Molecular and Cellular Biochemistry

, Volume 329, Issue 1–2, pp 17–33 | Cite as

The NM23 family in development

  • Aikaterini Bilitou
  • Julie Watson
  • Anton Gartner
  • Shin-ichi Ohnuma


The NM23 (non-metastatic 23) family is almost universally conserved across all three domains of life: eubacteria, archaea and eucaryotes. Unicellular organisms possess one NM23 ortholog, whilst vertebrates possess several. Gene multiplication through evolution has been accompanied by structural and functional diversification. Many NM23 orthologs are nucleoside diphosphate kinases (NDP kinases), but some more recently evolved members lack NDP kinase activity and/or display other functions, for instance, acting as protein kinases or transcription factors. These members display overlapping but distinct expression patterns during vertebrate development. In this review, we describe the functional differences and similarities among various NM23 family members. Moreover, we establish orthologous relationships through a phylogenetic analysis of NM23 members across vertebrate species, including Xenopus laevis and zebrafish, primitive chordates and several phyla of invertebrates. Finally, we summarize the involvement of NM23 proteins in development, in particular neural development. Carcinogenesis is a process of misregulated development, and NM23 was initially implicated as a metastasis suppressor. A more detailed understanding of the evolution of the family and its role in vertebrate development will facilitate elucidation of the mechanism of NM23 involvement in human cancer.


NM23 Development Xenopus Neurogenesis NDP kinase 



We are grateful to Dr. T. Mochizuki for contribution of the in situ images. This work was supported by Cancer Research, UK, and Fight for Sight.


  1. 1.
    Steeg PS, Bevilacqua G, Kopper L, Thorgeirsson UP, Talmadge JE, Liotta LA, Sobel ME (1988) Evidence for a novel gene associated with low tumor metastatic potential. J Natl Cancer Inst 80:200–204. doi: 10.1093/jnci/80.3.200 PubMedCrossRefGoogle Scholar
  2. 2.
    Garzia L, Roma C, Tata N, Pagnozzi D, Pucci P, Zollo M (2006) H-prune-nm23-H1 protein complex and correlation to pathways in cancer metastasis. J Bioenerg Biomembr 38:205–213. doi: 10.1007/s10863-006-9036-z PubMedCrossRefGoogle Scholar
  3. 3.
    Ouatas T, Salerno M, Palmieri D, Steeg PS (2003) Basic and translational advances in cancer metastasis: Nm23. J Bioenerg Biomembr 35:73–79. doi: 10.1023/A:1023497924277 PubMedCrossRefGoogle Scholar
  4. 4.
    Leone A, Flatow U, King CR, Sandeen MA, Margulies IM, Liotta LA, Steeg PS (1991) Reduced tumor incidence, metastatic potential, and cytokine responsiveness of nm23-transfected melanoma cells. Cell 65:25–35. doi: 10.1016/0092-8674(91)90404-M PubMedCrossRefGoogle Scholar
  5. 5.
    Leone A, Flatow U, VanHoutte K, Steeg PS (1993) Transfection of human nm23-H1 into the human MDA-MB-435 breast carcinoma cell line: effects on tumor metastatic potential, colonization and enzymatic activity. Oncogene 8:2325–2333PubMedGoogle Scholar
  6. 6.
    Miyazaki H, Fukuda M, Ishijima Y, Takagi Y, Iimura T, Negishi A, Hirayama R, Ishikawa N, Amagasa T, Kimura N (1999) Overexpression of nm23-H2/NDP kinase B in a human oral squamous cell carcinoma cell line results in reduced metastasis, differentiated phenotype in the metastatic site, and growth factor-independent proliferative activity in culture. Clin Cancer Res 5:4301–4307PubMedGoogle Scholar
  7. 7.
    Tagashira H, Hamazaki K, Tanaka N, Gao C, Namba M (1998) Reduced metastatic potential and c-myc overexpression of colon adenocarcinoma cells (Colon 26 line) transfected with nm23-R2/rat nucleoside diphosphate kinase alpha isoform. Int J Mol Med 2:65–68PubMedGoogle Scholar
  8. 8.
    Biggs J, Hersperger E, Steeg PS, Liotta LA, Shearn A (1990) A Drosophila gene that is homologous to a mammalian gene associated with tumor metastasis codes for a nucleoside diphosphate kinase. Cell 63:933–940. doi: 10.1016/0092-8674(90)90496-2 PubMedCrossRefGoogle Scholar
  9. 9.
    MacDonald NJ, De la Rosa A, Benedict MA, Freije JM, Krutsch H, Steeg PS (1993) A serine phosphorylation of Nm23, and not its nucleoside diphosphate kinase activity, correlates with suppression of tumor metastatic potential. J Biol Chem 268:25780–25789PubMedGoogle Scholar
  10. 10.
