A critical evaluation of biochemical activities reported for the nucleoside diphosphate kinase/Nm23/Awd family proteins: opportunities and missteps in understanding their biological functions.

Abstract

The nucleoside diphosphate kinase (NDP kinase or NDPK) protein family has been discovered several times, with implications for the fields of development, signaling, and cancer. In the 1950s, the Nobel laureates, Paul Berg and Hans Krebs, independently identified a biochemical activity that removed the terminal phosphate from a nucleoside triphosphate (NTP), and added it to a nucleoside diphosphate (NDP), the NDPK activity (Berg and Joklik, 1953; Krebs and Hems, 1953). Consequently, the correct biochemical name for the enzyme is NTP/NDP transphosphorylase. NDPK activity was implicated in the regulation multiple aspects of cellular physiology, including nucleotide pools and consequent growth, G-protein signaling, microtubule dynamics, and mutational susceptibility. In the late 1980s, a furor erupted when cancer metastasis, the spread of tumor cells from a primary tumor to a distant site, was linked to the loss of a gene of unknown function, named nm23 (Steeg et al. 1988). A functional link was established several years later when transfection of nm23 into a murine melanoma cell line significantly reduced its metastatic spread, without effects on primary tumor size (Leone et al. 1991). Sequencing of the two forms of human Nm23 (Nm23-H1 and –H2) revealed an identity to two NDPKs A and B (Wallet et al. 1990). At the same time, developmental processes in the imaginal discs of Drosophila were reported to be regulated by the abnormal wing disc (awd) gene, almost 90% identical to human NDPK/Nm23 through evolution (Rosengard et al. 1989). A complex story thus began. Today, it is clear that NDPK-A and NDPK-B belong to a protein family encoded by the NME genes of which ten different genes have been found in man. Phylogenetic analyses identified two distinct subgroups (Bilitou et al. 2009; Desvignes et al. 2009). The first group consists of four genes (nme1-4) encoding homologous proteins (NDPKs A–D) with NDPK activity. Group II genes appeared also early in evolution (see (Desvignes et al. 2011; Perina et al. 2011) in this issue of Naunyn-Schmiedeberg's Archives of Pharmacology). They encode more divergent proteins with low or no demonstrated NDPK activity. Recent reviews presenting different aspects of the proposed activities of NDPK/Nm23/Awd proteins in tumor metastasis are presented in this issue of NaunynSchmiedeberg's Archives of Pharmacology (Andolfo et al. 2011; Bruneel et al. 2011; Hsu, 2011; Marino et al. 2011; Novak et al. 2011; Thakur et al. 2011). With over 50 years of research experience on this protein family between the authors, we have reviewed the reported biochemical activities of Nme proteins with a critical eye, concentrating on the first two members of the NDPK family. Our analysis reveals a list of tantalizing activities that may P. S. Steeg Women’s Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Building 37, Room 1122, National Institutes of Health, Bethesda, MD 20892, USA e-mail: steegp@mail.nih.gov