Full text data of NME1
NME1
(NDPKA, NM23)
[Confidence: low (only semi-automatic identification from reviews)]
Nucleoside diphosphate kinase A; NDK A; NDP kinase A; 2.7.4.6 (Granzyme A-activated DNase; GAAD; Metastasis inhibition factor nm23; Tumor metastatic process-associated protein; nm23-H1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Nucleoside diphosphate kinase A; NDK A; NDP kinase A; 2.7.4.6 (Granzyme A-activated DNase; GAAD; Metastasis inhibition factor nm23; Tumor metastatic process-associated protein; nm23-H1)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P15531
ID NDKA_HUMAN Reviewed; 152 AA.
AC P15531; Q6FGK3; Q86XQ2; Q9UDJ6;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Nucleoside diphosphate kinase A;
DE Short=NDK A;
DE Short=NDP kinase A;
DE EC=2.7.4.6;
DE AltName: Full=Granzyme A-activated DNase;
DE Short=GAAD;
DE AltName: Full=Metastasis inhibition factor nm23;
DE AltName: Full=Tumor metastatic process-associated protein;
DE AltName: Full=nm23-H1;
GN Name=NME1; Synonyms=NDPKA, NM23;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2509941; DOI=10.1038/342177a0;
RA Rosengard A.M., Krutzsch H.C., Shearn A., Biggs J.R., Barker E.,
RA Margulies I.M.K., King C.R., Liotta L.A., Steeg P.S.;
RT "Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila
RT development.";
RL Nature 342:177-180(1989).
RN [2]
RP PROTEIN SEQUENCE (ISOFORM 1), SUBUNIT, AND ACTIVE SITE.
RX PubMed=1851158;
RA Gilles A.-M., Presecan E., Vonica A., Lascu I.;
RT "Nucleoside diphosphate kinase from human erythrocytes. Structural
RT characterization of the two polypeptide chains responsible for
RT heterogeneity of the hexameric enzyme.";
RL J. Biol. Chem. 266:8784-8789(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=7916650;
RA Wang L., Patel U., Ghosh L., Chen H.C., Banerjee S.;
RT "Mutation in the nm23 gene is associated with metastasis in colorectal
RT cancer.";
RL Cancer Res. 53:717-720(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=8270257; DOI=10.1007/BF00218915;
RA Dooley S., Seib T., Engel M., Theisinger B., Janz H., Piontek K.,
RA Zang K.D., Welter C.;
RT "Isolation and characterization of the human genomic locus coding for
RT the putative metastasis control gene nm23-H1.";
RL Hum. Genet. 93:63-66(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=12601555; DOI=10.1007/s100380300014;
RA Ni X., Gu S., Dai J., Cheng H., Guo L., Li L., Ji C., Xie Y., Ying K.,
RA Mao Y.;
RT "Isolation and characterization of a novel human NM23-H1B gene, a
RT different transcript of NM23-H1.";
RL J. Hum. Genet. 48:96-100(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 7-18; 40-49 AND 89-94 (ISOFORMS 1/2), AND
RP DISCUSSION OF THE ROLE IN TUMOR PROGRESSION.
RC TISSUE=Neuroblastoma;
RX PubMed=2056128; DOI=10.1172/JCI115299;
RA Hailat N., Keim D.R., Melhem R.F., Zhu X.X., Eckerskorn C.,
RA Brodeur G.M., Reynolds C.P., Seeger R.C., Lottspeich F.,
RA Strahler J.R., Hanash S.J.;
RT "High levels of p19/nm23 protein in neuroblastoma are associated with
RT advanced stage disease and with N-myc gene amplification.";
RL J. Clin. Invest. 88:341-345(1991).
RN [12]
RP PROTEIN SEQUENCE OF 7-26; 40-49; 57-85 AND 89-128 (ISOFORMS 1/2), AND
RP MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [13]
RP FUNCTION, AND MUTAGENESIS OF PRO-96; HIS-118 AND SER-120.
RX PubMed=8810265; DOI=10.1074/jbc.271.41.25107;
RA MacDonald N.J., Freije J.M., Stracke M.L., Manrow R.E., Steeg P.S.;
RT "Site-directed mutagenesis of nm23-H1. Mutation of proline 96 or
RT serine 120 abrogates its motility inhibitory activity upon
RT transfection into human breast carcinoma cells.";
RL J. Biol. Chem. 271:25107-25116(1996).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=10512675; DOI=10.1006/geno.1999.5939;
RA Manda R., Kohno T., Matsuno Y., Takenoshita S., Kuwano H., Yokota J.;
RT "Identification of genes (SPON2 and C20orf2) differentially expressed
RT between cancerous and noncancerous lung cells by mRNA differential
RT display.";
RL Genomics 61:5-14(1999).
RN [15]
RP FUNCTION, ENZYME REGULATION, AND INTERACTION WITH SET.
RX PubMed=12628186; DOI=10.1016/S0092-8674(03)00150-8;
RA Fan Z., Beresford P.J., Oh D.Y., Zhang D., Lieberman J.;
RT "Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-
RT mediated apoptosis, and the nucleosome assembly protein SET is its
RT inhibitor.";
RL Cell 112:659-672(2003).
RN [16]
RP ALTERNATIVE SPLICING (ISOFORM 3), SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=16442775; DOI=10.1016/j.ygeno.2005.11.004;
RA Valentijn L.J., Koster J., Versteeg R.;
RT "Read-through transcript from NM23-H1 into the neighboring NM23-H2
RT gene encodes a novel protein, NM23-LV.";
RL Genomics 87:483-489(2006).
RN [17]
RP INTERACTION WITH PRUNE.
RX PubMed=17906697; DOI=10.1038/sj.onc.1210822;
RA Garzia L., D'Angelo A., Amoresano A., Knauer S.K., Cirulli C.,
RA Campanella C., Stauber R.H., Steegborn C., Iolascon A., Zollo M.;
RT "Phosphorylation of nm23-H1 by CKI induces its complex formation with
RT h-prune and promotes cell motility.";
RL Oncogene 27:1853-1864(2008).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
RX PubMed=11835509; DOI=10.1002/prot.10038;
RA Min K., Song H.K., Chang C., Kim S.Y., Lee K.J., Suh S.W.;
RT "Crystal structure of human nucleoside diphosphate kinase A, a
RT metastasis suppressor.";
RL Proteins 46:340-342(2002).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), AND MUTAGENESIS OF PHE-60 AND
RP HIS-118.
RX PubMed=12972261; DOI=10.1016/j.jmb.2003.07.004;
RA Chen Y., Gallois-Montbrun S., Schneider B., Veron M., Morera S.,
RA Deville-Bonne D., Janin J.;
RT "Nucleotide binding to nucleoside diphosphate kinases: X-ray structure
RT of human NDPK-A in complex with ADP and comparison to protein
RT kinases.";
RL J. Mol. Biol. 332:915-926(2003).
RN [22]
RP VARIANT GLY-120.
RX PubMed=8047138; DOI=10.1038/370335a0;
RA Chang C.L., Zhu X.-X., Thoraval D.H., Ungar D., Rawwas J., Hora N.,
RA Strahler J.R., Hanash S.M.;
RT "Nm23-H1 mutation in neuroblastoma.";
RL Nature 370:335-336(1994).
CC -!- FUNCTION: Major role in the synthesis of nucleoside triphosphates
CC other than ATP. Possesses nucleoside-diphosphate kinase,
CC serine/threonine-specific protein kinase, geranyl and farnesyl
CC pyrophosphate kinase, histidine protein kinase and 3'-5'
CC exonuclease activities. Involved in cell proliferation,
CC differentiation and development, signal transduction, G protein-
CC coupled receptor endocytosis, and gene expression. Required for
CC neural development including neural patterning and cell fate
CC determination.
CC -!- CATALYTIC ACTIVITY: ATP + nucleoside diphosphate = ADP +
CC nucleoside triphosphate.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Autophosphorylation at His-118 increases
CC serine/threonine protein kinase activity of the enzyme.
CC Interaction with the SET complex inhibits exonuclease activity.
CC -!- SUBUNIT: Hexamer of two different chains: A and B (A6, A5B, A4B2,
CC A3B3, A2B4, AB5, B6). Interacts with SET and PRUNE.