    Hartsough MT, Morrison DK, Salerno M, Palmieri D, Ouatas T, Mair M, Patrick J, Steeg PS (2002) Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J Biol Chem 277:32389–32399. doi: 10.1074/jbc.M203115200 PubMedCrossRefGoogle Scholar
  11. 11.
    Wagner PD, Vu ND (2000) Phosphorylation of geranyl and farnesyl pyrophosphates by Nm23 proteins/nucleoside diphosphate kinases. J Biol Chem 275:35570–35576. doi: 10.1074/jbc.M006106200 PubMedCrossRefGoogle Scholar
  12. 12.
    Hippe HJ, Wieland T (2006) High energy phosphate transfer by NDPK B/Gbetagammacomplexes—an alternative signaling pathway involved in the regulation of basal cAMP production. J Bioenerg Biomembr 38:197–203. doi: 10.1007/s10863-006-9035-0 PubMedCrossRefGoogle Scholar
  13. 13.
    Srivastava S, Li Z, Ko K, Choudhury P, Albaqumi M, Johnson AK, Yan Y, Backer JM, Unutmaz D, Coetzee WA, Skolnik EY (2006) Histidine phosphorylation of the potassium channel KCa3.1 by nucleoside diphosphate kinase B is required for activation of KCa3.1 and CD4 T cells. Mol Cell 24:665–675. doi: 10.1016/j.molcel.2006.11.012 PubMedCrossRefGoogle Scholar
  14. 14.
    Postel EH, Berberich SJ, Flint SJ, Ferrone CA (1993) Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261:478–480. doi: 10.1126/science.8392752 PubMedCrossRefGoogle Scholar
  15. 15.
    Ma D, Xing Z, Liu B, Pedigo NG, Zimmer SG, Bai Z, Postel EH, Kaetzel DM (2002) NM23-H1 and NM23-H2 repress transcriptional activities of nuclease-hypersensitive elements in the platelet-derived growth factor-A promoter. J Biol Chem 277:1560–1567. doi: 10.1074/jbc.M108359200 PubMedCrossRefGoogle Scholar
  16. 16.
    Cheng S, Alfonso-Jaume MA, Mertens PR, Lovett DH (2002) Tumour metastasis suppressor, nm23-beta, inhibits gelatinase A transcription by interference with transactivator Y-box protein-1 (YB-1). Biochem J 366:807–816PubMedGoogle Scholar
  17. 17.
    Hildebrandt M, Lacombe ML, Mesnildrey S, Veron M (1995) A human NDP-kinase B specifically binds single-stranded poly-pyrimidine sequences. Nucleic Acids Res 23:3858–3864. doi: 10.1093/nar/23.19.3858 PubMedCrossRefGoogle Scholar
  18. 18.
    Postel EH (1999) Cleavage of DNA by human NM23-H2/nucleoside diphosphate kinase involves formation of a covalent protein-DNA complex. J Biol Chem 274:22821–22829. doi: 10.1074/jbc.274.32.22821 PubMedCrossRefGoogle Scholar
  19. 19.
    Ma D, McCorkle JR, Kaetzel DM (2004) The metastasis suppressor NM23-H1 possesses 3′–5′ exonuclease activity. J Biol Chem 279:18073–18084. doi: 10.1074/jbc.M400185200 PubMedCrossRefGoogle Scholar
  20. 20.
    Fan Z, Beresford PJ, Oh DY, Zhang D, Lieberman J (2003) Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-mediated apoptosis, and the nucleosome assembly protein SET is its inhibitor. Cell 112:659–672. doi: 10.1016/S0092-8674(03)00150-8 PubMedCrossRefGoogle Scholar
  21. 21.
    Roymans D, Vissenberg K, De Jonghe C, Willems R, Engler G, Kimura N, Grobben B, Claes P, Verbelen JP, Van Broeckhoven C, Slegers H (2001) Identification of the tumor metastasis suppressor Nm23-H1/Nm23-R1 as a constituent of the centrosome. Exp Cell Res 262:145–153. doi: 10.1006/excr.2000.5087 PubMedCrossRefGoogle Scholar
  22. 22.
    Du J, Hannon GJ (2002) The centrosomal kinase Aurora-A/STK15 interacts with a putative tumor suppressor NM23-H1. Nucleic Acids Res 30:5465–5475. doi: 10.1093/nar/gkf678 PubMedCrossRefGoogle Scholar
  23. 23.
