Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004550 nucleoside diphosphate kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0042981 regulation of apoptotic process	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0001726 ruffle	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
GO:0003677 DNA binding	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Use the specific G-quadruplex DNA binding annotation where possible rather than generic DNA binding.
GO:0004550 nucleoside diphosphate kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0004673 protein histidine kinase activity	IEA GO_REF:0000003	ACCEPT	Summary: Correct. NME2 has histidine kinase/phosphohistidine-generating capacity in mammalian phosphohistidine signaling contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md In mammalian cells, the NME family (including NME2) is considered among the limited set of enzymes with histidine kinase / phosphohistidine-generating capacity, despite technical challenges associated with phosphohistidine lability.
GO:0005634 nucleus	IEA GO_REF:0000044	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0005737 cytoplasm	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Prefer specific cytosol and nucleus annotations over generic cytoplasm.
GO:0006183 GTP biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0006228 UTP biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0006241 CTP biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0009117 nucleotide metabolic process	IEA GO_REF:0000043	ACCEPT	Summary: Accepted broadly as nucleotide metabolic process, but NME2 is more specifically an NDP kinase maintaining NTP/dNTP pools. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0009142 nucleoside triphosphate biosynthetic process	IEA GO_REF:0000117	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0016301 kinase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Use nucleoside diphosphate kinase activity rather than generic kinase/transferase activity.
GO:0016740 transferase activity	IEA GO_REF:0000043	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Use nucleoside diphosphate kinase activity rather than generic kinase/transferase activity.
GO:0030027 lamellipodium	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
GO:0046872 metal ion binding	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This cofactor/nucleotide-binding annotation should not drive the core function summary.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
GO:0005515 protein binding	IPI PMID:11919189 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005515 protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005515 protein binding	IPI PMID:17314099 NM23-H1 tumor suppressor physically interacts with serine-th...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005515 protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005515 protein binding	IPI PMID:24970086 Membrane trafficking. Nucleoside diphosphate kinases fuel dy...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005515 protein binding	IPI PMID:27499296 Mitochondrial Protein Interaction Mapping Identifies Regulat...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005515 protein binding	IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0042802 identical protein binding	IPI PMID:21988832 Toward an understanding of the protein interaction network o...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0042802 identical protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0042304 regulation of fatty acid biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0120225 coenzyme A binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Supported as a non-core recent NME1/2 metabolic regulatory finding involving CoA/acyl-CoA binding. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME1/2 are described as housekeeping NDP kinases that bind CoA and CoA-derivatives (AcCoA, SucCoA, long-chain fatty acyl–CoA).
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0001216 DNA-binding transcription activator activity	IDA PMID:8392752 Human c-myc transcription factor PuF identified as nm23-H2 n...	KEEP AS NON CORE	Summary: Supported as a non-core DNA/G-quadruplex transcriptional regulator role; the primary molecular function remains NDP kinase activity. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:0051880 G-quadruplex DNA binding	IDA PMID:19033359 Metastases suppressor NM23-H2 interaction with G-quadruplex ...	ACCEPT	Summary: Correct and informative. NME2/NM23-H2 binds promoter G-quadruplex DNA structures, classically in c-MYC-related transcriptional regulation. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:0051880 G-quadruplex DNA binding	IDA PMID:19435876 NM23-H2 may play an indirect role in transcriptional activat...	ACCEPT	Summary: Correct and informative. NME2/NM23-H2 binds promoter G-quadruplex DNA structures, classically in c-MYC-related transcriptional regulation. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:2000144 positive regulation of DNA-templated transcription initiation	IDA PMID:19033359 Metastases suppressor NM23-H2 interaction with G-quadruplex ...	KEEP AS NON CORE	Summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:2000144 positive regulation of DNA-templated transcription initiation	IDA PMID:19435876 NM23-H2 may play an indirect role in transcriptional activat...	KEEP AS NON CORE	Summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:0004518 nuclease activity	IDA NOT PMID:19435876 NM23-H2 may play an indirect role in transcriptional activat...	KEEP AS NON CORE	Summary: Correct negated annotation. NME2 was tested for nuclease activity in this c-MYC/NHE context and found not to cleave the substrate. Reason: The NOT annotation is biologically correct and should be retained as documented non-core negative evidence; NME2 is a phosphotransferase and DNA/G4-binding regulator, not a nuclease.
GO:0006183 GTP biosynthetic process	ISS GO_REF:0000024	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0003677 DNA binding	IDA PMID:11121025 Catalysis of DNA cleavage and nucleoside triphosphate synthe...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Use the specific G-quadruplex DNA binding annotation where possible rather than generic DNA binding.
GO:0004550 nucleoside diphosphate kinase activity	IDA PMID:16313181 Characterization of the 3' --> 5' exonuclease activity found...	ACCEPT	Summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0004673 protein histidine kinase activity	IDA PMID:17157250 Histidine phosphorylation of the potassium channel KCa3.1 by...	ACCEPT	Summary: Correct. NME2 has histidine kinase/phosphohistidine-generating capacity in mammalian phosphohistidine signaling contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md In mammalian cells, the NME family (including NME2) is considered among the limited set of enzymes with histidine kinase / phosphohistidine-generating capacity, despite technical challenges associated with phosphohistidine lability.
GO:0046042 ITP biosynthetic process	IDA PMID:1851158 Nucleoside diphosphate kinase from human erythrocytes. Struc...	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0016301 kinase activity	IDA PMID:8529641 A novel serine/threonine-specific protein phosphotransferase...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Use nucleoside diphosphate kinase activity rather than generic kinase/transferase activity.
GO:0005829 cytosol	TAS Reactome:R-HSA-482619	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0005829 cytosol	TAS Reactome:R-HSA-482621	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0005829 cytosol	TAS Reactome:R-HSA-9748969	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0005829 cytosol	TAS Reactome:R-HSA-9748999	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0005829 cytosol	TAS Reactome:R-HSA-9755013	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0004550 nucleoside diphosphate kinase activity	IDA PMID:9488696 Substrate specificity of human nucleoside-diphosphate kinase...	ACCEPT	Summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0005515 protein binding	IPI PMID:17532299 NM23-H2 involves in negative regulation of Diva and Bcl2L10 ...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
GO:0005737 cytoplasm	IDA PMID:17532299 NM23-H2 involves in negative regulation of Diva and Bcl2L10 ...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Prefer specific cytosol and nucleus annotations over generic cytoplasm.
GO:0045893 positive regulation of DNA-templated transcription	IDA PMID:8392752 Human c-myc transcription factor PuF identified as nm23-H2 n...	KEEP AS NON CORE	Summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:0003677 DNA binding	IDA PMID:19435876 NM23-H2 may play an indirect role in transcriptional activat...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Use the specific G-quadruplex DNA binding annotation where possible rather than generic DNA binding.
GO:0019003 GDP binding	IMP PMID:19435876 NM23-H2 may play an indirect role in transcriptional activat...	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This cofactor/nucleotide-binding annotation should not drive the core function summary.
GO:0045893 positive regulation of DNA-templated transcription	IMP PMID:19435876 NM23-H2 may play an indirect role in transcriptional activat...	KEEP AS NON CORE	Summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:0051880 G-quadruplex DNA binding	IDA PMID:25679041 The maize (Zea mays L.) nucleoside diphosphate kinase1 (ZmND...	ACCEPT	Summary: Correct and informative. NME2/NM23-H2 binds promoter G-quadruplex DNA structures, classically in c-MYC-related transcriptional regulation. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:0004550 nucleoside diphosphate kinase activity	IDA PMID:25679041 The maize (Zea mays L.) nucleoside diphosphate kinase1 (ZmND...	ACCEPT	Summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0009142 nucleoside triphosphate biosynthetic process	IDA PMID:25679041 The maize (Zea mays L.) nucleoside diphosphate kinase1 (ZmND...	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6798748	KEEP AS NON CORE	Summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
GO:0005576 extracellular region	TAS Reactome:R-HSA-6800434	KEEP AS NON CORE	Summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
GO:0034774 secretory granule lumen	TAS Reactome:R-HSA-6798748	KEEP AS NON CORE	Summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
GO:1904813 ficolin-1-rich granule lumen	TAS Reactome:R-HSA-6800434	KEEP AS NON CORE	Summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	KEEP AS NON CORE	Summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	ACCEPT	Summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	KEEP AS NON CORE	Summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
GO:0070062 extracellular exosome	HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote...	KEEP AS NON CORE	Summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
GO:0005737 cytoplasm	IDA PMID:15703214 Nuclear translocation of integrin cytoplasmic domain-associa...	MARK AS OVER ANNOTATED	Summary: Correct or plausible but too broad for useful NME2 annotation. Reason: Prefer specific cytosol and nucleus annotations over generic cytoplasm.
GO:0005925 focal adhesion	IDA NOT PMID:11919189 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-...	KEEP AS NON CORE	Summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
GO:0007229 integrin-mediated signaling pathway	IDA PMID:11919189 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-...	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0045944 positive regulation of transcription by RNA polymerase II	IDA PMID:15703214 Nuclear translocation of integrin cytoplasmic domain-associa...	KEEP AS NON CORE	Summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output.
GO:0071944 cell periphery	IDA PMID:11919189 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-...	KEEP AS NON CORE	Summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
GO:0004550 nucleoside diphosphate kinase activity	IDA PMID:1851158 Nucleoside diphosphate kinase from human erythrocytes. Struc...	ACCEPT	Summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0009142 nucleoside triphosphate biosynthetic process	IDA PMID:1851158 Nucleoside diphosphate kinase from human erythrocytes. Struc...	ACCEPT	Summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
GO:0043066 negative regulation of apoptotic process	IMP PMID:16862176 Novel roles of NM23 proteins in skin homeostasis, repair and...	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0045618 positive regulation of keratinocyte differentiation	IMP PMID:16862176 Novel roles of NM23 proteins in skin homeostasis, repair and...	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0045682 regulation of epidermis development	IMP PMID:16862176 Novel roles of NM23 proteins in skin homeostasis, repair and...	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0050679 positive regulation of epithelial cell proliferation	IMP PMID:16862176 Novel roles of NM23 proteins in skin homeostasis, repair and...	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0001726 ruffle	IDA PMID:11919189 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-...	KEEP AS NON CORE	Summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
GO:0007155 cell adhesion	TAS PMID:11919189 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-...	KEEP AS NON CORE	Summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
GO:0030027 lamellipodium	IDA PMID:11919189 Integrin cytoplasmic domain-associated protein 1alpha (ICAP-...	KEEP AS NON CORE	Summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization. Supporting Evidence: file:human/NME2/NME2-deep-research-falcon.md cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane

Core Functions

NME2 is an NDP kinase whose core function is phosphohistidine-mediated nucleotide phosphotransfer, maintaining cellular NTP/dNTP pools and supplying local GTP in signaling and membrane-remodeling contexts. It also has a supported nuclear G-quadruplex DNA-binding role in transcriptional regulation.

Molecular Function:

nucleoside diphosphate kinase activity

Directly Involved In:

nucleoside triphosphate biosynthetic process nucleotide metabolic process

Cellular Locations:

cytosol nucleus

Supporting Evidence:

file:human/NME2/NME2-deep-research-falcon.md
Human **NME2** (also known as **NM23-H2** / **NDPK-B**) is a highly conserved **nucleoside diphosphate kinase (NDPK)** whose *core biochemical function* is **phosphotransfer between nucleoside diphosphates and triphosphates** via an obligate **phosphohistidine** intermediate at **His118**.
file:human/NME2/NME2-deep-research-falcon.md
**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.
file:human/NME2/NME2-deep-research-falcon.md
A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:11121025

Catalysis of DNA cleavage and nucleoside triphosphate synthesis by NM23-H2/NDP kinase share an active site that implies a DNA repair function.

PMID:11919189

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.

PMID:15703214

Nuclear translocation of integrin cytoplasmic domain-associated protein 1 stimulates cellular proliferation.

PMID:16169070

A human protein-protein interaction network: a resource for annotating the proteome.

PMID:16313181

Characterization of the 3' --> 5' exonuclease activity found in human nucleoside diphosphate kinase 1 (NDK1) and several of its homologues.

PMID:16862176

Novel roles of NM23 proteins in skin homeostasis, repair and disease.

PMID:17157250

Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells.

PMID:17314099

NM23-H1 tumor suppressor physically interacts with serine-threonine kinase receptor-associated protein, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and negatively regulates TGF-beta signaling.

PMID:17532299

NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling.

PMID:1851158

Nucleoside diphosphate kinase from human erythrocytes. Structural characterization of the two polypeptide chains responsible for heterogeneity of the hexameric enzyme.

PMID:19033359

Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression.

PMID:19199708

Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).

PMID:19435876

NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III(1).

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:21988832

Toward an understanding of the protein interaction network of the human liver.

PMID:23533145

In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.

PMID:24970086

Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling.

PMID:25679041

The maize (Zea mays L.) nucleoside diphosphate kinase1 (ZmNDPK1) gene encodes a human NM23-H2 homologue that binds and stabilizes G-quadruplex DNA.

PMID:27499296

Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.

PMID:31980649

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:8392752

Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis.

PMID:8529641

A novel serine/threonine-specific protein phosphotransferase activity of Nm23/nucleoside-diphosphate kinase.

PMID:9488696

Substrate specificity of human nucleoside-diphosphate kinase revealed by transient kinetic analysis.

Reactome:R-HSA-482619

(d)NDP + ATP <=> (d)NTP + ADP (NME1,2,3)

Reactome:R-HSA-482621

(d)NTP + ADP <=> (d)NDP + ATP (NME1,2,3)

Reactome:R-HSA-6798748

Exocytosis of secretory granule lumen proteins

Reactome:R-HSA-6800434

Exocytosis of ficolin-rich granule lumen proteins

Reactome:R-HSA-9748969

NME1:2 hexamer phosphorylates 6TdGDP to 6TdGTP

Reactome:R-HSA-9748999

NME1:2 hexamer phosphorylates 6TGDP to 6TGTP

Reactome:R-HSA-9755013

NME1,2 hexamers phosphorylate RBV-DP

file:human/NME2/NME2-deep-research-falcon.md

Falcon deep research report for human NME2

Suggested Experiments

Experiment: Rescue NME2-depleted cells with wild-type or H118N NME2 and compare NTP/dNTP pools, G-protein phosphohistidine readouts, dynamin-dependent endocytosis, and transcriptional phenotypes.

Hypothesis: NME2 catalytic His118 is required for both NTP-pool maintenance and selected histidine phosphotransfer signaling outputs.

Experiment: Test DNA/G4-binding mutants and catalytic mutants side-by-side for c-MYC/hTERT promoter occupancy, transcriptional output, and NDP kinase activity.

Hypothesis: NME2 promoter G-quadruplex binding is separable from NDP kinase activity.

Deep Research

Falcon

(NME2-deep-research-falcon.md)

Comprehensive Research Report: Human **NME2** (UniProt **P22392**) Functional Annotation Falcon Edison Scientific Literature 27 citations 2026-05-11T14:56:54.559338

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human NME2 (UniProt P22392) Functional Annotation

Executive summary

Human NME2 (also known as NM23-H2 / NDPK-B) is a highly conserved nucleoside diphosphate kinase (NDPK) whose core biochemical function is phosphotransfer between nucleoside diphosphates and triphosphates via an obligate phosphohistidine intermediate at His118. Beyond nucleotide homeostasis, NME2 participates in histidine phosphotransfer (protein histidine kinase–like activity), local GTP channeling for membrane-remodeling GTPases (notably dynamins) during endocytosis, and DNA structure–dependent transcriptional regulation via binding to G-quadruplexes in promoters (classically c-MYC, and also hTERT). Recent work (2023–2024) has expanded the functional landscape of the NME1/2 pair (closely related to NME2) by revealing CoA/acyl-CoA binding as an energy-state–linked regulatory feature connected to lipid metabolism and epigenetic responses under high-fat diet conditions, with in vivo knockout evidence implicating Nme2 in protection against diet-induced hepatic steatosis. (adam2020nmenm23ndpkandhistidine pages 8-10, prunier2023mechanismsofaction pages 1-2, sharma2021emergingmolecularconnections pages 1-2, iuso2023nucleosidediphosphatekinases pages 1-3, iuso2024nucleosidediphosphatekinases pages 1-2)

1) Target identity verification (mandatory)

Verified target: The literature corpus explicitly maps UniProt accession P22392 to human NME2, annotated as “Nucleoside diphosphate kinase B” and identifying His118 as the active-site histidine (phosphohistidine) residue. (adam2020nmenm23ndpkandhistidine pages 8-10)

Independent reviews further corroborate that NME2 encodes NM23-H2/NDPK-B (with NME1 encoding NM23-H1/NDPK-A) and that these isoforms represent dominant cellular NDPK activities in mammals. (peuchant2017metastasissuppressornm23 pages 1-2, prunier2023mechanismsofaction pages 1-2)

2) Key concepts and definitions (current understanding)

2.1 Nucleoside diphosphate kinase (NDPK) activity (primary function)

Definition: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs. (prunier2023mechanismsofaction pages 1-2, amjadi2024mechanisticinsightsinto pages 1-2)

Mechanistic concept—ping-pong phosphotransfer: The reaction proceeds through a high-energy phosphohistidine intermediate on the enzyme; this feature is central to both canonical NDPK activity and many reported non-canonical phosphotransfer phenomena. (peuchant2017metastasissuppressornm23 pages 1-2, lim2024modellingdynamicsof pages 1-4, amjadi2024mechanisticinsightsinto pages 1-2)