CC -!- INTERACTION:
CC Self; NbExp=4; IntAct=EBI-741141, EBI-741141;
CC Q61097:Ksr1 (xeno); NbExp=7; IntAct=EBI-741141, EBI-1536336;
CC P10911:MCF2; NbExp=4; IntAct=EBI-741141, EBI-1914514;
CC P22392:NME2; NbExp=2; IntAct=EBI-741141, EBI-713693;
CC Q86TP1:PRUNE; NbExp=2; IntAct=EBI-741141, EBI-2127112;
CC Q9Y3F4:STRAP; NbExp=9; IntAct=EBI-741141, EBI-727414;
CC Q96HA8:WDYHV1; NbExp=3; IntAct=EBI-741141, EBI-741158;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cell-cycle
CC dependent nuclear localization which can be induced by interaction
CC with Epstein-barr viral proteins or by degradation of the SET
CC complex by GzmA.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=NM23-H1A;
CC IsoId=P15531-1; Sequence=Displayed;
CC Name=2; Synonyms=NM23-H1B;
CC IsoId=P15531-2; Sequence=VSP_036707;
CC Name=3; Synonyms=NM23-LV;
CC IsoId=P22392-2; Sequence=External;
CC Note=Based on a naturally occurring readthrough transcript which
CC produces an NME1-NME2 fusion protein;
CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in heart, brain,
CC placenta, lung, liver, skeletal muscle, pancreas, spleen and
CC thymus. Expressed in lung carcinoma cell lines but not in normal
CC lung tissues. Isoform 2 is ubiquitously expressed and its
CC expression is also related to tumor differentiation. Isoform 3 is
CC ubiquitously expressed.
CC -!- MISCELLANEOUS: The role of this protein in tumor development and
CC progression is uncertain. This protein is found in reduced amount
CC in some tumor cells of high metastatic potential. However,
CC increased NME1 levels correlate with aggressive tumor features in
CC neuroblastoma. May have distinct if not opposite roles in
CC different tumors.
CC -!- SIMILARITY: Belongs to the NDK family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA35621.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; X17620; CAA35621.1; ALT_INIT; mRNA.
DR EMBL; X73066; CAA51527.1; -; mRNA.
DR EMBL; X75598; CAA53270.1; -; Genomic_DNA.
DR EMBL; AF487339; AAO85436.1; -; mRNA.
DR EMBL; AK291105; BAF83794.1; -; mRNA.
DR EMBL; CR542104; CAG46901.1; -; mRNA.
DR EMBL; CR542115; CAG46912.1; -; mRNA.
DR EMBL; AC005839; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471109; EAW94568.1; -; Genomic_DNA.
DR EMBL; BC000293; AAH00293.1; -; mRNA.
DR EMBL; BC018994; AAH18994.1; -; mRNA.
DR PIR; A33386; A33386.
DR RefSeq; NP_000260.1; NM_000269.2.
DR RefSeq; NP_937818.1; NM_198175.1.
DR UniGene; Hs.463456; -.
DR PDB; 1JXV; X-ray; 2.20 A; A/B/C/D/E/F=1-152.
DR PDB; 1UCN; X-ray; 2.00 A; A/B/C=1-152.
DR PDB; 2HVD; X-ray; 2.15 A; A/B/C=1-152.
DR PDB; 2HVE; X-ray; 2.40 A; A/B/C=1-152.
DR PDB; 3L7U; X-ray; 2.10 A; A/B/C=1-152.
DR PDB; 4ENO; X-ray; 2.80 A; A/B=1-152.
DR PDBsum; 1JXV; -.
DR PDBsum; 1UCN; -.
DR PDBsum; 2HVD; -.
DR PDBsum; 2HVE; -.
DR PDBsum; 3L7U; -.
DR PDBsum; 4ENO; -.
DR ProteinModelPortal; P15531; -.
DR SMR; P15531; 1-152.
DR DIP; DIP-39164N; -.
DR IntAct; P15531; 23.
DR MINT; MINT-221462; -.
DR STRING; 9606.ENSP00000013034; -.
DR ChEMBL; CHEMBL2159; -.
DR DrugBank; DB00441; Gemcitabine.
DR DrugBank; DB00396; Progesterone.
DR PhosphoSite; P15531; -.
DR DMDM; 127981; -.
DR DOSAC-COBS-2DPAGE; P15531; -.
DR OGP; P15531; -.
DR PaxDb; P15531; -.
DR PRIDE; P15531; -.
DR DNASU; 4830; -.
DR Ensembl; ENST00000013034; ENSP00000013034; ENSG00000239672.
DR Ensembl; ENST00000336097; ENSP00000337060; ENSG00000239672.
DR Ensembl; ENST00000393196; ENSP00000376892; ENSG00000239672.
DR GeneID; 4830; -.
DR KEGG; hsa:4830; -.
DR UCSC; uc002iti.2; human.
DR CTD; 4830; -.
DR GeneCards; GC17P049231; -.
DR HGNC; HGNC:7849; NME1.
DR HPA; HPA008467; -.
DR HPA; HPA041113; -.
DR MIM; 156490; gene.
DR neXtProt; NX_P15531; -.
DR PharmGKB; PA249; -.
DR eggNOG; COG0105; -.
DR HOGENOM; HOG000224564; -.
DR HOVERGEN; HBG000423; -.
DR KO; K00940; -.
DR OMA; ARQMMGK; -.
DR OrthoDB; EOG7GJ6FG; -.
DR BioCyc; MetaCyc:ENSG00000011052-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; P15531; -.
DR GeneWiki; NME1; -.
DR GenomeRNAi; 4830; -.
DR NextBio; 18606; -.
DR PRO; PR:P15531; -.
DR ArrayExpress; P15531; -.
DR Bgee; P15531; -.
DR CleanEx; HS_NME1; -.
DR Genevestigator; P15531; -.
DR GO; GO:0005813; C:centrosome; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0032587; C:ruffle membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004536; F:deoxyribonuclease activity; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0004550; F:nucleoside diphosphate kinase activity; IDA:UniProtKB.
DR GO; GO:0043024; F:ribosomal small subunit binding; IPI:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II regulatory region sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003697; F:single-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0071398; P:cellular response to fatty acid; IEA:Ensembl.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0006241; P:CTP biosynthetic process; IEA:InterPro.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0006183; P:GTP biosynthetic process; IEA:InterPro.
DR GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; TAS:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0002762; P:negative regulation of myeloid leukocyte differentiation; IEA:Ensembl.
DR GO; GO:0015949; P:nucleobase-containing small molecule interconversion; TAS:Reactome.
DR GO; GO:0043388; P:positive regulation of DNA binding; IDA:UniProtKB.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IMP:HGNC.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:0014075; P:response to amine stimulus; IEA:Ensembl.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone stimulus; IEA:Ensembl.
DR GO; GO:0006228; P:UTP biosynthetic process; IEA:InterPro.
DR Gene3D; 3.30.70.141; -; 1.
DR InterPro; IPR001564; Nucleoside_diP_kinase.
DR InterPro; IPR023005; Nucleoside_diP_kinase_AS.
DR Pfam; PF00334; NDK; 1.
DR PRINTS; PR01243; NUCDPKINASE.
DR SMART; SM00562; NDK; 1.
DR SUPFAM; SSF54919; SSF54919; 1.
DR PROSITE; PS00469; NDP_KINASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Differentiation;
KW Direct protein sequencing; Endocytosis; Isopeptide bond; Kinase;
KW Magnesium; Metal-binding; Neurogenesis; Nucleotide metabolism;
KW Nucleotide-binding; Nucleus; Polymorphism; Reference proteome;
KW Transferase; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 152 Nucleoside diphosphate kinase A.
FT /FTId=PRO_0000137114.
FT ACT_SITE 118 118 Pros-phosphohistidine intermediate.
FT BINDING 12 12 ATP.
FT BINDING 60 60 ATP.
FT BINDING 88 88 ATP.
FT BINDING 94 94 ATP.
FT BINDING 105 105 ATP.
FT BINDING 115 115 ATP.
FT MOD_RES 2 2 N-acetylalanine.
FT CROSSLNK 100 100 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 1 1 M -> MVLLSTLGIVFQGEGPPISSCDTGTM (in
FT isoform 2).
FT /FTId=VSP_036707.
FT VARIANT 120 120 S -> G (in a neuroblastoma sample;
FT increased motility of carcinoma cells;
FT dbSNP:rs121917887).
FT /FTId=VAR_004625.
FT MUTAGEN 60 60 F->W: No loss of activity or substrate
FT binding.
FT MUTAGEN 96 96 P->S: Increased motility of carcinoma
FT cells.
FT MUTAGEN 118 118 H->F: Loss of serine/threonine kinase
FT activity. Some loss of motility of
FT carcinoma cells.
FT MUTAGEN 118 118 H->G: Loss of activity.
FT MUTAGEN 120 120 S->A: Limited increase in motility of
FT carcinoma cells.
FT HELIX 2 4
FT STRAND 6 11
FT HELIX 13 17
FT HELIX 21 31
FT STRAND 34 41
FT HELIX 45 51
FT HELIX 53 55
FT STRAND 56 58
FT HELIX 61 69
FT STRAND 73 80
FT HELIX 83 91
FT HELIX 96 98
FT HELIX 104 108
FT HELIX 112 114
FT STRAND 116 119
FT HELIX 123 133
FT HELIX 136 138
FT HELIX 147 150
SQ SEQUENCE 152 AA; 17149 MW; AAE9C0DF63CB70A1 CRC64;
MANCERTFIA IKPDGVQRGL VGEIIKRFEQ KGFRLVGLKF MQASEDLLKE HYVDLKDRPF
FAGLVKYMHS GPVVAMVWEG LNVVKTGRVM LGETNPADSK PGTIRGDFCI QVGRNIIHGS
DSVESAEKEI GLWFHPEELV DYTSCAQNWI YE
//
ID NDKA_HUMAN Reviewed; 152 AA.