    Fournier HN, Dupe-Manet S, Bouvard D, Lacombe ML, Marie C, Block MR, Albiges-Rizo C (2002) Integrin cytoplasmic domain-associated protein 1alpha (ICAP-1alpha) interacts directly with the metastasis suppressor nm23-H2, and both proteins are targeted to newly formed cell adhesion sites upon integrin engagement. J Biol Chem 277:20895–20902. doi: 10.1074/jbc.M200200200 PubMedCrossRefGoogle Scholar
  24. 24.
    Dammai V, Adryan B, Lavenburg KR, Hsu T (2003) Drosophila awd, the homolog of human nm23, regulates FGF receptor levels and functions synergistically with shi/dynamin during tracheal development. Genes Dev 17:2812–2824. doi: 10.1101/gad.1096903 PubMedCrossRefGoogle Scholar
  25. 25.
    Krishnan KS, Rikhy R, Rao S, Shivalkar M, Mosko M, Narayanan R, Etter P, Estes PS, Ramaswami M (2001) Nucleoside diphosphate kinase, a source of GTP, is required for dynamin-dependent synaptic vesicle recycling. Neuron 30:197–210. doi: 10.1016/S0896-6273(01)00273-2 PubMedCrossRefGoogle Scholar
  26. 26.
    Rochdi MD, Laroche G, Dupre E, Giguere P, Lebel A, Watier V, Hamelin E, Lepine MC, Dupuis G, Parent JL (2004) Nm23-H2 interacts with a G protein-coupled receptor to regulate its endocytosis through an Rac1-dependent mechanism. J Biol Chem 279:18981–18989. doi: 10.1074/jbc.M312621200 PubMedCrossRefGoogle Scholar
  27. 27.
    Dearolf CR, Hersperger E, Shearn A (1988) Developmental consequences of awdb3, a cell-autonomous lethal mutation of Drosophila induced by hybrid dysgenesis. Dev Biol 129:159–168. doi: 10.1016/0012-1606(88)90170-4 PubMedCrossRefGoogle Scholar
  28. 28.
    Biggs J, Tripoulas N, Hersperger E, Dearolf C, Shearn A (1988) Analysis of the lethal interaction between the prune and Killer of prune mutations of Drosophila. Genes Dev 2:1333–1343. doi: 10.1101/gad.2.10.1333 PubMedCrossRefGoogle Scholar
  29. 29.
    Munoz-Dorado J, Inouye M, Inouye S (1990) Nucleoside diphosphate kinase from Myxococcus xanthus. I. Cloning and sequencing of the gene. J Biol Chem 265:2702–2706PubMedGoogle Scholar
  30. 30.
    Lacombe ML, Wallet V, Troll H, Veron M (1990) Functional cloning of a nucleoside diphosphate kinase from Dictyostelium discoideum. J Biol Chem 265:10012–10018PubMedGoogle Scholar
  31. 31.
    Fraser CM, Gocayne JD, White O, Adams MD, Clayton RA, Fleischmann RD, Bult CJ, Kerlavage AR, Sutton G, Kelley JM, Fritchman RD, Weidman JF, Small KV, Sandusky M, Fuhrmann J, Nguyen D, Utterback TR, Saudek DM, Phillips CA, Merrick JM, Tomb JF, Dougherty BA, Bott KF, Hu PC, Lucier TS, Peterson SN, Smith HO, Hutchison CA III, Venter JC (1995) The minimal gene complement of Mycoplasma genitalium. Science 270:397–403. doi: 10.1126/science.270.5235.397 PubMedCrossRefGoogle Scholar
  32. 32.
    Troll H, Winckler T, Lascu I, Muller N, Saurin W, Veron M, Mutzel R (1993) Separate nuclear genes encode cytosolic and mitochondrial nucleoside diphosphate kinase in Dictyostelium discoideum. J Biol Chem 268:25469–25475PubMedGoogle Scholar
  33. 33.
    Mochizuki T, Bilitou A, Waters CT, Hussain K, Zollo M, Ohnuma S (2009) Xenopus NM23-X4 regulates retinal gliogenesis through interaction with p27Xic1. Neural Develop 4(1):1. doi: 10.1186/1749-8104-4-1 CrossRefGoogle Scholar
  34. 34.
    Ouatas T, Abdallah B, Gasmi L, Bourdais J, Postel E, Mazabraud A (1997) Three different genes encode NM23/nucleoside diphosphate kinases in Xenopus laevis. Gene 194:215–225. doi: 10.1016/S0378-1119(97)00160-1 PubMedCrossRefGoogle Scholar
  35. 35.
    Ouatas T, Selo M, Sadji Z, Hourdry J, Denis H, Mazabraud A (1998) Differential expression of nucleoside diphosphate kinases (NDPK/NM23) during Xenopus early development. Int J Dev Biol 42:43–52PubMedGoogle Scholar
  36. 36.