2.2 Catalytic residue and phosphohistidine intermediate

NME2’s catalytic histidine is H118 (explicitly listed for P22392), consistent with the conserved catalytic histidine that becomes phosphorylated during catalysis. (adam2020nmenm23ndpkandhistidine pages 8-10)

2.3 “Histidine kinase” / protein histidine phosphotransfer (in mammalian context)

In mammalian cells, the NME family (including NME2) is considered among the limited set of enzymes with histidine kinase / phosphohistidine-generating capacity, despite technical challenges associated with phosphohistidine lability. Reviews explicitly list NME1 and NME2 as histidine kinases regulating phosphohistidine biology. (adam2020nmenm23ndpkandhistidine pages 4-6, OpenTargets Search: -NME2)

2.4 NME2 as a DNA-binding transcriptional regulator (PuF)

A distinct concept in the NME2 literature is its role as the c-MYC purine-binding factor (PuF): NME2/NM23-H2 binds particular DNA elements and also binds non-B DNA structures such as promoter G-quadruplexes (G4), linking DNA secondary structure to transcriptional output. (sharma2021emergingmolecularconnections pages 1-2)

3) Molecular function and substrate specificity

3.1 Canonical enzymatic function

Reaction class: NME2 is an NDPK, transferring a γ-phosphate from NTPs (mainly ATP) to NDPs (commonly GDP) to form corresponding NTPs. (prunier2023mechanismsofaction pages 1-2)

Substrate preferences (as commonly summarized): Reviews emphasize ATP as the predominant phosphate donor and GDP as a frequent acceptor in conceptual models, reflecting physiological nucleotide pool maintenance. (prunier2023mechanismsofaction pages 1-2, amjadi2024mechanisticinsightsinto pages 1-2)

Structural requirement: Eukaryotic NDPKs (including NME1/2) are described as forming hexamers assembled from dimers and trimers, and this quaternary organization is tied to catalytic competence and interaction landscapes. (adam2020nmenm23ndpkandhistidine pages 4-6, amjadi2024mechanisticinsightsinto pages 1-2)

3.2 Protein histidine phosphotransfer targets and examples

Mechanistic review evidence supports NME2-dependent histidine phosphotransfer in signaling:
- G-protein signaling: NME2 forms complexes with Gβγ, generating a phosphohistidine intermediate on Gβ (H266); a catalytically inactive H118N-NME2 mutant abolishes the observed phosphotransfer and blocks associated receptor-independent basal G(s) activation in the described model. (adam2020nmenm23ndpkandhistidine pages 4-6)
- Reviews also connect NME family histidine phosphorylation to additional substrates including ion channels (e.g., KCa3.1) and metabolic enzymes (e.g., ACLY), supporting a broader histidine phosphotransfer capability in mammalian systems. (adam2020nmenm23ndpkandhistidine pages 4-6, adam2020nmenm23ndpkandhistidine pages 8-10)

4) Cellular localization and where NME2 carries out its function

4.1 Nucleo-cytosolic distribution

NME2/NM23-H2 is described as localized in both cytoplasm and nucleus, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus). (sharma2021emergingmolecularconnections pages 1-2, lim2024modellingdynamicsof pages 1-4)

4.2 Functional membrane proximity (plasma membrane endocytic sites)

While NME2 is not primarily a transmembrane protein, authoritative metastasis-focused reviews describe a model in which cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane to support endocytosis and attenuate receptor signaling. (prunier2023mechanismsofaction pages 1-2)

4.3 Secretion/extracellular observations (contextual)

NDPK-A/B family members have been reported as plasma-membrane associated and also detected in bloodstream in some contexts, supporting extracellular presence as an observed phenomenon for NDPK isoforms in mammalian biology; this may be relevant to biomarker studies but is less central to mechanistic function than nucleo-cytosolic roles. (peuchant2017metastasissuppressornm23 pages 1-2)

5) Pathways and interaction networks

5.1 Dynamin/endocytosis and metastasis-relevant signaling attenuation

A 2023 Cancer Metastasis Reviews synthesis proposes a mechanistic framework: NME1/2 maintain high local GTP availability for dynamin GTPases, enabling efficient membrane fission/fusion events in endocytosis, thereby attenuating signaling from surface receptors; disruption of NDPK activity is suggested to prolong signaling and contribute to metastatic progression in certain contexts. (prunier2023mechanismsofaction pages 1-2)

5.2 Heterotrimeric G-protein signaling via histidine phosphotransfer

NME2’s histidine phosphotransfer to Gβ (H266) provides a direct mechanistic link to heterotrimeric G-protein regulation (including basal activation scenarios discussed in the review). (adam2020nmenm23ndpkandhistidine pages 4-6)

5.3 DNA secondary structure–dependent transcriptional control (G-quadruplexes)

NME2/NM23-H2 is highlighted as a G-quadruplex-binding transcription factor:
- It binds G4 structures in the c-MYC promoter and is linked to c-MYC transcriptional regulation (PuF identity). (sharma2021emergingmolecularconnections pages 1-2)
- Additional promoter contexts include hTERT, where NME2 binding to G4 is described as facilitating recruitment of repressor machinery (REST–coREST–LSD1) in reviewed summaries of the field. (sharma2021emergingmolecularconnections pages 1-2)
A 2023 review on ROS–G4 crosstalk also reiterates NM23-H2’s high-affinity interaction with the c-MYC promoter G4 motif as an established example of G4-binding proteins affecting transcription. (sharma2021emergingmolecularconnections pages 1-2)

6) Recent developments and latest research (prioritizing 2023–2024)

6.1 NME1/2 as CoA/acyl-CoA binding proteins and metabolic/epigenetic regulators

A major 2023–2024 development is the expansion of NME1/2 biology into CoA/acyl-CoA binding and metabolic state sensing:

Primary study (Science Advances, 2023-09; URL https://doi.org/10.1126/sciadv.adh0140): NME1/2 are described as housekeeping NDP kinases that bind CoA and CoA-derivatives (AcCoA, SucCoA, long-chain fatty acyl–CoA). The study reports that Nme2 knockout mice fed a high-fat diet exhibit excessive triglyceride synthesis and liver steatosis, and that NME1/2 mediate a protective transcriptional program via targeted histone acetylation under HFD. (iuso2023nucleosidediphosphatekinases pages 1-3)
Review (IJMS, 2024-07; URL https://doi.org/10.3390/ijms25147528): Synthesizes evidence that NME1/2 are ATP-regulated carriers of short-chain acyl-CoAs, describing ligand competition in the nucleotide-binding pocket and the role of catalytic His118: when CoA is bound, His118 interacts with the 3′-phosphate of CoA; phosphorylated His118 prevents CoA binding, providing an energy-state–linked regulatory model. (iuso2024nucleosidediphosphatekinases pages 1-2)

These works collectively reframe NME1/2 (and by close homology, inform hypotheses for NME2) as nodes connecting nucleotide status (ATP/ADP), CoA pools, lipid metabolism, and transcriptional/epigenetic regulation. (iuso2024nucleosidediphosphatekinases pages 1-2, iuso2023nucleosidediphosphatekinases pages 1-3)

6.2 Metastasis-centered mechanistic synthesis and context dependence

A 2023 review explicitly positions NME2 (alongside NME1 and NME4) within metastasis biology, while emphasizing that NME2’s metastasis role is less documented and context-dependent; nevertheless, it supports a concrete mechanism (local GTP supply to dynamins/endocytosis) that is biochemically compatible with NME2’s NDPK activity. (prunier2023mechanismsofaction pages 1-2)

A 2024 review expands this metastasis framework through the lens of PRUNE1 interactions, arguing that disrupting PRUNE1–NME1/2 complexes could be therapeutically actionable, while also noting context-dependent pro/anti-oncogenic effects of class I NMEs. (ferrucci2024prune1andnmendpk pages 1-2)

6.3 2024 histidine phosphorylation overview (state of the field)

A 2024 IJMS review summarizes the small set of known mammalian phosphohistidine kinases and phosphatases, explicitly naming NME1 and NME2 as histidine kinases, reflecting expert consensus that NME2 is central to current mammalian pHis biology. (OpenTargets Search: -NME2)

7) Quantitative statistics and data points from recent studies

7.1 Quantitative CoA ligand binding and protein stabilization (figure-level evidence)

In the 2023 Science Advances study, figure-level data show:
- Stoichiometry: native MS peaks corresponding to 0–6 CoA-family ligands per NME1 hexamer (CoA/AcCoA/SucCoA), implying up to one ligand per monomeric active site. (iuso2023nucleosidediphosphatekinases media acadc5cd)
- Thermostability: nanoDSF shows unbound NME1 has Tm = 60.2 ± 0.3°C, and ligand binding stabilizes the hexamer by ΔTm ≈ 3.6–3.8°C (e.g., 3.7 ± 0.1°C for SucCoA; 3.6 ± 0.1°C for AcCoA). (iuso2023nucleosidediphosphatekinases media acadc5cd)
- Binding pocket interaction schematic: A schematic highlights binding interactions, including the CoA 3′-phosphate interaction with catalytic His118. (iuso2023nucleosidediphosphatekinases media acadc5cd)