AC P15531; Q6FGK3; Q86XQ2; Q9UDJ6;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1990, sequence version 1.
DT 22-JAN-2014, entry version 164.
DE RecName: Full=Nucleoside diphosphate kinase A;
DE Short=NDK A;
DE Short=NDP kinase A;
DE EC=2.7.4.6;
DE AltName: Full=Granzyme A-activated DNase;
DE Short=GAAD;
DE AltName: Full=Metastasis inhibition factor nm23;
DE AltName: Full=Tumor metastatic process-associated protein;
DE AltName: Full=nm23-H1;
GN Name=NME1; Synonyms=NDPKA, NM23;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=2509941; DOI=10.1038/342177a0;
RA Rosengard A.M., Krutzsch H.C., Shearn A., Biggs J.R., Barker E.,
RA Margulies I.M.K., King C.R., Liotta L.A., Steeg P.S.;
RT "Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila
RT development.";
RL Nature 342:177-180(1989).
RN [2]
RP PROTEIN SEQUENCE (ISOFORM 1), SUBUNIT, AND ACTIVE SITE.
RX PubMed=1851158;
RA Gilles A.-M., Presecan E., Vonica A., Lascu I.;
RT "Nucleoside diphosphate kinase from human erythrocytes. Structural
RT characterization of the two polypeptide chains responsible for
RT heterogeneity of the hexameric enzyme.";
RL J. Biol. Chem. 266:8784-8789(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=7916650;
RA Wang L., Patel U., Ghosh L., Chen H.C., Banerjee S.;
RT "Mutation in the nm23 gene is associated with metastasis in colorectal
RT cancer.";
RL Cancer Res. 53:717-720(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=8270257; DOI=10.1007/BF00218915;
RA Dooley S., Seib T., Engel M., Theisinger B., Janz H., Piontek K.,
RA Zang K.D., Welter C.;
RT "Isolation and characterization of the human genomic locus coding for
RT the putative metastasis control gene nm23-H1.";
RL Hum. Genet. 93:63-66(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND TISSUE SPECIFICITY.
RX PubMed=12601555; DOI=10.1007/s100380300014;
RA Ni X., Gu S., Dai J., Cheng H., Guo L., Li L., Ji C., Xie Y., Ying K.,
RA Mao Y.;
RT "Isolation and characterization of a novel human NM23-H1B gene, a
RT different transcript of NM23-H1.";
RL J. Hum. Genet. 48:96-100(2003).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Halleck A., Ebert L., Mkoundinya M., Schick M., Eisenstein S.,
RA Neubert P., Kstrang K., Schatten R., Shen B., Henze S., Mar W.,
RA Korn B., Zuo D., Hu Y., LaBaer J.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16625196; DOI=10.1038/nature04689;
RA Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R.,
RA Gnerre S., Goldstein S., Grafham D.V., Grocock R., Hafez N.,
RA Hagopian D.S., Hart E., Norman C.H., Humphray S., Jaffe D.B.,
RA Jones M., Kamal M., Khodiyar V.K., LaButti K., Laird G., Lehoczky J.,
RA Liu X., Lokyitsang T., Loveland J., Lui A., Macdonald P., Major J.E.,
RA Matthews L., Mauceli E., McCarroll S.A., Mihalev A.H., Mudge J.,
RA Nguyen C., Nicol R., O'Leary S.B., Osoegawa K., Schwartz D.C.,
RA Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT "DNA sequence of human chromosome 17 and analysis of rearrangement in
RT the human lineage.";
RL Nature 440:1045-1049(2006).
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, and Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 7-18; 40-49 AND 89-94 (ISOFORMS 1/2), AND
RP DISCUSSION OF THE ROLE IN TUMOR PROGRESSION.
RC TISSUE=Neuroblastoma;
RX PubMed=2056128; DOI=10.1172/JCI115299;
RA Hailat N., Keim D.R., Melhem R.F., Zhu X.X., Eckerskorn C.,
RA Brodeur G.M., Reynolds C.P., Seeger R.C., Lottspeich F.,
RA Strahler J.R., Hanash S.J.;
RT "High levels of p19/nm23 protein in neuroblastoma are associated with
RT advanced stage disease and with N-myc gene amplification.";
RL J. Clin. Invest. 88:341-345(1991).
RN [12]
RP PROTEIN SEQUENCE OF 7-26; 40-49; 57-85 AND 89-128 (ISOFORMS 1/2), AND
RP MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [13]
RP FUNCTION, AND MUTAGENESIS OF PRO-96; HIS-118 AND SER-120.
RX PubMed=8810265; DOI=10.1074/jbc.271.41.25107;
RA MacDonald N.J., Freije J.M., Stracke M.L., Manrow R.E., Steeg P.S.;
RT "Site-directed mutagenesis of nm23-H1. Mutation of proline 96 or
RT serine 120 abrogates its motility inhibitory activity upon
RT transfection into human breast carcinoma cells.";
RL J. Biol. Chem. 271:25107-25116(1996).
RN [14]
RP TISSUE SPECIFICITY.
RX PubMed=10512675; DOI=10.1006/geno.1999.5939;
RA Manda R., Kohno T., Matsuno Y., Takenoshita S., Kuwano H., Yokota J.;
RT "Identification of genes (SPON2 and C20orf2) differentially expressed
RT between cancerous and noncancerous lung cells by mRNA differential
RT display.";
RL Genomics 61:5-14(1999).
RN [15]
RP FUNCTION, ENZYME REGULATION, AND INTERACTION WITH SET.
RX PubMed=12628186; DOI=10.1016/S0092-8674(03)00150-8;
RA Fan Z., Beresford P.J., Oh D.Y., Zhang D., Lieberman J.;
RT "Tumor suppressor NM23-H1 is a granzyme A-activated DNase during CTL-
RT mediated apoptosis, and the nucleosome assembly protein SET is its
RT inhibitor.";
RL Cell 112:659-672(2003).
RN [16]
RP ALTERNATIVE SPLICING (ISOFORM 3), SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=16442775; DOI=10.1016/j.ygeno.2005.11.004;
RA Valentijn L.J., Koster J., Versteeg R.;
RT "Read-through transcript from NM23-H1 into the neighboring NM23-H2
RT gene encodes a novel protein, NM23-LV.";
RL Genomics 87:483-489(2006).
RN [17]
RP INTERACTION WITH PRUNE.
RX PubMed=17906697; DOI=10.1038/sj.onc.1210822;
RA Garzia L., D'Angelo A., Amoresano A., Knauer S.K., Cirulli C.,
RA Campanella C., Stauber R.H., Steegborn C., Iolascon A., Zollo M.;
RT "Phosphorylation of nm23-H1 by CKI induces its complex formation with
RT h-prune and promotes cell motility.";
RL Oncogene 27:1853-1864(2008).
RN [18]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS).
RX PubMed=11835509; DOI=10.1002/prot.10038;
RA Min K., Song H.K., Chang C., Kim S.Y., Lee K.J., Suh S.W.;
RT "Crystal structure of human nucleoside diphosphate kinase A, a
RT metastasis suppressor.";
RL Proteins 46:340-342(2002).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), AND MUTAGENESIS OF PHE-60 AND
RP HIS-118.
RX PubMed=12972261; DOI=10.1016/j.jmb.2003.07.004;
RA Chen Y., Gallois-Montbrun S., Schneider B., Veron M., Morera S.,
RA Deville-Bonne D., Janin J.;
RT "Nucleotide binding to nucleoside diphosphate kinases: X-ray structure
RT of human NDPK-A in complex with ADP and comparison to protein
RT kinases.";
RL J. Mol. Biol. 332:915-926(2003).
RN [22]
RP VARIANT GLY-120.
RX PubMed=8047138; DOI=10.1038/370335a0;
RA Chang C.L., Zhu X.-X., Thoraval D.H., Ungar D., Rawwas J., Hora N.,
RA Strahler J.R., Hanash S.M.;
RT "Nm23-H1 mutation in neuroblastoma.";
RL Nature 370:335-336(1994).
CC -!- FUNCTION: Major role in the synthesis of nucleoside triphosphates
CC other than ATP. Possesses nucleoside-diphosphate kinase,
CC serine/threonine-specific protein kinase, geranyl and farnesyl
CC pyrophosphate kinase, histidine protein kinase and 3'-5'
CC exonuclease activities. Involved in cell proliferation,
CC differentiation and development, signal transduction, G protein-
CC coupled receptor endocytosis, and gene expression. Required for
CC neural development including neural patterning and cell fate
CC determination.
CC -!- CATALYTIC ACTIVITY: ATP + nucleoside diphosphate = ADP +
CC nucleoside triphosphate.
CC -!- COFACTOR: Magnesium.
CC -!- ENZYME REGULATION: Autophosphorylation at His-118 increases
CC serine/threonine protein kinase activity of the enzyme.
CC Interaction with the SET complex inhibits exonuclease activity.
