.4×	2e-04
Regulation of activated PAK-2p34 by proteasome mediated degradation	6	11.0×	5e-04
SCF-beta-TrCP mediated degradation of Emi1	7	11.0×	2e-04
Degradation of DVL	7	11.0×	2e-04
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	7	11.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

0 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

514 predictions. Top by Δscore:

Variant	Effect	Δscore
17:51166821:CCGCA:C	acceptor_loss	1.0000
17:51166822:CGCA:C	acceptor_loss	1.0000
17:51166823:GCA:G	acceptor_loss	1.0000
17:51166824:CAGG:C	acceptor_loss	1.0000
17:51166824:CAGGA:C	acceptor_loss	1.0000
17:51166825:A:AG	acceptor_gain	1.0000
17:51166825:A:T	acceptor_loss	1.0000
17:51166825:AG:A	acceptor_gain	1.0000
17:51166826:G:A	acceptor_loss	1.0000
17:51166826:G:GA	acceptor_gain	1.0000
17:51166826:G:GG	acceptor_gain	1.0000
17:51166826:G:T	acceptor_loss	1.0000
17:51166826:GG:G	acceptor_gain	1.0000
17:51166826:GGACC:G	acceptor_gain	1.0000
17:51166944:G:GT	donor_gain	1.0000
17:51166953:CCGGG:C	donor_loss	1.0000
17:51166955:GG:G	donor_gain	1.0000
17:51166955:GGGT:G	donor_loss	1.0000
17:51166956:GG:G	donor_gain	1.0000
17:51166956:GGT:G	donor_loss	1.0000
17:51166957:G:GG	donor_gain	1.0000
17:51166957:GT:G	donor_loss	1.0000
17:51166958:T:A	donor_loss	1.0000
17:51168234:A:AG	acceptor_gain	1.0000
17:51168234:AAT:A	acceptor_gain	1.0000
17:51168236:T:G	acceptor_gain	1.0000
17:51168236:T:TA	acceptor_gain	1.0000
17:51168237:GCCA:G	acceptor_loss	1.0000
17:51168238:CCA:C	acceptor_loss	1.0000
17:51168239:CAG:C	acceptor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000099463 (17:51164192 A>G), RS1000321303 (17:51168650 A>G), RS1000422584 (17:51168503 C>G), RS1001811206 (17:51167741 A>G), RS1002267495 (17:51169173 T>G), RS1002788107 (17:51166484 C>T), RS1003510986 (17:51171651 C>A,G,T), RS1003695752 (17:51171301 T>C), RS1003763112 (17:51171590 T>C,G), RS1004302275 (17:51169084 C>A,G,T), RS1004458021 (17:51168918 A>G,T), RS1005309543 (17:51167702 T>C), RS1005361653 (17:51168159 C>G,T), RS1006160174 (17:51166064 A>G), RS1006233691 (17:51166390 G>A,C)

Disease associations

OMIM: gene MIM:156491 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000817_139	Height	3.000000e-08
GCST006585_2823	Blood protein levels	7.000000e-30
GCST008103_55	Bipolar disorder	4.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2160 (SINGLE PROTEIN), CHEMBL4296074 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,156 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL598797	CUDC-101	1	2,156

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

17 potent at pChembl≥5 of 79 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.85	Kd	142	nM	CUDC-101
5.75	Kd	1800	nM	CHEMBL4105151
5.70	Kd	2000	nM	CHEMBL4104243
5.51	Kd	3100	nM	CHEMBL4104243
5.47	Kd	3400	nM	CHEMBL4063228
5.34	Kd	4600	nM	CHEMBL4104243
5.34	Kd	4600	nM	CHEMBL4063228
5.19	Kd	6400	nM	CHEMBL4102519
5.12	Kd	7600	nM	CHEMBL4090566
5.12	Kd	7600	nM	CHEMBL4095292
5.11	Kd	7700	nM	CHEMBL4104243
5.09	Kd	8100	nM	CHEMBL4102519
5.07	Kd	8500	nM	CHEMBL4101313
5.05	Kd	8900	nM	CHEMBL4103750
5.04	Kd	9200	nM	CHEMBL4077960
5.02	Kd	9600	nM	CHEMBL4085831
5.00	Kd	1.01e+04	nM	CHEMBL4074606