Although these quantitative measurements are reported for NME1, they are mechanistically informative for NME2 because NME1 and NME2 are closely related class I NME/NDPKs and are discussed together as CoA-binding and metabolically regulated enzymes in the 2024 review. (iuso2024nucleosidediphosphatekinases pages 1-2, iuso2023nucleosidediphosphatekinases pages 1-3, iuso2023nucleosidediphosphatekinases media acadc5cd)

7.2 Fraction of total cellular NDPK activity

A 2023 metastasis-focused review states that NME1 and NME2 are the most abundant NME family members and are “thought to be responsible for at least 80% of the cell’s NDPK activity.” (prunier2023mechanismsofaction pages 1-2)

8) Current applications and real-world implementations

8.1 Therapeutic targeting hypotheses (expert synthesis)

Protein–protein interaction targeting: A 2024 Cancer Metastasis Reviews article proposes that disrupting PRUNE1–NME1/2 interactions could be a therapeutic strategy to modulate metastasis-relevant signaling and tumor microenvironment behavior, reflecting an expert opinion grounded in interaction biology and signaling regulation. (ferrucci2024prune1andnmendpk pages 1-2)

8.2 Biomarker and disease-association positioning (curated evidence pointer)

Open Targets provides curated disease–target association entries for NME2 across multiple disease areas (e.g., hepatocellular carcinoma, atrial fibrillation, coronary artery disease, neurodegenerative disease, gastric cancer), with linked PubMed/PMC evidence trails. This does not by itself establish causality, but it reflects ongoing translational interest and literature density across indications. (OpenTargets Search: -NME2)

8.3 Metabolic-state interventions

The NME1/2-CoA/acyl-CoA findings imply a practical implementation avenue: diet/metabolic-state modulation (e.g., high-fat diet contexts) could influence NME1/2-regulated pathways (histone acetylation, fatty acid synthesis), offering a biologically grounded framework for interpreting metabolic interventions and metabolic comorbidities in disease settings where NME2 is implicated. (iuso2023nucleosidediphosphatekinases pages 1-3, iuso2024nucleosidediphosphatekinases pages 1-2)

9) Expert analysis: what is well-established vs. still unresolved

Well-established

Core catalytic principle: phosphohistidine-mediated NDPK phosphotransfer with conserved catalytic histidine H118 in NME2 (P22392). (adam2020nmenm23ndpkandhistidine pages 8-10, peuchant2017metastasissuppressornm23 pages 1-2)
Multifunctionality: credible evidence supports additional roles in signaling (G proteins), membrane remodeling (dynamin/endocytosis), and transcriptional regulation via DNA/G4 binding. (adam2020nmenm23ndpkandhistidine pages 4-6, prunier2023mechanismsofaction pages 1-2, sharma2021emergingmolecularconnections pages 1-2)

Emerging / active research frontiers (2023–2024)

CoA/acyl-CoA binding and epigenetic responses: a newly integrated model connecting energy state (ATP/ADP), catalytic His118 phosphorylation, and CoA/acyl-CoA occupancy in the nucleotide pocket. (iuso2024nucleosidediphosphatekinases pages 1-2, iuso2023nucleosidediphosphatekinases pages 1-3)

Remaining uncertainties / caveats for functional annotation

NME2-specific quantitative enzymology (e.g., full kinetic constants for diverse substrates under varied Mg²⁺/nucleotide conditions) was not directly extractable from the retrieved recent corpus; available evidence supports mechanism and residue identity but not comprehensive NME2-only kinetics. (amjadi2024mechanisticinsightsinto pages 1-2, lim2024modellingdynamicsof pages 1-4)
Metastasis role is context-dependent: authoritative reviews explicitly note that NME2’s metastasis suppressor role is less documented and may be controversial compared with NME1 in some contexts. (prunier2023mechanismsofaction pages 1-2)

Evidence summary table

The following table consolidates identity, mechanisms, pathways, localization, and quantitative evidence (with publication dates and URLs):