    Lee JS, Lee SH (2000) Cloning and characterization of cDNA encoding zebrafish Danio rerio NM23-B gene. Gene 245:75–79. doi: 10.1016/S0378-1119(00)00037-8 PubMedCrossRefGoogle Scholar
  37. 37.
    Murphy M, Harte T, McInerney J, Smith TJ (2000) Molecular cloning of an Atlantic salmon nucleoside diphosphate kinase cDNA and its pattern of expression during embryogenesis. Gene 257:139–148. doi: 10.1016/S0378-1119(00)00374-7 PubMedCrossRefGoogle Scholar
  38. 38.
    Ishikawa N, Shimada N, Takagi Y, Ishijima Y, Fukuda M, Kimura N (2003) Molecular evolution of nucleoside diphosphate kinase genes: conserved core structures and multiple-layered regulatory regions. J Bioenerg Biomembr 35:7–18. doi: 10.1023/A:1023433504713 PubMedCrossRefGoogle Scholar
  39. 39.
    Xu J, Liu LZ, Deng XF, Timmons L, Hersperger E, Steeg PS, Veron M, Shearn A (1996) The enzymatic activity of Drosophila AWD/NDP kinase is necessary but not sufficient for its biological function. Dev Biol 177:544–557. doi: 10.1006/dbio.1996.0184 CrossRefGoogle Scholar
  40. 40.
    Putnam NH, Srivastava M, Hellsten U, Dirks B, Chapman J, Salamov A, Terry A, Shapiro H, Lindquist E, Kapitonov VV, Jurka J, Genikhovich G, Grigoriev IV, Lucas SM, Steele RE, Finnerty JR, Technau U, Martindale MQ, Rokhsar DS (2007) Sea anemone genome reveals ancestral eumetazoan gene repertoire and genomic organization. Science 317:86–94. doi: 10.1126/science.1139158 PubMedCrossRefGoogle Scholar
  41. 41.
    Srivastava M, Begovic E, Chapman J, Putnam NH, Hellsten U, Kawashima T, Kuo A, Mitros T, Salamov A, Carpenter ML, Signorovitch AY, Moreno MA, Kamm K, Grimwood J, Schmutz J, Shapiro H, Grigoriev IV, Buss LW, Schierwater B, Dellaporta SL, Rokhsar DS (2008) The trichoplax genome and the nature of placozoans. Nature 454:955–960. doi: 10.1038/nature07191 PubMedCrossRefGoogle Scholar
  42. 42.
    Tsuiki H, Nitta M, Furuya A, Hanai N, Fujiwara T, Inagaki M, Kochi M, Ushio Y, Saya H, Nakamura H (1999) A novel human nucleoside diphosphate (NDP) kinase, Nm23-H6, localizes in mitochondria and affects cytokinesis. J Cell Biochem 76:254–269. doi: 10.1002/(SICI)1097-4644(20000201)76:2<254::AID-JCB9>3.0.CO;2-G PubMedCrossRefGoogle Scholar
  43. 43.
    Gonin P, Xu Y, Milon L, Dabernat S, Morr M, Kumar R, Lacombe ML, Janin J, Lascu I (1999) Catalytic mechanism of nucleoside diphosphate kinase investigated using nucleotide analogues, viscosity effects, and X-ray crystallography. Biochemistry 38:7265–7272. doi: 10.1021/bi982990v PubMedCrossRefGoogle Scholar
  44. 44.
    Freije JM, Blay P, MacDonald NJ, Manrow RE, Steeg PS (1997) Site-directed mutation of Nm23-H1. Mutations lacking motility suppressive capacity upon transfection are deficient in histidine-dependent protein phosphotransferase pathways in vitro. J Biol Chem 272:5525–5532. doi: 10.1074/jbc.272.9.5525 PubMedCrossRefGoogle Scholar
  45. 45.
    Webb PA, Perisic O, Mendola CE, Backer JM, Williams RL (1995) The crystal structure of a human nucleoside diphosphate kinase, NM23-H2. J Mol Biol 251:574–587. doi: 10.1006/jmbi.1995.0457 PubMedCrossRefGoogle Scholar
  46. 46.
    Wagner PD, Vu ND (1995) Phosphorylation of ATP-citrate lyase by nucleoside diphosphate kinase. J Biol Chem 270:21758–21764. doi: 10.1074/jbc.270.37.21758 PubMedCrossRefGoogle Scholar
  47. 47.
    Wagner PD, Vu ND (2000) Histidine to aspartate phosphotransferase activity of nm23 proteins: phosphorylation of aldolase C on Asp-319. Biochem J 346(Pt 3):623–630. doi: 10.1042/0264-6021:3460623 PubMedCrossRefGoogle Scholar
  48. 48.
