Disease relevance of NME2

• No correlation was apparent between nm23-H2 mRNA abundance and intrahepatic metastasis [1].
• The NM23-H1 was expressed on myeloid leukemia lines but not lymphoid lines, while NM23-H2 was only expressed on erythroleukemia lines [2].
• Human nucleoside diphosphate kinase B (Nm23-H2) from melanoma cells shows altered phosphoryl transfer activity due to the S122P mutation [3].
• These observations suggest a major role for nm23-H1 and nm23-H2 in tumorigenesis of unfavorable neuroblastomas [4].
• The 2.8 A resolution X-ray structure of NM23-H2 has been determined by molecular replacement using the structure of Myxococcus xanthus nucleoside diphosphate (NDP) kinase [5].

High impact information on NME2

• Segmental differences in stability within the polycistronic transcripts of the puf operon contribute to differential expression of photosynthesis genes in R. capsulatus [6].
• An intercistronic stem-loop structure functions as an mRNA decay terminator necessary but insufficient for puf mRNA stability [6].
• Human c-myc transcription factor PuF identified as nm23-H2 nucleoside diphosphate kinase, a candidate suppressor of tumor metastasis [7].
• A human gene encoding the c-myc purine-binding transcription factor PuF was identified by screening of a cervical carcinoma cell complementary DNA library with a DNA fragment containing PuF binding sites [7].
• 1. NDPK-B directly binds and activates KCa3.1 by phosphorylating histidine 358 in the carboxyl terminus of KCa3 [8].

Chemical compound and disease context of NME2

• We also studied the effect of resveratrol on a panel of MDA-MB-435 cells transfected with nm23-H1 and nm23-H2 genes, which have been suggested to play a role in controlling metastasis in breast cancer cells [9].
• Pleiotropic effects of puf interposon mutagenesis on carotenoid biosynthesis in Rubrivivax gelatinosus. A new gene organization in purple bacteria [10].
• Comparing the deduced amino acid sequences of the puf genes of the Acidiphilium species with those of other purple bacteria showed that His L168, which is highly conserved in other bacteria, is replaced by a glutamic acid in the Acidiphilium species [11].

Biological context of NME2

• The human NME2 gene lies within 18kb of NME1 in chromosome 17 [12].
• We have isolated and characterized five yeast artificial chromosome (YAC) clones and three cosmid clones that contain both genes, demonstrating that the NME2 gene is also located on chromosome 17 and is separated by not more than 18 kb from the NME1 gene [12].
• NM23-H2/NDP kinase B has been identified as a sequence-specific DNA-binding protein with affinity for a nuclease-hypersensitive element of the c-MYC gene promoter (Postel et al., 1993) [13].
• We obtained a hen antibody that specifically reacts with Nme1 without any cross-reaction with Nme2 [14].
• Furthermore the identification of possible binding sites for MYC proteins and additionally the NM23-H2 protein itself (the transcription factor PuF for c-myc gene activation) is of importance with respect to possible para- and autoregulatory interactions [15].

Anatomical context of NME2

• To determine the human chromosomal location of the NME2 gene, we have analyzed DNA from rodent-human cell lines and hybrid cell lines containing portions of chromosome 17 by a combination of PCR amplification and Southern hybridization [16].
• Surface NM23-H1 and NM23-H2 proteins were decreased during in vitro erythroid and granulocyte differentiation [2].
• To examine what types of tumor cell line express the cell surface NM23 protein, we measured the cell surface NM23-H1 and NM23-H2 proteins of leukemia line cells on various cellular lineage and differentiation stages [2].
• These adhesion sites are enriched in occupied beta(1) integrins and precede the formation of focal adhesions devoid of ICAP-1alpha and nm23-H2, indicating the dynamic segregation of components of matrix adhesions [17].
• The physiological relevance of this interaction is provided by confocal fluorescence microscopy, which shows that ICAP-1alpha and nm23-H2 are co-localized in lamellipodia during the early stages of cell spreading [17].

Associations of NME2 with chemical compounds

• The pNM23-H2S complementary DNA clone predicted a Mr 17,000 protein 88% identical to nm23-H1. nm23-H2 also shared a significant homology with nucleoside diphosphate kinases and a Drosophila developmental gene [18].
• This is consistent with the fact that targeting of both ICAP-1alpha and nm23-H2 to the cell periphery is dependent on beta(1) integrin engagement rather than being a consequence of cell adhesion [17].
• In neutrophils, only one acidic isoform of each NDPKA and NDPKB was labelled in the presence of EDTA [19].
• Catalysis of DNA cleavage and nucleoside triphosphate synthesis by NM23-H2/NDP kinase share an active site that implies a DNA repair function [20].
• Confirmation of the SSCP data was provided by direct sequencing of nm23-H2 in a stage IV tumor, revealing a leucine to valine mutation at position 48 [21].

Physical interactions of NME2

• In vitro-binding assays using different recombinant nucleoside diphosphate kinases showed that TRF1 predominantly binds the nm23-H2 isoform rather than nm23-H1 [22].
• Nm23-H2 interacts with TPb (Thromboxane receptor isoform b) and through this association regulates TP endocytosis through a Rac1 dependent mechanism [23]

Enzymatic interactions of NME2

• NM23-H1 and NM23-H2 also cleaved within the PDGF-A basal promoter region, again exhibiting preferences for cleavage within the 5'- and 3'-portions of the element, respectively [24].

Regulatory relationships of NME2

• NM23-H1 and NM23-H2 repress transcriptional activities of nuclease-hypersensitive elements in the platelet-derived growth factor-A promoter [24].
• Nm23-H1 and nm23-H2 are strongly up-regulated downstream targets of N-myc [25].

Other interactions of NME2

• Subsequently, two related human nm23 genes, nm23-H1 and nm23-H2, were identified [1].
• Compared to typical proteins of this family such as NME1 and NME2, NME6 has three additional residues located in the Kpn loop, and a 22-residue extension at the COOH-terminal [26].
• Human metastasis-suppressor genes nm23-1 (NME1) and nm23-2 (NME2) are implicated in control of the metastatic potential of malignant cells [27].
• The relationship between expression of nm23-H1 and nm23-H2 in hepatocellular carcinoma specimens from 30 patients and metastatic potential was investigated with the use of a quantitative reverse transcription-PCR procedure [1].
• This finding represents the first evidence that the tumor suppressor nm23-H2 could act on beta(1) integrin-mediated cell adhesion by interacting with one of the integrin partners, ICAP-1alpha [17].

Analytical, diagnostic and therapeutic context of NME2

• A nuclear and nucleolar localization of NDP kinase B was shown by confocal microscopy which was not observed with the A enzyme [28].
• To investigate if the nm23 genes play a central role in the progression of renal tumors, we have examined nm23-H1 and nm23-H2 gene expression using Northern-blot analysis and immunohistochemistry [29].
• This direct interaction was confirmed in vitro, using purified recombinant ICAP-1alpha and nm23-H2, and by co-immunoprecipitation from CHO cell lysates over-expressing ICAP-1alpha [17].
• The aim of this study was to detect the protein expression pattern of NM23-H1 product in 24 OSCCs by immunohistochemistry in paraffin-embedded tissues using a monoclonal antibody non-cross-reactive with NM23-H2 [30].
• Increased expression of two oncogenes, JUN and NME2, was substantiated at the protein level, utilizing immunohistochemical evaluation of GCT sections and Western-blot analysis [31].

References