Category	Evidence summary	Key sources (author-year, journal, DOI/URL, pub date)	Context citation
Identity	Verified target: UniProt P22392 corresponds to human NME2 / NM23-H2 / NDP kinase B. Review evidence explicitly maps NME2 = P22392 and identifies it as a catalytically active Group I NME/NDPK family member that oligomerizes with NME1. Evidence is NME2-specific.	Adam et al. 2020, Int J Mol Sci, doi:10.3390/ijms21165848, https://doi.org/10.3390/ijms21165848, Aug 2020; Peuchant et al. 2017, FASEB J, doi:10.1096/fj.201600705r, https://doi.org/10.1096/fj.201600705r, Jan 2017	(adam2020nmenm23ndpkandhistidine pages 8-10, peuchant2017metastasissuppressornm23 pages 1-2)
Canonical enzymatic activity	Primary function: nucleoside diphosphate kinase activity, transferring the γ-phosphate from an NTP (mainly ATP) to an NDP (often GDP) via a ping-pong mechanism to maintain cellular NTP/dNTP pools; NME1 and NME2 together account for at least ~80% of total cellular NDPK activity in reviewed sources. Evidence is family-level with explicit inclusion of NME2/NME1-2.	Prunier et al. 2023, Cancer Metastasis Rev, doi:10.1007/s10555-023-10118-x, https://doi.org/10.1007/s10555-023-10118-x, Jun 2023; Amjadi et al. 2024, Int J Mol Sci, doi:10.3390/ijms25189768, https://doi.org/10.3390/ijms25189768, Sep 2024	(prunier2023mechanismsofaction pages 1-2, amjadi2024mechanisticinsightsinto pages 1-2)
Catalytic mechanism/residues	Catalysis proceeds through a high-energy phosphohistidine intermediate; the conserved catalytic histidine in human NME2 is His118 (H118), explicitly annotated for P22392. Mg²⁺ is required for efficient phosphotransferase activity in the NDPK family. NME1/2 function as active homo-/heterohexamers. Evidence is NME2-specific for H118/P22392, otherwise family-level.	Adam et al. 2020, Int J Mol Sci, doi:10.3390/ijms21165848, https://doi.org/10.3390/ijms21165848, Aug 2020; Lim & Natarajan 2024, bioRxiv, doi:10.1101/2024.09.19.613900, https://doi.org/10.1101/2024.09.19.613900, Sep 2024; Amjadi et al. 2024, Int J Mol Sci, doi:10.3390/ijms25189768, https://doi.org/10.3390/ijms25189768, Sep 2024	(adam2020nmenm23ndpkandhistidine pages 8-10, lim2024modellingdynamicsof pages 1-4, amjadi2024mechanisticinsightsinto pages 1-2)
Histidine kinase / protein phosphotransfer targets	Beyond canonical NDPK activity, NME2 is implicated in protein histidine phosphotransfer. Reviewed evidence supports NME2-dependent phosphotransfer to GNB1/Gβ (formation of phospho-H266; H118N-NME2 abolishes transfer and basal Gs activation) and links NME family members to phosphorylation of KCa3.1 (H358); broader NME substrates in reviews include ACLY and SUCLG1. Evidence is NME2-specific for GNB1, broader family-level for some other targets.	Adam et al. 2020, Int J Mol Sci, doi:10.3390/ijms21165848, https://doi.org/10.3390/ijms21165848, Aug 2020; Ning et al. 2024, Int J Mol Sci, doi:10.3390/ijms25147975, https://doi.org/10.3390/ijms25147975, Jul 2024	(adam2020nmenm23ndpkandhistidine pages 4-6, adam2020nmenm23ndpkandhistidine pages 8-10)
DNA/G-quadruplex binding and transcriptional regulation	NME2 is also the c-MYC purine-binding factor (PuF/NM23-H2) and has DNA/G-quadruplex-binding transcriptional functions. Reviews state that NM23-H2/NME2 binds the c-MYC promoter G4 with high affinity and is involved in hTERT promoter regulation via recruitment of the REST–coREST–LSD1 repressor complex; telomere/G4 associations are also discussed. Evidence is NME2-specific.	Sharma et al. 2021, Int J Mol Sci, doi:10.3390/ijms22073457, https://doi.org/10.3390/ijms22073457, Mar 2021; Sengupta et al. 2020, Acc Chem Res, doi:10.1021/acs.accounts.0c00431, https://doi.org/10.1021/acs.accounts.0c00431, Dec 2020; Wu et al. 2023, Cell Death Dis, doi:10.1038/s41419-023-05562-0, https://doi.org/10.1038/s41419-023-05562-0, Jan 2023	(sharma2021emergingmolecularconnections pages 1-2, lim2024modellingdynamicsof pages 1-4)
Subcellular localization	NME2 is reported as cytoplasmic and nuclear, with additional plasma-membrane-associated functional positioning when locally supplying GTP to membrane-remodeling proteins such as dynamin. Some reviews also note extracellular/secretion observations for NME proteins, but strongest evidence for NME2 is nucleo-cytosolic plus membrane-proximal signaling roles. Evidence is NME2/NME1-2 family-level, with explicit mention of cytoplasm + nucleus for NME2.	Sharma et al. 2021, Int J Mol Sci, doi:10.3390/ijms22073457, https://doi.org/10.3390/ijms22073457, Mar 2021; Lim & Natarajan 2024, bioRxiv, doi:10.1101/2024.09.19.613900, https://doi.org/10.1101/2024.09.19.613900, Sep 2024; Prunier et al. 2023, Cancer Metastasis Rev, doi:10.1007/s10555-023-10118-x, https://doi.org/10.1007/s10555-023-10118-x, Jun 2023	(sharma2021emergingmolecularconnections pages 1-2, lim2024modellingdynamicsof pages 1-4, prunier2023mechanismsofaction pages 1-2)
Key pathways/interactions	Major functional pathways include nucleotide homeostasis, heterotrimeric G-protein signaling, dynamin-dependent endocytosis/plasma-membrane remodeling, and gene regulation. Reviews describe NME1/2 as cytosolic enzymes that provide local GTP to dynamins at the plasma membrane, supporting endocytosis and attenuation of receptor signaling; other cited NME2-relevant interactions include PRUNE1, G proteins, and transcriptional complexes at promoter G4s. Evidence is mixed NME2-specific and NME1/2 family-level.	Prunier et al. 2023, Cancer Metastasis Rev, doi:10.1007/s10555-023-10118-x, https://doi.org/10.1007/s10555-023-10118-x, Jun 2023; Ferrucci et al. 2024, Cancer Metastasis Rev, doi:10.1007/s10555-023-10165-4, https://doi.org/10.1007/s10555-023-10165-4, Jan 2024; Amjadi et al. 2024, Int J Mol Sci, doi:10.3390/ijms25189768, https://doi.org/10.3390/ijms25189768, Sep 2024	(prunier2023mechanismsofaction pages 1-2, ferrucci2024prune1andnmendpk pages 1-2, amjadi2024mechanisticinsightsinto pages 16-18)
Recent developments 2023-2024	Metabolic/epigenetic expansion of function: 2023–2024 studies/reviews show NME1/2 bind CoA and short-chain acyl-CoAs, suggesting ATP-regulated carrier functions that connect energy state to histone acetylation, fatty-acid synthesis, and transcriptional adaptation during high-fat diet responses. A 2023 Science Advances study reports Nme2 knockout mice develop excessive triglyceride synthesis/liver steatosis under HFD, implicating NME2 in protective liver metabolic regulation. Additional 2024 reviews highlight NME1/2-PRUNE1 signaling and metastasis-related context dependence. Evidence is mostly NME1/2 family-level, with Nme2 knockout data directly relevant.	Iuso et al. 2023, Sci Adv, doi:10.1126/sciadv.adh0140, https://doi.org/10.1126/sciadv.adh0140, Sep 2023; Iuso et al. 2024, Int J Mol Sci, doi:10.3390/ijms25147528, https://doi.org/10.3390/ijms25147528, Jul 2024; Ferrucci et al. 2024, Cancer Metastasis Rev, doi:10.1007/s10555-023-10165-4, https://doi.org/10.1007/s10555-023-10165-4, Jan 2024	(iuso2023nucleosidediphosphatekinases pages 1-3, iuso2024nucleosidediphosphatekinases pages 1-2, ferrucci2024prune1andnmendpk pages 1-2)
Quantitative data/statistics	Recent quantitative findings include: NME1 hexamers bind 0–6 CoA/AcCoA/SucCoA ligands; unbound Tm = 60.2 ± 0.3°C; CoA ligands increase stability by ΔTm ≈ 3.6–3.8°C (3.7 ± 0.1°C for SucCoA; 3.6 ± 0.1°C for AcCoA). Reviews also state NME1/NME2 contribute ≥80% of cellular NDPK activity. These numbers are family-level / NME1-biophysical proxies for NME1/2, not direct human NME2-only biophysics, but are mechanistically relevant because NME1 and NME2 share highly similar active-site architecture and functions.	Iuso et al. 2023, Sci Adv, doi:10.1126/sciadv.adh0140, https://doi.org/10.1126/sciadv.adh0140, Sep 2023; Iuso et al. 2024, Int J Mol Sci, doi:10.3390/ijms25147528, https://doi.org/10.3390/ijms25147528, Jul 2024; Prunier et al. 2023, Cancer Metastasis Rev, doi:10.1007/s10555-023-10118-x, https://doi.org/10.1007/s10555-023-10118-x, Jun 2023	(iuso2023nucleosidediphosphatekinases media acadc5cd, iuso2023nucleosidediphosphatekinases media d5301a3f, iuso2024nucleosidediphosphatekinases pages 1-2, prunier2023mechanismsofaction pages 1-2)

Table: This table summarizes verified identity, core biochemical function, non-canonical signaling and transcription roles, localization, and recent 2023-2024 developments for human NME2 (UniProt P22392). It distinguishes NME2-specific evidence from broader NME1/2 family-level findings and includes explicit quantitative values where available.

Key references (selected; with dates and URLs)

Prunier C, Chavrier P, Boissan M. “Mechanisms of action of NME metastasis suppressors – a family affair.” Cancer Metastasis Reviews (2023-06). https://doi.org/10.1007/s10555-023-10118-x (prunier2023mechanismsofaction pages 1-2)
Ferrucci V, Lomada S, Wieland T, Zollo M. “PRUNE1 and NME/NDPK family proteins influence energy metabolism and signaling in cancer metastases.” Cancer Metastasis Reviews (2024-01). https://doi.org/10.1007/s10555-023-10165-4 (ferrucci2024prune1andnmendpk pages 1-2)
Iuso D et al. “Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet.” Science Advances (2023-09). https://doi.org/10.1126/sciadv.adh0140 (iuso2023nucleosidediphosphatekinases pages 1-3)
Iuso D et al. “Nucleoside Diphosphate Kinases Are ATP-Regulated Carriers of Short-Chain Acyl-CoAs.” International Journal of Molecular Sciences (2024-07). https://doi.org/10.3390/ijms25147528 (iuso2024nucleosidediphosphatekinases pages 1-2)
Ning J et al. “Histidine Phosphorylation: Protein Kinases and Phosphatases.” International Journal of Molecular Sciences (2024-07). https://doi.org/10.3390/ijms25147975 (OpenTargets Search: -NME2)
Adam K et al. “NME/NM23/NDPK and Histidine Phosphorylation.” International Journal of Molecular Sciences (2020-08). https://doi.org/10.3390/ijms21165848 (includes explicit mapping NME2 = P22392 and His118) (adam2020nmenm23ndpkandhistidine pages 8-10)
Sharma S et al. “Emerging Molecular Connections between NM23 Proteins, Telomeres and Telomere-Associated Factors.” International Journal of Molecular Sciences (2021-03). https://doi.org/10.3390/ijms22073457 (PuF/c-MYC G4; nuclear/cytoplasmic localization) (sharma2021emergingmolecularconnections pages 1-2)
Wu S et al. “Crosstalk between G-quadruplex and ROS.” Cell Death & Disease (2023-01). https://doi.org/10.1038/s41419-023-05562-0 (G4-binding proteins including NM23-H2 at c-MYC promoter) (sharma2021emergingmolecularconnections pages 1-2)