    Stock AM, Robinson VL, Goudreau PN (2000) Two-component signal transduction. Annu Rev Biochem 69:183–215. doi: 10.1146/annurev.biochem.69.1.183 PubMedCrossRefGoogle Scholar
  49. 49.
    Postel EH, Abramczyk BM, Levit MN, Kyin S (2000) Catalysis of DNA cleavage and nucleoside triphosphate synthesis by NM23-H2/NDP kinase share an active site that implies a DNA repair function. Proc Natl Acad Sci USA 97:14194–14199. doi: 10.1073/pnas.97.26.14194 PubMedCrossRefGoogle Scholar
  50. 50.
    Chen Y, Gallois-Montbrun S, Schneider B, Veron M, Morera S, Deville-Bonne D, Janin J (2003) Nucleotide binding to nucleoside diphosphate kinases: X-ray structure of human NDPK-A in complex with ADP and comparison to protein kinases. J Mol Biol 332:915–926. doi: 10.1016/j.jmb.2003.07.004 PubMedCrossRefGoogle Scholar
  51. 51.
    Dumas C, Lebras G, Wallet V, Lacombe ML, Veron M, Janin J (1991) Crystallization and preliminary X-ray diffraction studies of nucleoside diphosphate kinase from Dictyostelium discoideum. J Mol Biol 217:239–240. doi: 10.1016/0022-2836(91)90537-G PubMedCrossRefGoogle Scholar
  52. 52.
    Lascu I, Chaffotte A, Limbourg-Bouchon B, Veron M (1992) A Pro/Ser substitution in nucleoside diphosphate kinase of Drosophila melanogaster (mutation killer of prune) affects stability but not catalytic efficiency of the enzyme. J Biol Chem 267:12775–12781PubMedGoogle Scholar
  53. 53.
    Lascu I, Deville-Bonne D, Glaser P, Veron M (1993) Equilibrium dissociation and unfolding of nucleoside diphosphate kinase from Dictyostelium discoideum. Role of proline 100 in the stability of the hexameric enzyme. J Biol Chem 268:20268–20275PubMedGoogle Scholar
  54. 54.
    Lombardi D, Mileo AM (2003) Protein interactions provide new insight into Nm23/nucleoside diphosphate kinase functions. J Bioenerg Biomembr 35:67–71. doi: 10.1023/A:1023445907439 PubMedCrossRefGoogle Scholar
  55. 55.
    Reymond A, Volorio S, Merla G, Al-Maghtheh M, Zuffardi O, Bulfone A, Ballabio A, Zollo M (1999) Evidence for interaction between human PRUNE and nm23-H1 NDPKinase. Oncogene 18:7244–7252. doi: 10.1038/sj.onc.1203140 PubMedCrossRefGoogle Scholar
  56. 56.
    Barraud P, Amrein L, Dobremez E, Dabernat S, Masse K, Larou M, Daniel JY, Landry M (2002) Differential expression of nm23 genes in adult mouse dorsal root ganglia. J Comp Neurol 444:306–323. doi: 10.1002/cne.10150 PubMedCrossRefGoogle Scholar
  57. 57.
    Mitchell KA, Gallagher BC, Szabo G, Otero Ade S (2004) NDP kinase moves into developing primary cilia. Cell Motil Cytoskeleton 59:62–73. doi: 10.1002/cm.20025 PubMedCrossRefGoogle Scholar
  58. 58.
    Lutz S, Mura RA, Hippe HJ, Tiefenbacher C, Niroomand F (2003) Plasma membrane-associated nucleoside diphosphate kinase (nm23) in the heart is regulated by beta-adrenergic signaling. Br J Pharmacol 140:1019–1026. doi: 10.1038/sj.bjp.0705527 PubMedCrossRefGoogle Scholar
  59. 59.
    Okabe-Kado J, Kasukabe T, Honma Y, Hanada R, Nakagawara A, Kaneko Y (2005) Clinical significance of serum NM23-H1 protein in neuroblastoma. Cancer Sci 96:653–660. doi: 10.1111/j.1349-7006.2005.00091.x PubMedCrossRefGoogle Scholar
  60. 60.
    Milon L, Meyer P, Chiadmi M, Munier A, Johansson M, Karlsson A, Lascu I, Capeau J, Janin J, Lacombe ML (2000) The human nm23-H4 gene product is a mitochondrial nucleoside diphosphate kinase. J Biol Chem 275:14264–14272. doi: 10.1074/jbc.275.19.14264 PubMedCrossRefGoogle Scholar
  61. 61.