CC -!- SUBUNIT: Hexamer of two different chains: A and B (A6, A5B, A4B2,
CC A3B3, A2B4, AB5, B6). Interacts with SET and PRUNE.
CC -!- INTERACTION:
CC Self; NbExp=4; IntAct=EBI-741141, EBI-741141;
CC Q61097:Ksr1 (xeno); NbExp=7; IntAct=EBI-741141, EBI-1536336;
CC P10911:MCF2; NbExp=4; IntAct=EBI-741141, EBI-1914514;
CC P22392:NME2; NbExp=2; IntAct=EBI-741141, EBI-713693;
CC Q86TP1:PRUNE; NbExp=2; IntAct=EBI-741141, EBI-2127112;
CC Q9Y3F4:STRAP; NbExp=9; IntAct=EBI-741141, EBI-727414;
CC Q96HA8:WDYHV1; NbExp=3; IntAct=EBI-741141, EBI-741158;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Nucleus. Note=Cell-cycle
CC dependent nuclear localization which can be induced by interaction
CC with Epstein-barr viral proteins or by degradation of the SET
CC complex by GzmA.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1; Synonyms=NM23-H1A;
CC IsoId=P15531-1; Sequence=Displayed;
CC Name=2; Synonyms=NM23-H1B;
CC IsoId=P15531-2; Sequence=VSP_036707;
CC Name=3; Synonyms=NM23-LV;
CC IsoId=P22392-2; Sequence=External;
CC Note=Based on a naturally occurring readthrough transcript which
CC produces an NME1-NME2 fusion protein;
CC -!- TISSUE SPECIFICITY: Isoform 1 is expressed in heart, brain,
CC placenta, lung, liver, skeletal muscle, pancreas, spleen and
CC thymus. Expressed in lung carcinoma cell lines but not in normal
CC lung tissues. Isoform 2 is ubiquitously expressed and its
CC expression is also related to tumor differentiation. Isoform 3 is
CC ubiquitously expressed.
CC -!- MISCELLANEOUS: The role of this protein in tumor development and
CC progression is uncertain. This protein is found in reduced amount
CC in some tumor cells of high metastatic potential. However,
CC increased NME1 levels correlate with aggressive tumor features in
CC neuroblastoma. May have distinct if not opposite roles in
CC different tumors.
CC -!- SIMILARITY: Belongs to the NDK family.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA35621.1; Type=Erroneous initiation; Note=Translation N-terminally shortened;
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DR EMBL; X17620; CAA35621.1; ALT_INIT; mRNA.
DR EMBL; X73066; CAA51527.1; -; mRNA.
DR EMBL; X75598; CAA53270.1; -; Genomic_DNA.
DR EMBL; AF487339; AAO85436.1; -; mRNA.
DR EMBL; AK291105; BAF83794.1; -; mRNA.
DR EMBL; CR542104; CAG46901.1; -; mRNA.
DR EMBL; CR542115; CAG46912.1; -; mRNA.
DR EMBL; AC005839; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471109; EAW94568.1; -; Genomic_DNA.
DR EMBL; BC000293; AAH00293.1; -; mRNA.
DR EMBL; BC018994; AAH18994.1; -; mRNA.
DR PIR; A33386; A33386.
DR RefSeq; NP_000260.1; NM_000269.2.
DR RefSeq; NP_937818.1; NM_198175.1.
DR UniGene; Hs.463456; -.
DR PDB; 1JXV; X-ray; 2.20 A; A/B/C/D/E/F=1-152.
DR PDB; 1UCN; X-ray; 2.00 A; A/B/C=1-152.
DR PDB; 2HVD; X-ray; 2.15 A; A/B/C=1-152.
DR PDB; 2HVE; X-ray; 2.40 A; A/B/C=1-152.
DR PDB; 3L7U; X-ray; 2.10 A; A/B/C=1-152.
DR PDB; 4ENO; X-ray; 2.80 A; A/B=1-152.
DR PDBsum; 1JXV; -.
DR PDBsum; 1UCN; -.
DR PDBsum; 2HVD; -.
DR PDBsum; 2HVE; -.
DR PDBsum; 3L7U; -.
DR PDBsum; 4ENO; -.
DR ProteinModelPortal; P15531; -.
DR SMR; P15531; 1-152.
DR DIP; DIP-39164N; -.
DR IntAct; P15531; 23.
DR MINT; MINT-221462; -.
DR STRING; 9606.ENSP00000013034; -.
DR ChEMBL; CHEMBL2159; -.
DR DrugBank; DB00441; Gemcitabine.
DR DrugBank; DB00396; Progesterone.
DR PhosphoSite; P15531; -.
DR DMDM; 127981; -.
DR DOSAC-COBS-2DPAGE; P15531; -.
DR OGP; P15531; -.
DR PaxDb; P15531; -.
DR PRIDE; P15531; -.
DR DNASU; 4830; -.
DR Ensembl; ENST00000013034; ENSP00000013034; ENSG00000239672.
DR Ensembl; ENST00000336097; ENSP00000337060; ENSG00000239672.
DR Ensembl; ENST00000393196; ENSP00000376892; ENSG00000239672.
DR GeneID; 4830; -.
DR KEGG; hsa:4830; -.
DR UCSC; uc002iti.2; human.
DR CTD; 4830; -.
DR GeneCards; GC17P049231; -.
DR HGNC; HGNC:7849; NME1.
DR HPA; HPA008467; -.
DR HPA; HPA041113; -.
DR MIM; 156490; gene.
DR neXtProt; NX_P15531; -.
DR PharmGKB; PA249; -.
DR eggNOG; COG0105; -.
DR HOGENOM; HOG000224564; -.
DR HOVERGEN; HBG000423; -.
DR KO; K00940; -.
DR OMA; ARQMMGK; -.
DR OrthoDB; EOG7GJ6FG; -.
DR BioCyc; MetaCyc:ENSG00000011052-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR EvolutionaryTrace; P15531; -.
DR GeneWiki; NME1; -.
DR GenomeRNAi; 4830; -.
DR NextBio; 18606; -.
DR PRO; PR:P15531; -.
DR ArrayExpress; P15531; -.
DR Bgee; P15531; -.
DR CleanEx; HS_NME1; -.
DR Genevestigator; P15531; -.
DR GO; GO:0005813; C:centrosome; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0005739; C:mitochondrion; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:Ensembl.
DR GO; GO:0032587; C:ruffle membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0004536; F:deoxyribonuclease activity; IDA:UniProtKB.
DR GO; GO:0005525; F:GTP binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0004550; F:nucleoside diphosphate kinase activity; IDA:UniProtKB.
DR GO; GO:0043024; F:ribosomal small subunit binding; IPI:UniProtKB.
DR GO; GO:0000977; F:RNA polymerase II regulatory region sequence-specific DNA binding; IEA:Ensembl.
DR GO; GO:0003697; F:single-stranded DNA binding; IEA:Ensembl.
DR GO; GO:0035690; P:cellular response to drug; IEA:Ensembl.
DR GO; GO:0071398; P:cellular response to fatty acid; IEA:Ensembl.
DR GO; GO:0071333; P:cellular response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0006241; P:CTP biosynthetic process; IEA:InterPro.
DR GO; GO:0006897; P:endocytosis; IEA:UniProtKB-KW.
DR GO; GO:0006183; P:GTP biosynthetic process; IEA:InterPro.
DR GO; GO:0021766; P:hippocampus development; IEA:Ensembl.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0008285; P:negative regulation of cell proliferation; TAS:UniProtKB.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0002762; P:negative regulation of myeloid leukocyte differentiation; IEA:Ensembl.
DR GO; GO:0015949; P:nucleobase-containing small molecule interconversion; TAS:Reactome.
DR GO; GO:0043388; P:positive regulation of DNA binding; IDA:UniProtKB.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IMP:HGNC.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; TAS:UniProtKB.
DR GO; GO:0014075; P:response to amine stimulus; IEA:Ensembl.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0033574; P:response to testosterone stimulus; IEA:Ensembl.
DR GO; GO:0006228; P:UTP biosynthetic process; IEA:InterPro.
DR Gene3D; 3.30.70.141; -; 1.
DR InterPro; IPR001564; Nucleoside_diP_kinase.
DR InterPro; IPR023005; Nucleoside_diP_kinase_AS.
DR Pfam; PF00334; NDK; 1.
DR PRINTS; PR01243; NUCDPKINASE.
DR SMART; SM00562; NDK; 1.
DR SUPFAM; SSF54919; SSF54919; 1.
DR PROSITE; PS00469; NDP_KINASES; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Cytoplasm; Differentiation;
KW Direct protein sequencing; Endocytosis; Isopeptide bond; Kinase;
KW Magnesium; Metal-binding; Neurogenesis; Nucleotide metabolism;
KW Nucleotide-binding; Nucleus; Polymorphism; Reference proteome;
KW Transferase; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 152 Nucleoside diphosphate kinase A.
FT /FTId=PRO_0000137114.
FT ACT_SITE 118 118 Pros-phosphohistidine intermediate.
