Alternative titles; symbols
HGNC Approved Gene Symbol: NME2
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:51,165,536-51,171,744 (from NCBI)
NM23 is a heterodimeric protein that acts as a nucleoside diphosphate (NDP) kinase. Gilles et al. (1991) identified NME1 (156490) and NME2 as the A and B polypeptide chains of the NM23 enzyme. Each chain consists of 152 amino acids. NME2 is identical to the beta subunit of human erythrocyte NDP kinase. NDP kinases are involved in the synthesis of nucleoside triphosphates, and the NM23 protein may act in the regulation of signal transduction by complexing with G proteins, causing activation/inactivation of developmental pathways (Gilles et al., 1991).
Stahl et al. (1991) identified the NME2 gene, which they referred to as nm23-H2. Its cDNA predicts a 17-kD protein with 88% identity to nm23-H1. The nm23-H1 gene also shares a significant homology with nucleoside diphosphate kinases and the Drosophila developmental gene awd. Northern blot hybridization indicated that the expression of the nm23-H1 gene is reduced to a lesser extent in tumor cells of high metastatic potential than is nm23-H1. Both proteins are independently active nucleoside diphosphate kinases and readily form intra- and intermolecular disulfide bonds.
Using Northern blot analysis, Masse et al. (2002) detected high expression of mouse Nme2, which they called nm23-M2, in heart, liver, and kidney, with intermediate expression in skeletal muscle. Little to no expression was detected in other mouse tissues examined. In situ hybridization of 15-day postcoitum mouse embryos showed ubiquitous Nme2 expression.
By EST database analysis, Valentijn et al. (2006) identified a transcript that starts from the NM23H1 promoter and reads through the neighboring NM23H2 gene. This transcript, which they called NM23LV (NM23 long variant), is ubiquitously expressed and encodes a protein with most of the NM23H1 amino acids and all of the NM23H2 amino acids. See 156490 for further information on the NM23LV read-through transcript.
Srivastava et al. (2006) demonstrated that the 14 C-terminal amino acids of KCa3.1 (KCNN4; 602754) that mediate the regulation of KCa3.1 by phosphatidylinositol 3-phosphate (PI(3)P) recruit NDPKB to KCa3.1. NDPKB then activates KCa3.1 by phosphorylating residue H358, which is present in the same C-terminal 14-amino acid region. SiRNA treatment of NDPBK in CD4+ T cells resulted in a marked reduction of KCa3.1 channel activity. Srivastava et al. (2006) concluded that histidine phosphorylation regulates KCa3.1 channel activity and that NDPBK is critical to the channel activity and the activation of CD4 T cells.
Boissan et al. (2014) found that knockdown of nucleoside diphosphate kinases (NDPKs) NM23H1/H2 (NME1; 156490/NME2), which produce GTP through ATP-driven conversion of GDP, inhibited dynamin-mediated endocytosis. NM23H1/H2 localized at clathrin-coated pits and interacted with the proline-rich domain of dynamin. In vitro, NM23H1/H2 were recruited to dynamin-induced tubules, stimulated GTP-loading on dynamin, and triggered fission in the presence of ATP and GDP. NM23H4 (NME4; 601818), a mitochondria-specific NDPK, colocalized with mitochondrial dynamin-like OPA1 (605290), which is involved in mitochondria inner membrane fusion, and increased GTP-loading on OPA1. Like OPA1 loss of function, silencing of NM23H4 but not NM23H1/H2 resulted in mitochondrial fragmentation, reflecting fusion defects. Boissan et al. (2014) concluded that NDPKs interact with and provide GTP to dynamins, allowing these motor proteins to work with high thermodynamic efficiency.
Masse et al. (2002) determined that the mouse and human NME2 genes contain 5 exons and span about 6.0 kb. Their promoters, like those of other NME genes, contain several binding sites for AP2 (107580), NF1 (613113), Sp1 (189906), LEF1 (153245), and response elements to glucocorticoid receptors (138040). There are no TATA or CAAT boxes or pyrimidine-rich initiator (Inr) sequences.