    Amrein L, Barraud P, Daniel JY, Perel Y, Landry M (2005) Expression patterns of nm23 genes during mouse organogenesis. Cell Tissue Res 322:365–378. doi: 10.1007/s00441-005-0036-9 PubMedCrossRefGoogle Scholar
  62. 62.
    Lakso M, Steeg PS, Westphal H (1992) Embryonic expression of nm23 during mouse organogenesis. Cell Growth Differ 3:873–879PubMedGoogle Scholar
  63. 63.
    Hwang KC, Ok DW, Hong JC, Kim MO, Kim JH (2003) Cloning, sequencing, and characterization of the murine nm23-M5 gene during mouse spermatogenesis and spermiogenesis. Biochem Biophys Res Commun 306:198–207. doi: 10.1016/S0006-291X(03)00916-1 PubMedCrossRefGoogle Scholar
  64. 64.
    Munier A, Serres C, Kann ML, Boissan M, Lesaffre C, Capeau J, Fouquet JP, Lacombe ML (2003) Nm23/NDP kinases in human male germ cells: role in spermiogenesis and sperm motility? Exp Cell Res 289:295–306. doi: 10.1016/S0014-4827(03)00268-4 PubMedCrossRefGoogle Scholar
  65. 65.
    Munier A, Feral C, Milon L, Pinon VP, Gyapay G, Capeau J, Guellaen G, Lacombe ML (1998) A new human nm23 homologue (nm23-H5) specifically expressed in testis germinal cells. FEBS Lett 434:289–294. doi: 10.1016/S0014-5793(98)00996-X PubMedCrossRefGoogle Scholar
  66. 66.
    Mehus JG, Deloukas P, Lambeth DO (1999) NME6: a new member of the nm23/nucleoside diphosphate kinase gene family located on human chromosome 3p21.3. Hum Genet 104:454–459. doi: 10.1007/s004390050987 PubMedCrossRefGoogle Scholar
  67. 67.
    Wallet V, Mutzel R, Troll H, Barzu O, Wurster B, Veron M, Lacombe ML (1990) Dictyostelium nucleoside diphosphate kinase highly homologous to Nm23 and Awd proteins involved in mammalian tumor metastasis and Drosophila development. J Natl Cancer Inst 82:1199–1202. doi: 10.1093/jnci/82.14.1199 PubMedCrossRefGoogle Scholar
  68. 68.
    Rosengard AM, Krutzsch HC, Shearn A, Biggs JR, Barker E, Margulies IM, King CR, Liotta LA, Steeg PS (1989) Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development. Nature 342:177–180. doi: 10.1038/342177a0 PubMedCrossRefGoogle Scholar
  69. 69.
    Timmons L, Hersperger E, Woodhouse E, Xu J, Liu LZ, Shearn A (1993) The expression of the Drosophila awd gene during normal development and in neoplastic brain tumors caused by lgl mutations. Dev Biol 158:364–379. doi: 10.1006/dbio.1993.1195 PubMedCrossRefGoogle Scholar
  70. 70.
    Eggenschwiler JT, Anderson KV (2007) Cilia and developmental signaling. Annu Rev Cell Dev Biol 23:345–373. doi: 10.1146/annurev.cellbio.23.090506.123249 PubMedCrossRefGoogle Scholar
  71. 71.
    Lombardi D, Sacchi A, D’Agostino G, Tibursi G (1995) The association of the Nm23-M1 protein and beta-tubulin correlates with cell differentiation. Exp Cell Res 217:267–271. doi: 10.1006/excr.1995.1086 PubMedCrossRefGoogle Scholar
  72. 72.
    Pinon VP, Millot G, Munier A, Vassy J, Linares-Cruz G, Capeau J, Calvo F, Lacombe ML (1999) Cytoskeletal association of the A and B nucleoside diphosphate kinases of interphasic but not mitotic human carcinoma cell lines: specific nuclear localization of the B subunit. Exp Cell Res 246:355–367. doi: 10.1006/excr.1998.4318 PubMedCrossRefGoogle Scholar
  73. 73.
    Otsuki Y, Tanaka M, Yoshii S, Kawazoe N, Nakaya K, Sugimura H (2001) Tumor metastasis suppressor nm23H1 regulates Rac1 GTPase by interaction with Tiam1. Proc Natl Acad Sci USA 98:4385–4390. doi: 10.1073/pnas.071411598 PubMedCrossRefGoogle Scholar
  74. 74.
    Okabe-Kado J (1992) Factors inhibiting differentiation of myeloid leukemia cells. Crit Rev Oncog 3:293–319PubMedGoogle Scholar
  75. 75.