FT BINDING 12 12 ATP.
FT BINDING 60 60 ATP.
FT BINDING 88 88 ATP.
FT BINDING 94 94 ATP.
FT BINDING 105 105 ATP.
FT BINDING 115 115 ATP.
FT MOD_RES 2 2 N-acetylalanine.
FT CROSSLNK 100 100 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT VAR_SEQ 1 1 M -> MVLLSTLGIVFQGEGPPISSCDTGTM (in
FT isoform 2).
FT /FTId=VSP_036707.
FT VARIANT 120 120 S -> G (in a neuroblastoma sample;
FT increased motility of carcinoma cells;
FT dbSNP:rs121917887).
FT /FTId=VAR_004625.
FT MUTAGEN 60 60 F->W: No loss of activity or substrate
FT binding.
FT MUTAGEN 96 96 P->S: Increased motility of carcinoma
FT cells.
FT MUTAGEN 118 118 H->F: Loss of serine/threonine kinase
FT activity. Some loss of motility of
FT carcinoma cells.
FT MUTAGEN 118 118 H->G: Loss of activity.
FT MUTAGEN 120 120 S->A: Limited increase in motility of
FT carcinoma cells.
FT HELIX 2 4
FT STRAND 6 11
FT HELIX 13 17
FT HELIX 21 31
FT STRAND 34 41
FT HELIX 45 51
FT HELIX 53 55
FT STRAND 56 58
FT HELIX 61 69
FT STRAND 73 80
FT HELIX 83 91
FT HELIX 96 98
FT HELIX 104 108
FT HELIX 112 114
FT STRAND 116 119
FT HELIX 123 133
FT HELIX 136 138
FT HELIX 147 150
SQ SEQUENCE 152 AA; 17149 MW; AAE9C0DF63CB70A1 CRC64;
MANCERTFIA IKPDGVQRGL VGEIIKRFEQ KGFRLVGLKF MQASEDLLKE HYVDLKDRPF
FAGLVKYMHS GPVVAMVWEG LNVVKTGRVM LGETNPADSK PGTIRGDFCI QVGRNIIHGS
DSVESAEKEI GLWFHPEELV DYTSCAQNWI YE
//
MIM
156490
*RECORD*
*FIELD* NO
156490
*FIELD* TI
*156490 NONMETASTATIC CELLS 1, PROTEIN EXPRESSED IN; NME1
;;METASTASIS INHIBITION FACTOR NM23;;
read moreNONMETASTATIC PROTEIN 23; NM23;;
NONMETASTATIC PROTEIN 23, HOMOLOG 1; NM23H1;;
NUCLEOSIDE DIPHOSPHATE KINASE-A; NDPKA;;
GZMA-ACTIVATED DNase; GAAD;;
AWD, DROSOPHILA, HOMOLOG OF; AWD
NM23H1B, INCLUDED;;
NM23 LONG VARIANT, INCLUDED; NM23LV, INCLUDED;;
NME1-NME2 SPLICED READ-THROUGH TRANSCRIPT, INCLUDED
*FIELD* TX
CLONING
Steeg et al. (1988) gave the name NM23 to a gene they cloned from a
murine melanoma cell line. Expression of the gene correlated inversely
with metastatic potential. NM23 RNA levels are highest in cell lines
with low metastatic potential. RNA levels did not correlate with cell
sensitivity to host immune responses. The authors therefore hypothesized
that expression of this gene may be associated with intrinsic
aggressiveness of the line. Several observations suggested that NM23
activity may be correlated with inhibition of the tumor metastatic
process. Bevilacqua et al. (1989) concluded that NM23 RNA levels are
differentially expressed in human breast tumors and that low NM23 RNA
levels are associated with histopathologic indications of high
metastatic potential. The product of the NM23 gene is a nucleoside
diphosphate kinase, which has been designated p19/nm23. Keim et al.
(1992) presented evidence that the expression of the gene is related to
cell proliferative activity.
Rosengard et al. (1989) found that the human NM23 protein has sequence
homology over the entire translated region with a developmentally
related protein in Drosophila encoded by the 'abnormal wing discs' (awd)
gene. Mutations in awd cause abnormal tissue morphology and necrosis and
widespread aberrant differentiation in Drosophila, analogous to the
changes in malignant progression.
Postel et al. (1993) reported evidence suggesting that the protein
encoded by 1 of the 2 closely related NM23 genes (see NME2; 156491) may
be a transcription factor. The gene that may be turned on is the MYC
oncogene (190080). Although a dozen DNA binding proteins had been
identified for the MYC gene, only one, called PuF (for purine-binding
factor, because the DNA sequence it recognizes has a high content of
purine bases), was known to regulate MYC transcription in vitro. PuF was
identified by Postel and her colleagues (Postel et al., 1989; Postel,
1992) as a partially purified HeLa cell (human cervical carcinoma)
factor that binds to a nuclease-hypersensitive element (NHE) at
positions -142 to -115 of the human MYC P1 promoter and is necessary for
efficient P1 and P2 transcription initiation in vitro. Postel et al.
(1993) identified the human gene encoding PuF by screening a cervical
carcinoma cell cDNA library with a DNA fragment containing PuF binding
sites. DNA sequence analysis of recombinant PuF demonstrated perfect
identity with the NM23 gene. Although no clear correlation has yet been
established between overexpression of MYC and tumor metastasis, the
inverse relation between MYC expression and cell differentiation is well
documented. Furthermore, Okabe-Kado et al. (1992) identified a
differentiation inhibiting factor in the mouse myeloid leukemia cells as
a murine homolog of NM23. Findings leave the conundrum of how NM23 can
be both a tumor suppressor and an activator of MYC.
Gilles et al. (1991) showed that nucleoside diphosphate kinases A and B
are identical to NM23-H1 and NM23-H2, respectively. The genes NME1 and
NME2 encode 2 polypeptide chains that are responsible for heterogeneity
of the hexameric enzyme.
Using Northern blot analysis of several mouse tissues, Masse et al.
(2002) found that mouse Nme1, which they called nm23-M1, was expressed
as 2 transcripts due to the use of 2 alternate polyadenylation signals.
Expression was highest in the central nervous system, liver, and kidney.
In situ hybridization of 15-day postcoitum mouse embryos showed Nme1
expressed predominantly in the central and peripheral nervous system,
sensory organs, and thymus.
Ni et al. (2003) cloned a different transcript (designated NM23H1B) of
the NM23H1 gene from 18-week-old human fetal brain. The 987-bp cDNA
encoded a protein of 177 amino acid residues. Compared with NM23H1, the
cDNA contained an additional NH2-terminal region (25 amino acid
residues). Bioinformatics analysis showed that the second exon does not
exist in NM23H1. The expression pattern of NM23H1B showed that it is
ubiquitously expressed in normal tissues (15 tissues except colon) at
different levels. The data also indicated that the expression of the
transcript in tumors related to tumor differentiation: there was no
expression in poorly differentiated breast carcinoma, pancreatic
adenocarcinoma, and undifferentiated ovarian carcinoma.
- NME1-NME2 Spliced Read-Through Transcript
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), lacks exon 5 of NM23H1, which contains the stop codon,
and exon 1 of NM23H2, which is untranslated sequence. The deduced
267-amino acid NM23LV protein has a calculated molecular mass of 33 kD.
It has only 7 beta sheets, which cannot adapt to the antiparallel
beta-sheet formation. RT-PCR detected ubiquitous NM23LV expression, with
reduced expression in lung and very little expression in kidney. NM23H1,
NM23H2, and NM23LV were highly expressed in 8 neuroblastoma cell lines
examined, but they were not expressed in HEK293 cells. Western blot
analysis detected NM23LV at an apparent molecular mass of 33 kD.
GENE FUNCTION
MacDonald et al. (1996) performed site-directed mutagenesis on the
NM23-H1 gene and transfected the mutant DNAs into human breast carcinoma
cells. They found that mutations of proline-96 or serine-120 reduce the
ability of NM23-H1 to inhibit cell motility. In the wildtype protein,
serine-120 is a site of phosphorylation; proline-96 is part of a loop of
unknown function.
Epstein-Barr virus (EBV) is a herpesvirus that causes infectious
mononucleosis in adolescents and lymphoproliferative disease (308240) in
immunocompromised individuals and is associated with human cancers,
including Burkitt lymphoma (BL; 113970), nasopharyngeal cancer (161550),
and Hodgkin disease (236000). EBNA3C is a large, EBV-encoded
transcription factor that is expressed with other latent nuclear
proteins after infection of B lymphocytes. It upregulates expression of
the EBV and complement receptor, CD21 (120650), as well as EBV latent
membrane protein (LMP1). Subramanian et al. (2001) showed that the
C-terminal region of EBNA3C (amino acids 365 to 992), without which EBV
cannot immortalize B lymphocytes, interacts with NME1.
Immunofluorescence microscopy demonstrated colocalization of NME1 in
nuclei of B cells expressing EBNA3C. Expression of EBNA3C reversed the
ability of NME1 to inhibit migration of BL and breast carcinoma (114480)
cells.