References

(adam2020nmenm23ndpkandhistidine pages 8-10): Kevin Adam, Jia Ning, Jeffrey Reina, and Tony Hunter. Nme/nm23/ndpk and histidine phosphorylation. International Journal of Molecular Sciences, 21:5848, Aug 2020. URL: https://doi.org/10.3390/ijms21165848, doi:10.3390/ijms21165848. This article has 52 citations.
(prunier2023mechanismsofaction pages 1-2): Céline Prunier, Philippe Chavrier, and Mathieu Boissan. Mechanisms of action of nme metastasis suppressors – a family affair. Cancer Metastasis Reviews, 42:1155-1167, Jun 2023. URL: https://doi.org/10.1007/s10555-023-10118-x, doi:10.1007/s10555-023-10118-x. This article has 17 citations.
(sharma2021emergingmolecularconnections pages 1-2): Shalu Sharma, Antara Sengupta, and Shantanu Chowdhury. Emerging molecular connections between nm23 proteins, telomeres and telomere-associated factors: implications in cancer metastasis and ageing. International Journal of Molecular Sciences, 22:3457, Mar 2021. URL: https://doi.org/10.3390/ijms22073457, doi:10.3390/ijms22073457. This article has 5 citations.
(iuso2023nucleosidediphosphatekinases pages 1-3): Domenico Iuso, Isabel Garcia-Saez, Yohann Couté, Yoshiki Yamaryo-Botté, Elisabetta Boeri Erba, Annie Adrait, Nour Zeaiter, Malgorzata Tokarska-Schlattner, Zuzana Macek Jilkova, Fayçal Boussouar, Sophie Barral, Luca Signor, Karine Couturier, Azadeh Hajmirza, Florent Chuffart, Ekaterina Bourova-Flin, Anne-Laure Vitte, Lisa Bargier, Denis Puthier, Thomas Decaens, Sophie Rousseaux, Cyrille Botté, Uwe Schlattner, Carlo Petosa, and Saadi Khochbin. Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet. Science Advances, Sep 2023. URL: https://doi.org/10.1126/sciadv.adh0140, doi:10.1126/sciadv.adh0140. This article has 15 citations and is from a highest quality peer-reviewed journal.
(iuso2024nucleosidediphosphatekinases pages 1-2): Domenico Iuso, Julie Guilliaumet, Uwe Schlattner, and Saadi Khochbin. Nucleoside diphosphate kinases are atp-regulated carriers of short-chain acyl-coas. International Journal of Molecular Sciences, 25:7528, Jul 2024. URL: https://doi.org/10.3390/ijms25147528, doi:10.3390/ijms25147528. This article has 3 citations.
(peuchant2017metastasissuppressornm23 pages 1-2): Evelyne Peuchant, Marie‐Lise Bats, Isabelle Moranvillier, Michel Lepoivre, Jérôme Guitton, Dominique Wendum, Marie‐Lise Lacombe, François Moreau‐Gaudry, Mathieu Boissan, and Sandrine Dabernat. Metastasis suppressor nm23 limits oxidative stress in mammals by preventing activation of stress‐activated protein kinases/jnks through its nucleoside diphosphate kinase activity. The FASEB Journal, 31:1531-1546, Jan 2017. URL: https://doi.org/10.1096/fj.201600705r, doi:10.1096/fj.201600705r. This article has 15 citations.
(amjadi2024mechanisticinsightsinto pages 1-2): Rezan Amjadi, Sebastiaan Werten, Santosh Kumar Lomada, Clara Baldin, Klaus Scheffzek, Theresia Dunzendorfer-Matt, and Thomas Wieland. Mechanistic insights into substrate recognition of human nucleoside diphosphate kinase c based on nucleotide-induced structural changes. International Journal of Molecular Sciences, 25:9768, Sep 2024. URL: https://doi.org/10.3390/ijms25189768, doi:10.3390/ijms25189768. This article has 2 citations.
(lim2024modellingdynamicsof pages 1-4): Yee Ying Lim and Kedar Nath Natarajan. Modelling dynamics of human ndpk hexamer structure, stability and interactions. bioRxiv, Sep 2024. URL: https://doi.org/10.1101/2024.09.19.613900, doi:10.1101/2024.09.19.613900. This article has 1 citations.
(adam2020nmenm23ndpkandhistidine pages 4-6): Kevin Adam, Jia Ning, Jeffrey Reina, and Tony Hunter. Nme/nm23/ndpk and histidine phosphorylation. International Journal of Molecular Sciences, 21:5848, Aug 2020. URL: https://doi.org/10.3390/ijms21165848, doi:10.3390/ijms21165848. This article has 52 citations.
(OpenTargets Search: -NME2): Open Targets Query (-NME2, 5 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(ferrucci2024prune1andnmendpk pages 1-2): Veronica Ferrucci, Santosh Lomada, Thomas Wieland, and Massimo Zollo. Prune1 and nme/ndpk family proteins influence energy metabolism and signaling in cancer metastases. Cancer Metastasis Reviews, 43:755-775, Jan 2024. URL: https://doi.org/10.1007/s10555-023-10165-4, doi:10.1007/s10555-023-10165-4. This article has 10 citations.
(iuso2023nucleosidediphosphatekinases media acadc5cd): Domenico Iuso, Isabel Garcia-Saez, Yohann Couté, Yoshiki Yamaryo-Botté, Elisabetta Boeri Erba, Annie Adrait, Nour Zeaiter, Malgorzata Tokarska-Schlattner, Zuzana Macek Jilkova, Fayçal Boussouar, Sophie Barral, Luca Signor, Karine Couturier, Azadeh Hajmirza, Florent Chuffart, Ekaterina Bourova-Flin, Anne-Laure Vitte, Lisa Bargier, Denis Puthier, Thomas Decaens, Sophie Rousseaux, Cyrille Botté, Uwe Schlattner, Carlo Petosa, and Saadi Khochbin. Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet. Science Advances, Sep 2023. URL: https://doi.org/10.1126/sciadv.adh0140, doi:10.1126/sciadv.adh0140. This article has 15 citations and is from a highest quality peer-reviewed journal.
(amjadi2024mechanisticinsightsinto pages 16-18): Rezan Amjadi, Sebastiaan Werten, Santosh Kumar Lomada, Clara Baldin, Klaus Scheffzek, Theresia Dunzendorfer-Matt, and Thomas Wieland. Mechanistic insights into substrate recognition of human nucleoside diphosphate kinase c based on nucleotide-induced structural changes. International Journal of Molecular Sciences, 25:9768, Sep 2024. URL: https://doi.org/10.3390/ijms25189768, doi:10.3390/ijms25189768. This article has 2 citations.
(iuso2023nucleosidediphosphatekinases media d5301a3f): Domenico Iuso, Isabel Garcia-Saez, Yohann Couté, Yoshiki Yamaryo-Botté, Elisabetta Boeri Erba, Annie Adrait, Nour Zeaiter, Malgorzata Tokarska-Schlattner, Zuzana Macek Jilkova, Fayçal Boussouar, Sophie Barral, Luca Signor, Karine Couturier, Azadeh Hajmirza, Florent Chuffart, Ekaterina Bourova-Flin, Anne-Laure Vitte, Lisa Bargier, Denis Puthier, Thomas Decaens, Sophie Rousseaux, Cyrille Botté, Uwe Schlattner, Carlo Petosa, and Saadi Khochbin. Nucleoside diphosphate kinases 1 and 2 regulate a protective liver response to a high-fat diet. Science Advances, Sep 2023. URL: https://doi.org/10.1126/sciadv.adh0140, doi:10.1126/sciadv.adh0140. This article has 15 citations and is from a highest quality peer-reviewed journal.

Citations

sharma2021emergingmolecularconnections pages 1-2
prunier2023mechanismsofaction pages 1-2
iuso2023nucleosidediphosphatekinases pages 1-3
iuso2024nucleosidediphosphatekinases pages 1-2
amjadi2024mechanisticinsightsinto pages 1-2
lim2024modellingdynamicsof pages 1-4
amjadi2024mechanisticinsightsinto pages 16-18
https://doi.org/10.1126/sciadv.adh0140
https://doi.org/10.3390/ijms25147528
https://doi.org/10.3390/ijms21165848,
https://doi.org/10.1096/fj.201600705r,
https://doi.org/10.1007/s10555-023-10118-x,
https://doi.org/10.3390/ijms25189768,
https://doi.org/10.1101/2024.09.19.613900,
https://doi.org/10.3390/ijms25147975,
https://doi.org/10.3390/ijms22073457,
https://doi.org/10.1021/acs.accounts.0c00431,
https://doi.org/10.1038/s41419-023-05562-0,
https://doi.org/10.1007/s10555-023-10165-4,
https://doi.org/10.1126/sciadv.adh0140,
https://doi.org/10.3390/ijms25147528,
https://doi.org/10.1007/s10555-023-10118-x
https://doi.org/10.1007/s10555-023-10165-4
https://doi.org/10.3390/ijms25147975
https://doi.org/10.3390/ijms21165848
https://doi.org/10.3390/ijms22073457
https://doi.org/10.1038/s41419-023-05562-0