    Okabe-Kado J, Kasukabe T, Baba H, Urano T, Shiku H, Honma Y (1995) Inhibitory action of nm23 proteins on induction of erythroid differentiation of human leukemia cells. Biochim Biophys Acta 1267:101–106. doi: 10.1016/0167-4889(95)00037-S PubMedCrossRefGoogle Scholar
  76. 76.
    Martinez R, Venturelli D, Perrotti D, Veronese ML, Kastury K, Druck T, Huebner K, Calabretta B (1997) Gene structure, promoter activity, and chromosomal location of the DR-nm23 gene, a related member of the nm23 gene family. Cancer Res 57:1180–1187PubMedGoogle Scholar
  77. 77.
    Gervasi F, D’Agnano I, Vossio S, Zupi G, Sacchi A, Lombardi D (1996) nm23 influences proliferation and differentiation of PC12 cells in response to nerve growth factor. Cell Growth Differ 7:1689–1695PubMedGoogle Scholar
  78. 78.
    Ishijima Y, Shimada N, Fukuda M, Miyazaki H, Orlov NY, Orlova TG, Yamada T, Kimura N (1999) Overexpression of nucleoside diphosphate kinases induces neurite outgrowth and their substitution to inactive forms leads to suppression of nerve growth factor- and dibutyryl cyclic AMP-induced effects in PC12D cells. FEBS Lett 445:155–159. doi: 10.1016/S0014-5793(99)00116-7 PubMedCrossRefGoogle Scholar
  79. 79.
    Nguyen L, Besson A, Heng JI, Schuurmans C, Teboul L, Parras C, Philpott A, Roberts JM, Guillemot F (2006) p27kip1 independently promotes neuronal differentiation and migration in the cerebral cortex. Genes Dev 20:1511–1524. doi: 10.1101/gad.377106 PubMedCrossRefGoogle Scholar
  80. 80.
    Yokoo T, Toyoshima H, Miura M, Wang Y, Iida KT, Suzuki H, Sone H, Shimano H, Gotoda T, Nishimori S, Tanaka K, Yamada N (2003) p57Kip2 regulates actin dynamics by binding and translocating LIM-kinase 1 to the nucleus. J Biol Chem 278:52919–52923. doi: 10.1074/jbc.M309334200 PubMedCrossRefGoogle Scholar
  81. 81.
    Besson A, Gurian-West M, Schmidt A, Hall A, Roberts JM (2004) p27Kip1 modulates cell migration through the regulation of RhoA activation. Genes Dev 18:862–876. doi: 10.1101/gad.1185504 PubMedCrossRefGoogle Scholar
  82. 82.
    Lee S, Helfman DM (2004) Cytoplasmic p21Cip1 is involved in Ras-induced inhibition of the ROCK/LIMK/cofilin pathway. J Biol Chem 279:1885–1891. doi: 10.1074/jbc.M306968200 PubMedCrossRefGoogle Scholar
  83. 83.
    Baldassarre G, Belletti B, Nicoloso MS, Schiappacassi M, Vecchione A, Spessotto P, Morrione A, Canzonieri V, Colombatti A (2005) p27(Kip1)-stathmin interaction influences sarcoma cell migration and invasion. Cancer Cell 7:51–63. doi: 10.1016/j.ccr.2004.11.025 PubMedCrossRefGoogle Scholar
  84. 84.
    Ruchhoeft ML, Ohnuma S, McNeill L, Holt CE, Harris WA (1999) The neuronal architecture of Xenopus retinal ganglion cells is sculpted by rho-family GTPases in vivo. J Neurosci 19:8454–8463PubMedGoogle Scholar
  85. 85.
    Baillat G, Gaillard S, Castets F, Monneron A (2002) Interactions of phocein with nucleoside-diphosphate kinase, Eps15, and Dynamin I. J Biol Chem 277:18961–18966. doi: 10.1074/jbc.M108818200 PubMedCrossRefGoogle Scholar
  86. 86.
    Cremisi F, Philpott A, Ohnuma S (2003) Cell cycle and cell fate interactions in neural development. Curr Opin Neurobiol 13:26–33. doi: 10.1016/S0959-4388(03)00005-9 PubMedCrossRefGoogle Scholar
  87. 87.
    Ohnuma S, Harris WA (2003) Neurogenesis and the cell cycle. Neuron 40:199–208. doi: 10.1016/S0896-6273(03)00632-9 PubMedCrossRefGoogle Scholar
  88. 88.
    Ohnuma S, Hopper S, Wang KC, Philpott A, Harris WA (2002) Co-ordinating retinal histogenesis: early cell cycle exit enhances early cell fate determination in the Xenopus retina. Development 129:2435–2446PubMedGoogle Scholar
  89. 89.