PubChem BioAssay actives

32 with measured affinity, of 344 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
7-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]oxy-N-hydroxyheptanamide	1425091: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.1420	uM
N-[4-[(E)-[7-fluoro-6-(4-methylpiperazin-1-yl)-9-oxo-1,2-dihydropyrrolo[2,1-b]quinazolin-3-ylidene]methyl]phenyl]-3-[4-(2-hydroxyethyl)piperazin-1-yl]propanamide	1432002: Binding affinity to NT647-labeled His-tagged NM23-H2 (unknown origin) expressed in Escherichia coli BL21(DE3) after 30 mins by microscale thermophoresis method	kd	1.8000	uM
(3E)-6-[3-(dimethylamino)propylamino]-7-fluoro-3-[(2-hydroxy-4-phenylmethoxyphenyl)methylidene]-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450617: Binding affinity to N-terminal NT-647-NHS labeled NM23-H2 (unknown origin) after 30 mins by MST analysis	kd	2.0000	uM
(3E)-6-[3-(diethylamino)propylamino]-7-fluoro-3-[(2-hydroxy-4-phenylmethoxyphenyl)methylidene]-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450617: Binding affinity to N-terminal NT-647-NHS labeled NM23-H2 (unknown origin) after 30 mins by MST analysis	kd	3.4000	uM
(3E)-6-[2-(dimethylamino)ethylamino]-7-fluoro-3-[(2-hydroxy-4-phenylmethoxyphenyl)methylidene]-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450617: Binding affinity to N-terminal NT-647-NHS labeled NM23-H2 (unknown origin) after 30 mins by MST analysis	kd	6.4000	uM
(3E)-7-fluoro-3-[(2-hydroxy-4-phenylmethoxyphenyl)methylidene]-6-(2-piperidin-1-ylethylamino)-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450617: Binding affinity to N-terminal NT-647-NHS labeled NM23-H2 (unknown origin) after 30 mins by MST analysis	kd	7.6000	uM
N-[3-(diethylamino)propyl]-4-[(E)-[7-fluoro-9-oxo-6-(2-pyrrolidin-1-ylethylamino)-1,2-dihydropyrrolo[2,1-b]quinazolin-3-ylidene]methyl]benzamide	1450616: Binding affinity to NM23-H2 (unknown origin) by SPR analysis	kd	7.6000	uM
(3E)-6-[3-(dimethylamino)propylamino]-7-fluoro-3-[[4-[(E)-2-pyridin-2-ylethenyl]phenyl]methylidene]-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450616: Binding affinity to NM23-H2 (unknown origin) by SPR analysis	kd	8.5000	uM
(3E)-6-[3-(dimethylamino)propylamino]-7-fluoro-3-[(4-prop-2-ynoxyphenyl)methylidene]-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450617: Binding affinity to N-terminal NT-647-NHS labeled NM23-H2 (unknown origin) after 30 mins by MST analysis	kd	8.9000	uM
(3E)-3-[(3,4-dihydroxyphenyl)methylidene]-6-[3-(dimethylamino)propylamino]-7-fluoro-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450616: Binding affinity to NM23-H2 (unknown origin) by SPR analysis	kd	9.2000	uM
(3E)-6-[3-(dimethylamino)propylamino]-7-fluoro-3-[(4-propan-2-yloxyphenyl)methylidene]-1,2-dihydropyrrolo[2,1-b]quinazolin-9-one	1450616: Binding affinity to NM23-H2 (unknown origin) by SPR analysis	kd	9.6000	uM

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Calcitriol	decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	decreases expression, increases reaction	2
2,4,6-tribromophenol	increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
tributyltin	decreases expression, increases reaction	1
triphenyltin chloride	decreases expression, increases reaction	1
arsenite	affects binding, increases reaction	1
tetrabromobisphenol A	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
ochratoxin A	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
triphenyltin	decreases expression	1
quinoline	increases expression	1
tributyltinisothiocyanate	decreases expression	1
JP8 aviation fuel	increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	increases expression	1
pyrimidifen	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
hexabrominated diphenyl ether 153	increases expression	1
N’-(10H-indolo(3,2-b)quinolin-11-yl)-N,N-dimethylpropane-1,3-diamine	decreases reaction, affects binding	1
(+)-JQ1 compound	decreases expression	1
Decitabine	affects methylation	1
Alitretinoin	decreases expression	1

ChEMBL screening assays

34 unique, capped per target: 34 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991804	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.