In the course of in situ hybridization mapping of NME1, Leone et al. (1991) demonstrated a cross-hybridizing sequence on chromosome 16. This, however, cannot be NME2 because Backer et al. (1993) assigned both NME1 and NME2 to 17q21.3 by somatic cell hybrid analysis and fluorescence in situ hybridization. By analyzing DNA from rodent/human somatic cell hybrid lines and hybrid cell lines containing portions of chromosome 17 with a combination of PCR amplification and Southern hybridization, Kelsell et al. (1993) mapped NME2 to 17q21-q22. By isolating and characterizing 5 YACs and 3 cosmid clones that contained both the NME1 and NME2 genes, Chandrasekharappa et al. (1993) demonstrated that the NME2 gene is separated from the NME1 gene by no more than 18 kb. The 2 putative tumor suppressor genes may have arisen by a tandem duplication. Since NME1 has been excluded as the site of the type I breast cancer gene (BRCA1; 113705), the close situation of NME2 to NME1 probably excludes NME2 also.
Backer, J. M., Mendola, C. E., Kovesdi, I., Fairhurst, J. L., O'Hara, B., Eddy, R. L., Jr., Shows, T. B., Mathew, S., Murty, V. V. V. S., Chaganti, R. S. K. Chromosomal localization and nucleoside diphosphate kinase activity of human metastasis-suppressor genes NM23-1 and NM23-2. Oncogene 8: 497-502, 1993. [PubMed: 8381224]
Boissan, M., Montagnac, G., Shen, Q., Griparic, L., Guitton, J., Romao, M., Sauvonnet, N., Lagache, T., Lascu, I., Raposo, G., Desbourdes, C., Schlattner, U., Lacombe, M.-L., Polo, S., van der Bliek, A. M., Roux, A., Chavrier, P. Nucleoside diphosphate kinases fuel dynamin superfamily proteins with GTP for membrane remodeling. Science 344: 1510-1515, 2014. [PubMed: 24970086] [Full Text: https://doi.org/10.1126/science.1253768]
Chandrasekharappa, S. C., Gross, L. A., King, S. E., Collins, F. S. The human NME2 gene lies within 18kb of NME1 in chromosome 17. Genes Chromosomes Cancer 6: 245-248, 1993. [PubMed: 7685630] [Full Text: https://doi.org/10.1002/gcc.2870060411]
Gilles, A. M., Presecan, E., Vonica, A., Lascu, I. Nucleoside diphosphate kinase from human erythrocytes: structural characterization of the two polypeptide chains responsible for heterogeneity of the hexameric enzyme. J. Biol. Chem. 266: 8784-8789, 1991. [PubMed: 1851158]
Kelsell, D. P., Black, D. M., Solomon, E., Spurr, N. K. Localization of a second NM23 gene, NME2, to chromosome 17q21-q22. Genomics 17: 522-524, 1993. [PubMed: 8406509] [Full Text: https://doi.org/10.1006/geno.1993.1362]
Leone, A., McBride, O. W., Weston, A., Wang, M. G., Anglard, P., Cropp, C. S., Goepel, J. R., Lidereau, R., Callahan, R., Marston Linehan, W., Rees, R. C., Harris, C. C., Liotta, L. A., Steeg, P. S. Somatic allelic deletion of nm23 in human cancer. Cancer Res. 51: 2490-2493, 1991. [PubMed: 2015608]
Masse, K., Dabernat, S., Bourbon, P.-M., Larou, M., Amrein, L., Barraud, P., Perel, Y., Camara, M., Landry, M., Lacombe, M.-L., Daniel, J.-Y. Characterization of the nm23-M2, nm23-M3 and nm23-M4 mouse genes: comparison with their human homologs. Gene 296: 87-97, 2002. [PubMed: 12383506] [Full Text: https://doi.org/10.1016/s0378-1119(02)00836-3]
Srivastava, S., Li, Z., Ko, K., Choudhury, P., Albaqumi, M., Johnson, A. K., Yan, Y., Backer, J. M., Unutmaz, D., Coetzee, W. A., Skolnik, E. Y. Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Molec. Cell 24: 665-675, 2006. [PubMed: 17157250] [Full Text: https://doi.org/10.1016/j.molcel.2006.11.012]
Stahl, J. A., Leone, A., Rosengard, A. M., Porter, L., King, C. R., Steeg, P. S. Identification of a second human nm23 gene, nm23-H2. Cancer Res. 51: 445-449, 1991. [PubMed: 1988104]
Valentijn, L. J., Koster, J., Versteeg, R. Read-through transcript from NM23-H1 into the neighboring NM23-H2 gene encodes a novel protein, NM23-LV. Genomics 87: 483-489, 2006. [PubMed: 16442775] [Full Text: https://doi.org/10.1016/j.ygeno.2005.11.004]