    Howlett AR, Petersen OW, Steeg PS, Bissell MJ (1994) A novel function for the nm23-H1 gene: overexpression in human breast carcinoma cells leads to the formation of basement membrane and growth arrest. J Natl Cancer Inst 86:1838–1844. doi: 10.1093/jnci/86.24.1838 PubMedCrossRefGoogle Scholar
  90. 90.
    Braun S, Mauch C, Boukamp P, Werner S (2007) Novel roles of NM23 proteins in skin homeostasis, repair and disease. Oncogene 26:532–542. doi: 10.1038/sj.onc.1209822 PubMedCrossRefGoogle Scholar
  91. 91.
    Amendola R, Martinez R, Negroni A, Venturelli D, Tanno B, Calabretta B, Raschella G (1997) DR-nm23 gene expression in neuroblastoma cells: relationship to integrin expression, adhesion characteristics, and differentiation. J Natl Cancer Inst 89:1300–1310. doi: 10.1093/jnci/89.17.1300 PubMedCrossRefGoogle Scholar
  92. 92.
    Bosnar MH, De Gunzburg J, Bago R, Brecevic L, Weber I, Pavelic J (2004) Subcellular localization of A and B Nm23/NDPK subunits. Exp Cell Res 298:275–284. doi: 10.1016/j.yexcr.2004.04.018 PubMedCrossRefGoogle Scholar
  93. 93.
    Nallamothu G, Woolworth JA, Dammai V, Hsu T (2008) Awd, the homolog of metastasis suppressor gene Nm23, regulates Drosophila epithelial cell invasion. Mol Cell Biol 28:1964–1973. doi: 10.1128/MCB.01743-07 PubMedCrossRefGoogle Scholar
  94. 94.
    Kim SY, Ferrell JE Jr, Chae SK, Lee KJ (2000) Inhibition of progesterone-induced Xenopus oocyte maturation by Nm23. Cell Growth Differ 11:485–490PubMedGoogle Scholar
  95. 95.
    Sadek CM, Damdimopoulos AE, Pelto-Huikko M, Gustafsson JA, Spyrou G, Miranda-Vizuete A (2001) Sptrx-2, a fusion protein composed of one thioredoxin and three tandemly repeated NDP-kinase domains is expressed in human testis germ cells. Genes Cells 6:1077–1090. doi: 10.1046/j.1365-2443.2001.00484.x PubMedCrossRefGoogle Scholar
  96. 96.
    Guyon F, Marnet B, Arnaud-Dabernat S, Carles D, Mathieu C, Saura R, Perel Y, Horovitz J, Landry M, Bischof P, Daniel JY (2004) Differential expression of the nm23 genes in the developing human trophoblast. Placenta 25:20–28. doi: 10.1016/j.placenta.2003.08.003 PubMedCrossRefGoogle Scholar
  97. 97.
    Wei SJ, Trempus CS, Ali RC, Hansen LA, Tennant RW (2004) 12-O-tetradecanoylphorbol-13-acetate and UV radiation-induced nucleoside diphosphate protein kinase B mediates neoplastic transformation of epidermal cells. J Biol Chem 279:5993–6004. doi: 10.1074/jbc.M310820200 PubMedCrossRefGoogle Scholar
  98. 98.
    Gromov P, Skovgaard GL, Palsdottir H, Gromova I, Ostergaard M, Celis JE (2003) Protein profiling of the human epidermis from the elderly reveals up-regulation of a signature of interferon-gamma-induced polypeptides that includes manganese-superoxide dismutase and the p85beta subunit of phosphatidylinositol 3-kinase. Mol Cell Proteomics 2:70–84. doi: 10.1074/mcp.M200051-MCP200 PubMedCrossRefGoogle Scholar
  99. 99.
    Clamp M, Cuff J, Searle SM, Barton GJ (2004) The Jalview Java alignment editor. Bioinformatics 20:426–427. doi: 10.1093/bioinformatics/btg430 PubMedCrossRefGoogle Scholar
  100. 100.
    Huson DH, Bryant D (2006) Application of phylogenetic networks in evolutionary studies. Mol Biol Evol 23:254–267. doi: 10.1093/molbev/msj030 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Aikaterini Bilitou
    • 1
  • Julie Watson
    • 1
  • Anton Gartner
    • 2
  • Shin-ichi Ohnuma
    • 1
    • 3
  1. 1.Department of Oncology, Hutchison/MRC Research CentreUniversity of CambridgeCambridgeUK
  2. 2.Wellcome Trust Centre for Gene Regulation and ExpressionUniversity of DundeeDundeeUK
  3. 3.UCL Institute of OphthalmologyUniversity College LondonLondonUK

Personalised recommendations