📄 View Raw YAML

id: P22392
gene_symbol: NME2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: NME2 encodes nucleoside diphosphate kinase B/NM23-H2, a conserved NDP kinase whose primary activity is phosphohistidine-mediated transfer of terminal phosphate between nucleoside triphosphates and diphosphates to maintain NTP/dNTP pools. It also has supported secondary roles in protein histidine phosphotransfer, local GTP supply for endocytosis, G-quadruplex-dependent transcriptional regulation, and CoA/acyl-CoA-linked metabolic regulation.
alternative_products:
- name: 1 (NM23-H2)
  id: P22392-1
- name: 3 (NM23-LV)
  id: P22392-2
  sequence_note: VSP_036708
existing_annotations:
- term:
    id: GO:0004550
    label: nucleoside diphosphate kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0042981
    label: regulation of apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0001726
    label: ruffle
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Use the specific G-quadruplex DNA binding annotation where possible rather than generic DNA binding.
- term:
    id: GO:0004550
    label: nucleoside diphosphate kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0004673
    label: protein histidine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  review:
    summary: Correct. NME2 has histidine kinase/phosphohistidine-generating capacity in mammalian phosphohistidine signaling contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: In mammalian cells, the NME family (including NME2) is considered among the limited set of enzymes with **histidine kinase / phosphohistidine-generating capacity**, despite technical challenges associated with phosphohistidine lability.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Prefer specific cytosol and nucleus annotations over generic cytoplasm.
- term:
    id: GO:0006183
    label: GTP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0006228
    label: UTP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0006241
    label: CTP biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0009117
    label: nucleotide metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Accepted broadly as nucleotide metabolic process, but NME2 is more specifically an NDP kinase maintaining NTP/dNTP pools.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0009142
    label: nucleoside triphosphate biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Use nucleoside diphosphate kinase activity rather than generic kinase/transferase activity.
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Use nucleoside diphosphate kinase activity rather than generic kinase/transferase activity.
- term:
    id: GO:0030027
    label: lamellipodium
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This cofactor/nucleotide-binding annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  review:
    summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11919189
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16169070
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17314099
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24970086
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27499296
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:21988832
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0042304
    label: regulation of fatty acid biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0120225
    label: coenzyme A binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  review:
    summary: Supported as a non-core recent NME1/2 metabolic regulatory finding involving CoA/acyl-CoA binding.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: "NME1/2 are described as housekeeping NDP kinases that bind **CoA and CoA-derivatives** (AcCoA, SucCoA, long-chain fatty acyl\u2013CoA)."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0001216
    label: DNA-binding transcription activator activity
  evidence_type: IDA
  original_reference_id: PMID:8392752
  review:
    summary: Supported as a non-core DNA/G-quadruplex transcriptional regulator role; the primary molecular function remains NDP kinase activity.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:0051880
    label: G-quadruplex DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19033359
  review:
    summary: Correct and informative. NME2/NM23-H2 binds promoter G-quadruplex DNA structures, classically in c-MYC-related transcriptional regulation.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:0051880
    label: G-quadruplex DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19435876
  review:
    summary: Correct and informative. NME2/NM23-H2 binds promoter G-quadruplex DNA structures, classically in c-MYC-related transcriptional regulation.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:2000144
    label: positive regulation of DNA-templated transcription initiation
  evidence_type: IDA
  original_reference_id: PMID:19033359
  review:
    summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:2000144
    label: positive regulation of DNA-templated transcription initiation
  evidence_type: IDA
  original_reference_id: PMID:19435876
  review:
    summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:0004518
    label: nuclease activity
  evidence_type: IDA
  original_reference_id: PMID:19435876
  negated: true
  review:
    summary: Correct negated annotation. NME2 was tested for nuclease activity in this c-MYC/NHE context and found not to cleave the substrate.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: The NOT annotation is biologically correct and should be retained as documented non-core negative evidence; NME2 is a phosphotransferase and DNA/G4-binding regulator, not a nuclease.
- term:
    id: GO:0006183
    label: GTP biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IDA
  original_reference_id: PMID:11121025
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Use the specific G-quadruplex DNA binding annotation where possible rather than generic DNA binding.
- term:
    id: GO:0004550
    label: nucleoside diphosphate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:16313181
  review:
    summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0004673
    label: protein histidine kinase activity
  evidence_type: IDA
  original_reference_id: PMID:17157250
  review:
    summary: Correct. NME2 has histidine kinase/phosphohistidine-generating capacity in mammalian phosphohistidine signaling contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: In mammalian cells, the NME family (including NME2) is considered among the limited set of enzymes with **histidine kinase / phosphohistidine-generating capacity**, despite technical challenges associated with phosphohistidine lability.
- term:
    id: GO:0046042
    label: ITP biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1851158
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0016301
    label: kinase activity
  evidence_type: IDA
  original_reference_id: PMID:8529641
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Use nucleoside diphosphate kinase activity rather than generic kinase/transferase activity.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-482619
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-482621
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9748969
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9748999
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9755013
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0004550
    label: nucleoside diphosphate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:9488696
  review:
    summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17532299
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Generic protein/identical protein binding is less informative than hexameric NDPK activity, G4 binding, and specific signaling complex contexts.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:17532299
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Prefer specific cytosol and nucleus annotations over generic cytoplasm.
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IDA
  original_reference_id: PMID:8392752
  review:
    summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:0003677
    label: DNA binding
  evidence_type: IDA
  original_reference_id: PMID:19435876
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Use the specific G-quadruplex DNA binding annotation where possible rather than generic DNA binding.
- term:
    id: GO:0019003
    label: GDP binding
  evidence_type: IMP
  original_reference_id: PMID:19435876
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This cofactor/nucleotide-binding annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IMP
  original_reference_id: PMID:19435876
  review:
    summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:0051880
    label: G-quadruplex DNA binding
  evidence_type: IDA
  original_reference_id: PMID:25679041
  review:
    summary: Correct and informative. NME2/NM23-H2 binds promoter G-quadruplex DNA structures, classically in c-MYC-related transcriptional regulation.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:0004550
    label: nucleoside diphosphate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:25679041
  review:
    summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0009142
    label: nucleoside triphosphate biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:25679041
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  review:
    summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  review:
    summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0034774
    label: secretory granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798748
  review:
    summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:1904813
    label: ficolin-1-rich granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6800434
  review:
    summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  review:
    summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  review:
    summary: Correct. NME2 localizes to both cytosolic and nuclear compartments consistent with nucleotide homeostasis/signaling and gene regulation roles.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: NME2/NM23-H2 is described as **localized in both cytoplasm and nucleus**, aligning with dual roles in nucleotide homeostasis/signaling (cytosol) and gene regulation (nucleus).
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19199708
  review:
    summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:20458337
  review:
    summary: Kept as non-core. Extracellular or granule/exosome detection is observed in some contexts but is secondary to nucleo-cytosolic NME2 functions.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:15703214
  review:
    summary: Correct or plausible but too broad for useful NME2 annotation.
    action: MARK_AS_OVER_ANNOTATED
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    reason: Prefer specific cytosol and nucleus annotations over generic cytoplasm.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IDA
  original_reference_id: PMID:11919189
  negated: true
  review:
    summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
- term:
    id: GO:0007229
    label: integrin-mediated signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:11919189
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0045944
    label: positive regulation of transcription by RNA polymerase II
  evidence_type: IDA
  original_reference_id: PMID:15703214
  review:
    summary: Supported as a non-core transcriptional output of NME2 promoter/G-quadruplex binding rather than the primary catalytic function.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
- term:
    id: GO:0071944
    label: cell periphery
  evidence_type: IDA
  original_reference_id: PMID:11919189
  review:
    summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
- term:
    id: GO:0004550
    label: nucleoside diphosphate kinase activity
  evidence_type: IDA
  original_reference_id: PMID:1851158
  review:
    summary: Correct and core. NME2/NDPK-B catalyzes phosphotransfer between nucleoside diphosphates and triphosphates through His118 phosphohistidine chemistry.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0009142
    label: nucleoside triphosphate biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:1851158
  review:
    summary: Accepted as the pathway-level consequence of NME2 NDP kinase activity maintaining NTP pools, though individual nucleotides are substrate-specific contexts.
    action: ACCEPT
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IMP
  original_reference_id: PMID:16862176
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0045618
    label: positive regulation of keratinocyte differentiation
  evidence_type: IMP
  original_reference_id: PMID:16862176
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0045682
    label: regulation of epidermis development
  evidence_type: IMP
  original_reference_id: PMID:16862176
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0050679
    label: positive regulation of epithelial cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:16862176
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0001726
    label: ruffle
  evidence_type: IDA
  original_reference_id: PMID:11919189
  review:
    summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: TAS
  original_reference_id: PMID:11919189
  review:
    summary: Supported or plausible for NME2 but non-core relative to its primary NDP kinase/phosphohistidine chemistry and nuclear G-quadruplex transcriptional role. This downstream cell-process annotation should not drive the core function summary.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
- term:
    id: GO:0030027
    label: lamellipodium
  evidence_type: IDA
  original_reference_id: PMID:11919189
  review:
    summary: Kept as non-core. Peripheral membrane/actin-edge localizations fit NME2 roles in local GTP supply and membrane remodeling but are not its primary localization.
    action: KEEP_AS_NON_CORE
    additional_reference_ids:
    - file:human/NME2/NME2-deep-research-falcon.md
    supported_by:
    - reference_id: file:human/NME2/NME2-deep-research-falcon.md
      supporting_text: cytosolic NME1 and NME2 provide local GTP to dynamins at the plasma membrane
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11121025
  title: Catalysis of DNA cleavage and nucleoside triphosphate synthesis by NM23-H2/NDP kinase share an active site that implies a DNA repair function.
  findings: []
- id: PMID:11919189
  title: 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.
  findings: []
- id: PMID:15703214
  title: Nuclear translocation of integrin cytoplasmic domain-associated protein 1 stimulates cellular proliferation.
  findings: []
- id: PMID:16169070
  title: 'A human protein-protein interaction network: a resource for annotating the proteome.'
  findings: []
- id: PMID:16313181
  title: Characterization of the 3' --> 5' exonuclease activity found in human nucleoside diphosphate kinase 1 (NDK1) and several of its homologues.
  findings: []
- id: PMID:16862176
  title: Novel roles of NM23 proteins in skin homeostasis, repair and disease.
  findings: []
- id: PMID:17157250
  title: Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells.
  findings: []
- id: PMID:17314099
  title: NM23-H1 tumor suppressor physically interacts with serine-threonine kinase receptor-associated protein, a transforming growth factor-beta (TGF-beta) receptor-interacting protein, and negatively regulates TGF-beta signaling.
  findings: []
- id: PMID:17532299
  title: NM23-H2 involves in negative regulation of Diva and Bcl2L10 in apoptosis signaling.
  findings: []
- id: PMID:1851158
  title: Nucleoside diphosphate kinase from human erythrocytes. Structural characterization of the two polypeptide chains responsible for heterogeneity of the hexameric enzyme.
  findings: []
- id: PMID:19033359
  title: Metastases suppressor NM23-H2 interaction with G-quadruplex DNA within c-MYC promoter nuclease hypersensitive element induces c-MYC expression.
  findings: []
- id: PMID:19199708
  title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT).
  findings: []
- id: PMID:19435876
  title: NM23-H2 may play an indirect role in transcriptional activation of c-myc gene expression but does not cleave the nuclease hypersensitive element III(1).
  findings: []
- id: PMID:20458337
  title: MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis.
  findings: []
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
- id: PMID:21988832
  title: Toward an understanding of the protein interaction network of the human liver.
  findings: []
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine.
  findings: []
- id: PMID:24970086
  title: Membrane trafficking. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling.
  findings: []
- id: PMID:25679041
  title: The maize (Zea mays L.) nucleoside diphosphate kinase1 (ZmNDPK1) gene encodes a human NM23-H2 homologue that binds and stabilizes G-quadruplex DNA.
  findings: []
- id: PMID:27499296
  title: Mitochondrial Protein Interaction Mapping Identifies Regulators of Respiratory Chain Function.
  findings: []
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
  findings: []
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
  findings: []
- id: PMID:8392752
  title: Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis.
  findings: []
- id: PMID:8529641
  title: A novel serine/threonine-specific protein phosphotransferase activity of Nm23/nucleoside-diphosphate kinase.
  findings: []
- id: PMID:9488696
  title: Substrate specificity of human nucleoside-diphosphate kinase revealed by transient kinetic analysis.
  findings: []
- id: Reactome:R-HSA-482619
  title: (d)NDP + ATP <=> (d)NTP + ADP (NME1,2,3)
  findings: []
- id: Reactome:R-HSA-482621
  title: (d)NTP + ADP <=> (d)NDP + ATP (NME1,2,3)
  findings: []
- id: Reactome:R-HSA-6798748
  title: Exocytosis of secretory granule lumen proteins
  findings: []
- id: Reactome:R-HSA-6800434
  title: Exocytosis of ficolin-rich granule lumen proteins
  findings: []
- id: Reactome:R-HSA-9748969
  title: NME1:2 hexamer phosphorylates 6TdGDP to 6TdGTP
  findings: []
- id: Reactome:R-HSA-9748999
  title: NME1:2 hexamer phosphorylates 6TGDP to 6TGTP
  findings: []
- id: Reactome:R-HSA-9755013
  title: NME1,2 hexamers phosphorylate RBV-DP
  findings: []
- id: file:human/NME2/NME2-deep-research-falcon.md
  title: Falcon deep research report for human NME2
  findings: []
core_functions:
- description: NME2 is an NDP kinase whose core function is phosphohistidine-mediated nucleotide phosphotransfer, maintaining cellular NTP/dNTP pools and supplying local GTP in signaling and membrane-remodeling contexts. It also has a supported nuclear G-quadruplex DNA-binding role in transcriptional regulation.
  supported_by:
  - reference_id: file:human/NME2/NME2-deep-research-falcon.md
    supporting_text: Human **NME2** (also known as **NM23-H2** / **NDPK-B**) is a highly conserved **nucleoside diphosphate kinase (NDPK)** whose *core biochemical function* is **phosphotransfer between nucleoside diphosphates and triphosphates** via an obligate **phosphohistidine** intermediate at **His118**.
  - reference_id: file:human/NME2/NME2-deep-research-falcon.md
    supporting_text: '**Definition**: NDPKs catalyze the transfer of a terminal phosphate from a nucleoside triphosphate donor (often ATP) to a nucleoside diphosphate acceptor (often GDP), thereby supporting balanced intracellular pools of NTPs/dNTPs.'
  - reference_id: file:human/NME2/NME2-deep-research-falcon.md
    supporting_text: 'A distinct concept in the NME2 literature is its role as the **c-MYC purine-binding factor (PuF)**: NME2/NM23-H2 binds particular DNA elements and also binds **non-B DNA structures** such as promoter **G-quadruplexes (G4)**, linking DNA secondary structure to transcriptional output.'
  molecular_function:
    id: GO:0004550
    label: nucleoside diphosphate kinase activity
  directly_involved_in:
  - id: GO:0009142
    label: nucleoside triphosphate biosynthetic process
  - id: GO:0009117
    label: nucleotide metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0005634
    label: nucleus
proposed_new_terms: []
suggested_questions:
- question: Which NME2 cellular phenotypes require canonical NDP kinase activity versus protein histidine phosphotransfer or G-quadruplex DNA binding?
  experts: []
- question: How much of the CoA/acyl-CoA regulatory model is NME2-specific versus shared with NME1-containing hexamers in human tissues?
  experts: []
suggested_experiments:
- hypothesis: NME2 catalytic His118 is required for both NTP-pool maintenance and selected histidine phosphotransfer signaling outputs.
  description: Rescue NME2-depleted cells with wild-type or H118N NME2 and compare NTP/dNTP pools, G-protein phosphohistidine readouts, dynamin-dependent endocytosis, and transcriptional phenotypes.
- hypothesis: NME2 promoter G-quadruplex binding is separable from NDP kinase activity.
  description: Test DNA/G4-binding mutants and catalytic mutants side-by-side for c-MYC/hTERT promoter occupancy, transcriptional output, and NDP kinase activity.

