NME4 Gene

Name	NME/NM23 nucleoside diphosphate kinase 4
Description	The nucleoside diphosphate (NDP) kinases (EC 2.7.4.6) are ubiquitous enzymes that catalyze transfer of gamma-phosphates, via a phosphohistidine intermediate, between nucleoside and dioxynucleoside tri- and diphosphates. The enzymes are products of the nm23 gene family, which includes NME4 (Milon et al., 1997 [PubMed 9099850]).[supplied by OMIM, May 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNME4, also known as NM23‐H4 or NDPK‐D, is a mitochondrial enzyme with dual functions that are essential for mitochondrial homeostasis. On one hand, through its nucleoside diphosphate kinase (NDPK) activity it regenerates nucleoside triphosphates using ATP, thereby locally supplying GTP to mitochondrial GTPases such as OPA1, which in turn modulate inner membrane fusion and fission dynamics. On the other hand, NME4 binds the anionic phospholipid cardiolipin (CL) and facilitates its transfer from the inner mitochondrial membrane to the outer membrane. This CL redistribution is critical because externalized CL serves as an “eat‐me” signal to initiate mitophagy and, under certain conditions, can also promote apoptotic signaling. Moreover, the enzyme appears to act as a lipid‐dependent regulatory switch, with its phosphotransfer and lipid transfer functions being mutually exclusive and dictated by its degree of membrane interaction."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant expression of NME4 is increasingly being linked to cancer progression and unfavorable clinical outcomes. High NME4 expression has been correlated with poor prognosis in hematological malignancies such as myelodysplastic syndrome (MDS) and its progression to acute myeloid leukemia, while in non‐small cell lung cancer it appears to promote cell cycle progression, proliferation, and colony formation. In squamous cell carcinomas of the esophagus and cervix, NME4 not only influences tumor cell aggressiveness but also modulates the immune microenvironment. For example, studies have shown that downregulation of NME4 may lead to decreased levels of PD‐L1 via reduced STAT3 phosphorylation, and that NME4 can control the NFκB2–CCL5 signaling axis to prevent CD8⁺ T cell tumor infiltration. In addition, targeted metabolomic screening following NME4 knockdown revealed alterations in pathways linked to tumor metabolism and immunomodulation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a broader physiological context, NME4 also plays a crucial role in placental function. By ensuring the local supply of nucleotide triphosphates required for mitochondrial DNA replication and transcription, NME4 is implicated in the maintenance of mitochondrial integrity in trophoblast cells. This function is particularly significant under pathological conditions such as preeclampsia, where impaired trophoblast invasion and placental ischemia lead to oxidative stress and mitochondrial dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Uwe Schlattner, Malgorzata Tokarska-Schlattner, Sacnicte Ramirez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dual function of mitochondrial Nm23-H4 protein in phosphotransfer and intermembrane lipid transfer: a cardiolipin-dependent switch."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.408633"}], "href": "https://doi.org/10.1074/jbc.M112.408633"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23150663"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23150663"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Mathieu Boissan, Guillaume Montagnac, Qinfang Shen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1253768"}], "href": "https://doi.org/10.1126/science.1253768"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24970086"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24970086"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "L Francois-Moutal, O Marcillat, T Granjon "}, {"type": "b", "children": [{"type": "t", "text": "Structural comparison of highly similar nucleoside-diphosphate kinases: Molecular explanation of distinct membrane-binding behavior."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochimie (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.biochi.2014.06.025"}], "href": "https://doi.org/10.1016/j.biochi.2014.06.025"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25010650"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25010650"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Uwe Schlattner, Malgorzata Tokarska-Schlattner, Richard M Epand, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial NM23-H4/NDPK-D: a bifunctional nanoswitch for bioenergetics and lipid signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Naunyn Schmiedebergs Arch Pharmacol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00210-014-1047-4"}], "href": "https://doi.org/10.1007/s00210-014-1047-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25231795"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25231795"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "V E Kagan, J Jiang, Z Huang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Differ (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/cdd.2015.160"}], "href": "https://doi.org/10.1038/cdd.2015.160"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26742431"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26742431"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Uwe Schlattner, Malgorzata Tokarska-Schlattner, Richard M Epand, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lab Invest (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/labinvest.2017.113"}], "href": "https://doi.org/10.1038/labinvest.2017.113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29035377"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29035377"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Alzbeta Kracmarova, Jaroslav Cermak, Radim Brdicka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "High expression of ERCC1, FLT1, NME4 and PCNA associated with poor prognosis and advanced stages in myelodysplastic syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Leuk Lymphoma (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/10428190802129918"}], "href": "https://doi.org/10.1080/10428190802129918"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18604718"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18604718"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Wenqian Wang, Ming Dong, Jie Cui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NME4 may enhance non‑small cell lung cancer progression by overcoming cell cycle arrest and promoting cellular proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Med Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3892/mmr.2019.10413"}], "href": "https://doi.org/10.3892/mmr.2019.10413"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31257488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31257488"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Shutao Zheng, Qing Liu, Tao Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NME4 modulates PD-L1 expression via the STAT3 signaling pathway in squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2020.03.055"}], "href": "https://doi.org/10.1016/j.bbrc.2020.03.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32192776"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32192776"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Shutao Zheng, Tao Liu, Qing Liu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Widely targeted metabolomic analyses unveil the metabolic variations after stable knock-down of NME4 in esophageal squamous cell carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biochem (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11010-020-03768-w"}], "href": "https://doi.org/10.1007/s11010-020-03768-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32504364"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32504364"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Shutao Zheng, Shuo He, Yan Liang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "NME4 suppresses NFκB2-CCL5 axis, restricting CD8+ T cell tumour infiltration in oesophageal squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Immunology (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/imm.13838"}], "href": "https://doi.org/10.1111/imm.13838"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "39016535"}], "href": "https://pubmed.ncbi.nlm.nih.gov/39016535"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Ji Hea Yu, Yun Ji Jung, Myung-Sun Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Differential Expression of "}, {"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "NME4"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " in Trophoblast Stem-Like Cells and Peripheral Blood Mononuclear Cells of Normal Pregnancy and Preeclampsia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Korean Med Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3346/jkms.2023.38.e128"}], "href": "https://doi.org/10.3346/jkms.2023.38.e128"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37096311"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37096311"}]}]}]}
Synonyms	NDPK-D, NM23H4, NM23-H4
Proteins	NDKM_HUMAN
NCBI Gene ID	4833
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

NME4 has 10,219 functional associations with biological entities spanning 9 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA, sequence feature) extracted from 124 datasets.

Click the + buttons to view associations for NME4 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

NME4 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by NME4 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of NME4 gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of NME4 gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of NME4 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of NME4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of NME4 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of NME4 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of NME4 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NME4 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of NME4 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of NME4 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of NME4 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of NME4 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with NME4 protein from the CCLE Cell Line Proteomics dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with NME4 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of NME4 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of NME4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of NME4 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CM4AI U2OS Cell Map Protein Localization Assemblies	assemblies containing NME4 protein from integrated AP-MS and IF data from the CM4AI U2OS Cell Map Protein Localization Assemblies dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of NME4 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing NME4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing NME4 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with NME4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with NME4 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of NME4 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with NME4 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with NME4 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with NME4 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DeepCoverMOA Drug Mechanisms of Action	small molecule perturbations with high or low expression of NME4 protein relative to other small molecule perturbations from the DeepCoverMOA Drug Mechanisms of Action dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by NME4 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with NME4 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with NME4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with NME4 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with NME4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with NME4 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at NME4 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of NME4 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of NME4 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing NME4 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD High Level Gene-Disease Associations	diseases associated with NME4 gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.