There is evidence that the NM23 genes, initially documented as
suppressors of the invasive phenotype in some cancer types, are involved
in the control of normal development and cell differentiation (Lombardi
et al., 2000).
Granzyme A (GZMA; 140050) induces a caspase-independent cell death
pathway characterized by single-stranded DNA nicks and other features of
apoptosis. A GZMA-activated DNase (GAAD) is in an endoplasmic
reticulum-associated complex containing pp32 (600832) and the GZMA
substrates SET (600960), HMG2 (163906), and APE1 (107748). Fan et al.
(2003) showed that GAAD is NM23H1 and its specific inhibitor (IGAAD) is
SET. NM23H1 bound SET and was released from inhibition by GZMA cleavage
of SET. After GZMA loading or cytotoxic T lymphocyte attack, SET and
NM23H1 translocated to the nucleus and SET was degraded, allowing NM23H1
to nick chromosomal DNA. GZMA-treated cells with silenced NM23H1
expression were resistant to GZMA-mediated DNA damage and cytolysis,
while cells overexpressing NM23H1 were more sensitive.
Using a Drosophila model system, Dammai et al. (2003) showed that the
Drosophila NME1 homolog, awd, regulates trachea cell motility by
modulating FGFR (see 136350) levels through a dynamin (see
602377)-mediated pathway.
GENE STRUCTURE
Dooley et al. (1994) isolated and sequenced genomic PCR fragments that
included the entire coding region of the NME1 gene, revealing that the
gene consists of 5 exons and 4 introns spanning 8.5 kb. Comparison with
the homologous gene in the rat showed that the exon-intron boundaries
are well conserved between the 2 species.
Masse et al. (2002) determined that the mouse Nme1 gene contains 5 exons
and spans about 9.0 kb, similar to the human gene. The promoters of the
mouse and human NME1 genes, 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.
MAPPING
NM23 was assigned to 17q12-q21 by in situ hybridization, by analysis of
somatic cell hybrids, and by linkage studies with markers in the CEPH
panel (Leone et al., 1991). Somatic allelic deletion of the gene was
observed in DNA from human breast, renal, colorectal, and lung
carcinomas. In several cases the deletion of NM23 was independent of
other chromosome 17 deletions. Eddy et al. (1991) mapped the NME1 gene
to 17p11-qter by analysis of human-mouse somatic cell hybrid DNAs.
Varesco et al. (1992) mapped the gene to 17q22 by in situ hybridization.
They also demonstrated a 2-allele polymorphism with BglII. By linkage
studies using markers for the NME1 locus, Sudbrak et al. (1993)
demonstrated localization of NME1 on 17q. Ni et al. (2003) mapped the
NM23H1 gene to chromosome 17q21.3 using bioinformatics analysis.
MOLECULAR GENETICS
Whereas reduced expression of NM23 is associated with a high potential
for metastasis in some tumor types, its expression is increased in
aggressive neuroblastoma (256700). Chang et al. (1994) looked for
mutations in the NM23 gene in 24 primary neuroblastoma tumors at
different stages of the disease by use of PCR combined with SSCP
analysis and Southern blotting. They found an acquired ser120-to-gly
(S120G) substitution in 6 of 28 advanced tumors but in none of 22
limited-stage tumors. They indicated that the mutant enzyme still
retains its catalytic activity but is more susceptible to the
denaturation.
*FIELD* RF
1. Bevilacqua, G.; Sobel, M. E.; Liotta, L. A.; Steeg, P. S.: Association
of low nm23 RNA levels in human primary infiltrating ductal breast
carcinomas with lymph node involvement and other histopathological
indicators of high metastatic potential. Cancer Res. 49: 5185-5190,
1989.
2. Chang, C. L.; Zhu, X.; Thoraval, D. H.; Ungar, D.; Rawwas, J.;
Hora, N.; Strahler, J. R.; Hanash, S. M.; Radany, E.: nm23-H1 mutation
in neuroblastoma. (Letter) Nature 370: 335-336, 1994.
3. Dammai, V.; Adryan, B.; Lavenburg, K. R.; Hsu, T.: 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, 2003.
4. Dooley, S.; Seib, T.; Engel, M.; Theisinger, B.; Janz, H.; Piontek,
K.; Zang, K.-D.; Welter, C.: Isolation and characterization of the
human genomic locus coding for the putative metastasis control gene
nm23-H1. Hum. Genet. 93: 63-66, 1994.
5. Eddy, R. L.; Mendola, C. E.; Fairhurst, J. L.; Shows, T. B.; O'Hara,
B.; Kovesdi, I.; Backer, J. M.: Metastasis suppressor gene is mapped
to human chromosome 17p11-qter. (Abstract) Cytogenet. Cell Genet. 58:
2005 only, 1991.
6. Fan, Z.; Beresford, P. J.; Oh, D. Y.; Zhang, D.; Lieberman, J.
: 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, 2003. Note: Erratum: Cell 115:
241 only, 2003.
7. 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.
8. Keim, D.; Hailat, N.; Melhem, R.; Zhu, X. X.; Lascu, I.; Veron,
M.; Strahler, J.; Hanash, S. M.: Proliferation-related expression
of p19/nm23 nucleoside diphosphate kinase. J. Clin. Invest. 89:
919-924, 1992.
9. 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.
10. Lombardi, D.; Lacombe, M.-L.; Paggi, M. G.: nm23: unraveling
its biological function in cell differentiation. J. Cell Physiol. 182:
144-149, 2000.
11. MacDonald, N. J.; Freije, J. M. P.; Stracke, M. L.; Manrow, R.
E.; Steeg, P. S.: Site-directed mutagenesis of nm23-H1: mutation
of proline 96 or serine 120 abrogates its motility inhibitory activity
upon transfection into human breast carcinoma cells. J. Biol. Chem. 271:
25107-25116, 1996.
12. 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.
13. Ni, X.; Gu, S.; Dai, J.; Cheng, H.; Guo, L.; Li, L.; Ji, C.; Xie,
Y.; Ying, K.; Mao, Y.: Isolation and characterization of a novel
human NM23-H1B gene, a different transcript of NM23-H1. J. Hum. Genet. 48:
96-100, 2003.
14. Okabe-Kado, J.; Kasukabe, T.; Honma, Y.; Hayashi, M.; Henzel,
W. J.; Hozumi, M.: Identity of a differentiation inhibiting factor
for mouse myeloid leukemia cells with NM23/nucleoside diphosphate
kinase. Biochem. Biophys. Res. Commun. 182: 987-994, 1992.
15. Postel, E. H.: Modulation of c-myc transcription by triple helix
formation. Ann. N.Y. Acad. Sci. 660: 57-63, 1992.
16. Postel, E. H.; Berberich, S. J.; Flint, S. J.; Ferrone, C. A.
: Human c-myc transcription factor PuF identified as nm23-H2 nucleoside
diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261:
478-480, 1993.
17. Postel, E. H.; Mango, S. E.; Flint, S. J.: A nuclease-hypersensitive
element of the human c-myc promoter interacts with a transcription
initiation factor. Molec. Cell. Biol. 9: 5123-5133, 1989.
18. Rosengard, A. M.; Krutzsch, H. C.; Shearn, A.; Biggs, J. R.; Barker,
E.; Margulies, I. M. K.; King, C. R.; Liotta, L. A.; Steeg, P. S.
: Reduced nm23/awd protein in tumour metastasis and aberrant Drosophila
development. Nature 342: 177-180, 1989.
19. Steeg, P. S.; Bevilacqua, G.; Kopper, L.; Thorgeirsson, U. P.;
Talmadge, J. E.; Liotta, L. A.; Sobel, M. E.: Evidence for a novel
gene associated with a low tumor metastatic potential. J. Nat. Cancer
Inst. 80: 200-204, 1988.
20. Subramanian, C.; Cotter, M. A., II; Robertson, E. S.: Epstein-Barr
virus nuclear protein EBNA-3C interacts with the human metastatic
suppressor Nm23-H1: a molecular link to cancer metastasis. Nature
Med. 7: 350-355, 2001.
21. Sudbrak, R.; Golla, A.; Hogan, K.; Powers, P.; Gregg, R.; Du Chesne,
I.; Lehmann-Horn, F.; Deufel, T.: Exclusion of malignant hyperthermia
susceptibility (MHS) from a putative MHS2 locus on chromosome 17q
and of the alpha-1, beta-1, and gamma subunits of the dihydropyridine
receptor calcium channel as candidates for the molecular defect. Hum.
Molec. Genet. 2: 857-862, 1993.
22. 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.
23. Varesco, L.; Caligo, M. A.; Simi, P.; Black, D. M.; Nardini, V.;
Casarino, L.; Rocchi, M.; Ferrara, G.; Solomon, E.; Bevilacqua, G.
: The NM23 gene maps to human chromosome band 17q22 and shows a restriction
fragment length polymorphism with BglII. Genes Chromosomes Cancer 4:
84-88, 1992.