NME2

Gene Description

Existing Annotations Review

Core Functions

NME2 is an NDP kinase whose core function is phosphohistidine-mediated nucleotide phosphotransfer, maintaining cellular NTP/dNTP pools and supplying local GTP in signaling and membrane-remodeling contexts. It also has a supported nuclear G-quadruplex DNA-binding role in transcriptional regulation.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human NME2 (UniProt P22392) Functional Annotation

Executive summary

1) Target identity verification (mandatory)

2) Key concepts and definitions (current understanding)

2.1 Nucleoside diphosphate kinase (NDPK) activity (primary function)

2.2 Catalytic residue and phosphohistidine intermediate

2.3 “Histidine kinase” / protein histidine phosphotransfer (in mammalian context)

2.4 NME2 as a DNA-binding transcriptional regulator (PuF)

3) Molecular function and substrate specificity

3.1 Canonical enzymatic function

3.2 Protein histidine phosphotransfer targets and examples

4) Cellular localization and where NME2 carries out its function

4.1 Nucleo-cytosolic distribution

4.2 Functional membrane proximity (plasma membrane endocytic sites)

4.3 Secretion/extracellular observations (contextual)

5) Pathways and interaction networks

5.1 Dynamin/endocytosis and metastasis-relevant signaling attenuation

5.2 Heterotrimeric G-protein signaling via histidine phosphotransfer

5.3 DNA secondary structure–dependent transcriptional control (G-quadruplexes)

6) Recent developments and latest research (prioritizing 2023–2024)

6.1 NME1/2 as CoA/acyl-CoA binding proteins and metabolic/epigenetic regulators

6.2 Metastasis-centered mechanistic synthesis and context dependence

6.3 2024 histidine phosphorylation overview (state of the field)

7) Quantitative statistics and data points from recent studies

7.1 Quantitative CoA ligand binding and protein stabilization (figure-level evidence)

7.2 Fraction of total cellular NDPK activity

8) Current applications and real-world implementations

8.1 Therapeutic targeting hypotheses (expert synthesis)

8.2 Biomarker and disease-association positioning (curated evidence pointer)

8.3 Metabolic-state interventions

9) Expert analysis: what is well-established vs. still unresolved

Well-established

Emerging / active research frontiers (2023–2024)

Remaining uncertainties / caveats for functional annotation

Evidence summary table

Key references (selected; with dates and URLs)

Citations

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