Nucleoside diphosphate kinases (NDPKs) in animal development

Abstract

In textbooks of biochemistry, nucleoside diphosphate conversion to a triphosphate by nucleoside diphosphate 'kinases' (NDPKs, also named NME or NM23 proteins) merits a few lines of text. Yet this essential metabolic function, mediated by a multimeric phosphotransferase protein, has effects that lie beyond a simple housekeeping role. NDPKs attracted more attention when NM23-H1 was identified as the first metastasis suppressor gene. In this review, we examine these NDPK enzymes from a developmental perspective because of the tractable phenotypes found in simple animal models that point to common themes. The data suggest that NDPK enzymes control the availability of surface receptors to regulate cellsensing cues during cell migration. NDPKs regulate different forms of membrane enclosure that engulf dying cells during development. We suggest that NDPK enzymes have been essential for the regulated uptake of objects such as bacteria or micronutrients, and this evolutionarily conserved endocytic function contributes to their activity towards the regulation of metastasis.

Hydrogen/Deuterium Exchange Mass Spectrometry Reveals Mechanistic Details of Activation of Nucleoside Diphosphate Kinases by Oligomerization

“…High eukaryotes have several isoforms of NDPK with additional functions: metastasis suppression in humans (35,36,69,70) and involvement in animal development. (71)(72)(73) Interestingly, natural mutants for these two hexameric NDPKs present folding or assembly defects. (72) Since our present study on Mt-NDPK shows that flexibility is increased by the hexamer's destabilization, we suggest these mutants are inactive because of aberrant conformational dynamics.…”

The NDPK/NME superfamily: state of the art

“…Taken together, these data clearly indicate that dynamin and NME/ NDPKs are close functional partners involved in membrane remodeling and trafficking across different species. 109 Dynamin superfamily proteins are unique molecular motors that use GTP instead of ATP.…”

NM23 proteins: innocent bystanders or local energy boosters for CFTR?

“…We need to speak in a common language if those working on CFTR, membrane blocks in autophagy, endosome recycling, and apical membrane function are ever to meet in a common research arena with those interested in phosphohistidine generation. For example, we suggest that new research might aim to link up the following ideas: (a) CK2 is log-orders overactive in CF cells bearing the common CFTR mutation; 93 (b) CK2 phosphorylates key residues on calmodulin located between two of its EF hands; 94 (c) NDPK controls dynamin as the terminal step in endocytosis and is important in cell homing during embryogenesis; 95,96 (d) AMPK and NDPK control adjacent supply points for the cytosolic availability of acetyl units needed for new membrane synthesis; 97 (e) CK2 phosphorylation controls both the localization and function of sodium channels that become dysfunctional after CFTR mutation. [98][99][100] These are some of the known unknowns in CFTR and NDPK research that our model seeks to clarify.…”