*FIELD* CN
Patricia A. Hartz - updated: 6/8/2006
Patricia A. Hartz - updated: 3/22/2004
Patricia A. Hartz - updated: 12/18/2003
Stylianos E. Antonarakis - updated: 4/14/2003
Victor A. McKusick - updated: 3/7/2003
Paul J. Converse - updated: 5/1/2002
Jennifer P. Macke - updated: 5/20/1997
*FIELD* CD
Victor A. McKusick: 6/8/1988
*FIELD* ED
carol: 11/23/2009
alopez: 12/5/2008
mgross: 6/20/2006
mgross: 6/8/2006
mgross: 3/30/2004
terry: 3/22/2004
mgross: 12/18/2003
terry: 6/9/2003
mgross: 4/14/2003
cwells: 3/13/2003
terry: 3/7/2003
mgross: 5/1/2002
alopez: 2/23/1999
carol: 1/13/1999
dkim: 7/24/1998
alopez: 8/12/1997
alopez: 7/25/1997
alopez: 6/2/1997
mark: 5/20/1997
carol: 11/10/1994
carol: 9/10/1993
carol: 8/27/1993
carol: 8/25/1993
carol: 8/17/1993
carol: 5/4/1992
*RECORD*
*FIELD* NO
156490
*FIELD* TI
*156490 NONMETASTATIC CELLS 1, PROTEIN EXPRESSED IN; NME1
;;METASTASIS INHIBITION FACTOR NM23;;
read moreNONMETASTATIC PROTEIN 23; NM23;;
NONMETASTATIC PROTEIN 23, HOMOLOG 1; NM23H1;;
NUCLEOSIDE DIPHOSPHATE KINASE-A; NDPKA;;
GZMA-ACTIVATED DNase; GAAD;;
AWD, DROSOPHILA, HOMOLOG OF; AWD
NM23H1B, INCLUDED;;
NM23 LONG VARIANT, INCLUDED; NM23LV, INCLUDED;;
NME1-NME2 SPLICED READ-THROUGH TRANSCRIPT, INCLUDED
*FIELD* TX
CLONING
Steeg et al. (1988) gave the name NM23 to a gene they cloned from a
murine melanoma cell line. Expression of the gene correlated inversely
with metastatic potential. NM23 RNA levels are highest in cell lines
with low metastatic potential. RNA levels did not correlate with cell
sensitivity to host immune responses. The authors therefore hypothesized
that expression of this gene may be associated with intrinsic
aggressiveness of the line. Several observations suggested that NM23
activity may be correlated with inhibition of the tumor metastatic
process. Bevilacqua et al. (1989) concluded that NM23 RNA levels are
differentially expressed in human breast tumors and that low NM23 RNA
levels are associated with histopathologic indications of high
metastatic potential. The product of the NM23 gene is a nucleoside
diphosphate kinase, which has been designated p19/nm23. Keim et al.
(1992) presented evidence that the expression of the gene is related to
cell proliferative activity.
Rosengard et al. (1989) found that the human NM23 protein has sequence
homology over the entire translated region with a developmentally
related protein in Drosophila encoded by the 'abnormal wing discs' (awd)
gene. Mutations in awd cause abnormal tissue morphology and necrosis and
widespread aberrant differentiation in Drosophila, analogous to the
changes in malignant progression.
Postel et al. (1993) reported evidence suggesting that the protein
encoded by 1 of the 2 closely related NM23 genes (see NME2; 156491) may
be a transcription factor. The gene that may be turned on is the MYC
oncogene (190080). Although a dozen DNA binding proteins had been
identified for the MYC gene, only one, called PuF (for purine-binding
factor, because the DNA sequence it recognizes has a high content of
purine bases), was known to regulate MYC transcription in vitro. PuF was
identified by Postel and her colleagues (Postel et al., 1989; Postel,
1992) as a partially purified HeLa cell (human cervical carcinoma)
factor that binds to a nuclease-hypersensitive element (NHE) at
positions -142 to -115 of the human MYC P1 promoter and is necessary for
efficient P1 and P2 transcription initiation in vitro. Postel et al.
(1993) identified the human gene encoding PuF by screening a cervical
carcinoma cell cDNA library with a DNA fragment containing PuF binding
sites. DNA sequence analysis of recombinant PuF demonstrated perfect
identity with the NM23 gene. Although no clear correlation has yet been
established between overexpression of MYC and tumor metastasis, the
inverse relation between MYC expression and cell differentiation is well
documented. Furthermore, Okabe-Kado et al. (1992) identified a
differentiation inhibiting factor in the mouse myeloid leukemia cells as
a murine homolog of NM23. Findings leave the conundrum of how NM23 can
be both a tumor suppressor and an activator of MYC.
Gilles et al. (1991) showed that nucleoside diphosphate kinases A and B
are identical to NM23-H1 and NM23-H2, respectively. The genes NME1 and
NME2 encode 2 polypeptide chains that are responsible for heterogeneity
of the hexameric enzyme.
Using Northern blot analysis of several mouse tissues, Masse et al.
(2002) found that mouse Nme1, which they called nm23-M1, was expressed
as 2 transcripts due to the use of 2 alternate polyadenylation signals.
Expression was highest in the central nervous system, liver, and kidney.
In situ hybridization of 15-day postcoitum mouse embryos showed Nme1
expressed predominantly in the central and peripheral nervous system,
sensory organs, and thymus.
Ni et al. (2003) cloned a different transcript (designated NM23H1B) of
the NM23H1 gene from 18-week-old human fetal brain. The 987-bp cDNA
encoded a protein of 177 amino acid residues. Compared with NM23H1, the
cDNA contained an additional NH2-terminal region (25 amino acid
residues). Bioinformatics analysis showed that the second exon does not
exist in NM23H1. The expression pattern of NM23H1B showed that it is
ubiquitously expressed in normal tissues (15 tissues except colon) at
different levels. The data also indicated that the expression of the
transcript in tumors related to tumor differentiation: there was no
expression in poorly differentiated breast carcinoma, pancreatic
adenocarcinoma, and undifferentiated ovarian carcinoma.
- NME1-NME2 Spliced Read-Through Transcript
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), lacks exon 5 of NM23H1, which contains the stop codon,
and exon 1 of NM23H2, which is untranslated sequence. The deduced
267-amino acid NM23LV protein has a calculated molecular mass of 33 kD.
It has only 7 beta sheets, which cannot adapt to the antiparallel
beta-sheet formation. RT-PCR detected ubiquitous NM23LV expression, with
reduced expression in lung and very little expression in kidney. NM23H1,
NM23H2, and NM23LV were highly expressed in 8 neuroblastoma cell lines
examined, but they were not expressed in HEK293 cells. Western blot
analysis detected NM23LV at an apparent molecular mass of 33 kD.
GENE FUNCTION
MacDonald et al. (1996) performed site-directed mutagenesis on the
NM23-H1 gene and transfected the mutant DNAs into human breast carcinoma
cells. They found that mutations of proline-96 or serine-120 reduce the
ability of NM23-H1 to inhibit cell motility. In the wildtype protein,
serine-120 is a site of phosphorylation; proline-96 is part of a loop of
unknown function.
Epstein-Barr virus (EBV) is a herpesvirus that causes infectious
mononucleosis in adolescents and lymphoproliferative disease (308240) in
immunocompromised individuals and is associated with human cancers,
including Burkitt lymphoma (BL; 113970), nasopharyngeal cancer (161550),
and Hodgkin disease (236000). EBNA3C is a large, EBV-encoded
transcription factor that is expressed with other latent nuclear
proteins after infection of B lymphocytes. It upregulates expression of
the EBV and complement receptor, CD21 (120650), as well as EBV latent
membrane protein (LMP1). Subramanian et al. (2001) showed that the
C-terminal region of EBNA3C (amino acids 365 to 992), without which EBV
cannot immortalize B lymphocytes, interacts with NME1.
Immunofluorescence microscopy demonstrated colocalization of NME1 in
nuclei of B cells expressing EBNA3C. Expression of EBNA3C reversed the
ability of NME1 to inhibit migration of BL and breast carcinoma (114480)
cells.
There is evidence that the NM23 genes, initially documented as
suppressors of the invasive phenotype in some cancer types, are involved
in the control of normal development and cell differentiation (Lombardi
et al., 2000).
Granzyme A (GZMA; 140050) induces a caspase-independent cell death
pathway characterized by single-stranded DNA nicks and other features of
apoptosis. A GZMA-activated DNase (GAAD) is in an endoplasmic
reticulum-associated complex containing pp32 (600832) and the GZMA
substrates SET (600960), HMG2 (163906), and APE1 (107748). Fan et al.
(2003) showed that GAAD is NM23H1 and its specific inhibitor (IGAAD) is
SET. NM23H1 bound SET and was released from inhibition by GZMA cleavage
of SET. After GZMA loading or cytotoxic T lymphocyte attack, SET and
NM23H1 translocated to the nucleus and SET was degraded, allowing NM23H1
to nick chromosomal DNA. GZMA-treated cells with silenced NM23H1
expression were resistant to GZMA-mediated DNA damage and cytolysis,
while cells overexpressing NM23H1 were more sensitive.
Using a Drosophila model system, Dammai et al. (2003) showed that the
Drosophila NME1 homolog, awd, regulates trachea cell motility by
modulating FGFR (see 136350) levels through a dynamin (see
602377)-mediated pathway.
GENE STRUCTURE
Dooley et al. (1994) isolated and sequenced genomic PCR fragments that
included the entire coding region of the NME1 gene, revealing that the
gene consists of 5 exons and 4 introns spanning 8.5 kb. Comparison with
the homologous gene in the rat showed that the exon-intron boundaries
are well conserved between the 2 species.
Masse et al. (2002) determined that the mouse Nme1 gene contains 5 exons
and spans about 9.0 kb, similar to the human gene. The promoters of the
mouse and human NME1 genes, 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.
MAPPING
NM23 was assigned to 17q12-q21 by in situ hybridization, by analysis of
somatic cell hybrids, and by linkage studies with markers in the CEPH
panel (Leone et al., 1991). Somatic allelic deletion of the gene was
observed in DNA from human breast, renal, colorectal, and lung
carcinomas. In several cases the deletion of NM23 was independent of
other chromosome 17 deletions. Eddy et al. (1991) mapped the NME1 gene
to 17p11-qter by analysis of human-mouse somatic cell hybrid DNAs.
Varesco et al. (1992) mapped the gene to 17q22 by in situ hybridization.
They also demonstrated a 2-allele polymorphism with BglII. By linkage
studies using markers for the NME1 locus, Sudbrak et al. (1993)
demonstrated localization of NME1 on 17q. Ni et al. (2003) mapped the
NM23H1 gene to chromosome 17q21.3 using bioinformatics analysis.
MOLECULAR GENETICS
Whereas reduced expression of NM23 is associated with a high potential
for metastasis in some tumor types, its expression is increased in
aggressive neuroblastoma (256700). Chang et al. (1994) looked for
mutations in the NM23 gene in 24 primary neuroblastoma tumors at
different stages of the disease by use of PCR combined with SSCP
analysis and Southern blotting. They found an acquired ser120-to-gly
(S120G) substitution in 6 of 28 advanced tumors but in none of 22
limited-stage tumors. They indicated that the mutant enzyme still
retains its catalytic activity but is more susceptible to the
denaturation.
*FIELD* RF
1. Bevilacqua, G.; Sobel, M. E.; Liotta, L. A.; Steeg, P. S.: Association
of low nm23 RNA levels in human primary infiltrating ductal breast
carcinomas with lymph node involvement and other histopathological
indicators of high metastatic potential. Cancer Res. 49: 5185-5190,
1989.
2. Chang, C. L.; Zhu, X.; Thoraval, D. H.; Ungar, D.; Rawwas, J.;
Hora, N.; Strahler, J. R.; Hanash, S. M.; Radany, E.: nm23-H1 mutation
in neuroblastoma. (Letter) Nature 370: 335-336, 1994.
3. Dammai, V.; Adryan, B.; Lavenburg, K. R.; Hsu, T.: 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, 2003.
4. Dooley, S.; Seib, T.; Engel, M.; Theisinger, B.; Janz, H.; Piontek,
K.; Zang, K.-D.; Welter, C.: Isolation and characterization of the
human genomic locus coding for the putative metastasis control gene
nm23-H1. Hum. Genet. 93: 63-66, 1994.
5. Eddy, R. L.; Mendola, C. E.; Fairhurst, J. L.; Shows, T. B.; O'Hara,
B.; Kovesdi, I.; Backer, J. M.: Metastasis suppressor gene is mapped
to human chromosome 17p11-qter. (Abstract) Cytogenet. Cell Genet. 58:
2005 only, 1991.
6. Fan, Z.; Beresford, P. J.; Oh, D. Y.; Zhang, D.; Lieberman, J.
: 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, 2003. Note: Erratum: Cell 115:
241 only, 2003.
7. 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.
8. Keim, D.; Hailat, N.; Melhem, R.; Zhu, X. X.; Lascu, I.; Veron,
M.; Strahler, J.; Hanash, S. M.: Proliferation-related expression
of p19/nm23 nucleoside diphosphate kinase. J. Clin. Invest. 89:
919-924, 1992.
9. 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.
10. Lombardi, D.; Lacombe, M.-L.; Paggi, M. G.: nm23: unraveling
its biological function in cell differentiation. J. Cell Physiol. 182:
144-149, 2000.
11. MacDonald, N. J.; Freije, J. M. P.; Stracke, M. L.; Manrow, R.
E.; Steeg, P. S.: Site-directed mutagenesis of nm23-H1: mutation
of proline 96 or serine 120 abrogates its motility inhibitory activity
upon transfection into human breast carcinoma cells. J. Biol. Chem. 271:
25107-25116, 1996.
12. 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.
13. Ni, X.; Gu, S.; Dai, J.; Cheng, H.; Guo, L.; Li, L.; Ji, C.; Xie,
Y.; Ying, K.; Mao, Y.: Isolation and characterization of a novel
human NM23-H1B gene, a different transcript of NM23-H1. J. Hum. Genet. 48:
96-100, 2003.
14. Okabe-Kado, J.; Kasukabe, T.; Honma, Y.; Hayashi, M.; Henzel,
W. J.; Hozumi, M.: Identity of a differentiation inhibiting factor
for mouse myeloid leukemia cells with NM23/nucleoside diphosphate
kinase. Biochem. Biophys. Res. Commun. 182: 987-994, 1992.
15. Postel, E. H.: Modulation of c-myc transcription by triple helix
formation. Ann. N.Y. Acad. Sci. 660: 57-63, 1992.
16. Postel, E. H.; Berberich, S. J.; Flint, S. J.; Ferrone, C. A.
: Human c-myc transcription factor PuF identified as nm23-H2 nucleoside
diphosphate kinase, a candidate suppressor of tumor metastasis. Science 261:
478-480, 1993.
17. Postel, E. H.; Mango, S. E.; Flint, S. J.: A nuclease-hypersensitive
element of the human c-myc promoter interacts with a transcription
initiation factor. Molec. Cell. Biol. 9: 5123-5133, 1989.
18. Rosengard, A. M.; Krutzsch, H. C.; Shearn, A.; Biggs, J. R.; Barker,
E.; Margulies, I. M. K.; King, C. R.; Liotta, L. A.; Steeg, P. S.
: Reduced nm23/awd protein in tumour metastasis and aberrant Drosophila
development. Nature 342: 177-180, 1989.
19. Steeg, P. S.; Bevilacqua, G.; Kopper, L.; Thorgeirsson, U. P.;
Talmadge, J. E.; Liotta, L. A.; Sobel, M. E.: Evidence for a novel
gene associated with a low tumor metastatic potential. J. Nat. Cancer
Inst. 80: 200-204, 1988.
20. Subramanian, C.; Cotter, M. A., II; Robertson, E. S.: Epstein-Barr
virus nuclear protein EBNA-3C interacts with the human metastatic
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Med. 7: 350-355, 2001.
21. Sudbrak, R.; Golla, A.; Hogan, K.; Powers, P.; Gregg, R.; Du Chesne,
I.; Lehmann-Horn, F.; Deufel, T.: Exclusion of malignant hyperthermia
susceptibility (MHS) from a putative MHS2 locus on chromosome 17q
and of the alpha-1, beta-1, and gamma subunits of the dihydropyridine
receptor calcium channel as candidates for the molecular defect. Hum.
Molec. Genet. 2: 857-862, 1993.
22. 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.
23. Varesco, L.; Caligo, M. A.; Simi, P.; Black, D. M.; Nardini, V.;
Casarino, L.; Rocchi, M.; Ferrara, G.; Solomon, E.; Bevilacqua, G.
: The NM23 gene maps to human chromosome band 17q22 and shows a restriction
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84-88, 1992.
*FIELD* CN
Patricia A. Hartz - updated: 6/8/2006
Patricia A. Hartz - updated: 3/22/2004
Patricia A. Hartz - updated: 12/18/2003
Stylianos E. Antonarakis - updated: 4/14/2003
Victor A. McKusick - updated: 3/7/2003
Paul J. Converse - updated: 5/1/2002
Jennifer P. Macke - updated: 5/20/1997
*FIELD* CD
Victor A. McKusick: 6/8/1988
*FIELD* ED
carol: 11/23/2009
alopez: 12/5/2008
mgross: 6/20/2006
mgross: 6/8/2006
mgross: 3/30/2004
terry: 3/22/2004
mgross: 12/18/2003
terry: 6/9/2003
mgross: 4/14/2003
cwells: 3/13/2003
terry: 3/7/2003
mgross: 5/1/2002
alopez: 2/23/1999
carol: 1/13/1999
dkim: 7/24/1998
alopez: 8/12/1997
alopez: 7/25/1997
alopez: 6/2/1997
mark: 5/20/1997
carol: 11/10/1994
carol: 9/10/1993
carol: 8/27/1993
carol: 8/25/1993
carol: 8/17/1993
carol: 5/4/1992