NME genes in epithelial morphogenesis

Abstract

The NME family of genes encodes highly conserved multifunctional proteins that have been shown to participate in nucleic acid metabolism, energy homeostasis, cell signaling, and cancer progression. Some family members, particularly isoforms 1 and 2, have attracted extensive interests because of their potential anti-metastasis activity. Unfortunately, there have been few consensus mechanistic explanations for this critical function because of the numerous molecular functions ascribed to these proteins, including nucleoside diphosphate kinase, protein kinase, nuclease, transcription factor, growth factor, among others. In addition, different studies showed contradictory prognostic correlations between NME expression levels and tumor progression in clinical samples. Thus, analyses using pliable in vivo systems have become critical for unraveling at least some aspects of the complex functions of this family of genes. Recent works using the Drosophila genetic system have suggested a role for NME in regulating epithelial cell motility and morphogenesis, which has also been demonstrated in mammalian epithelial cell culture. This function is mediated by promoting internalization of growth factor receptors in motile epithelial cells, and the adherens junction components such as E-cadherin and β-catenin in epithelia that form the tissue linings. Interestingly, NME genes in epithelial cells appear to function in a defined range of expression levels. Either down-regulation or over-expression can perturb epithelial integrity, resulting in different aspects of epithelial abnormality. Such biphasic functions provide a plausible explanation for the documented anti-metastatic activity and the suspected oncogenic function. This review summarizes these recent findings and discusses their implications.

The dosage-dependent effect exerted by the NM23-H1/H2 homolog NDK-1 on distal tip cell migration in C. elegans

“…56 These data first showed that both lack or have an excess AWD activity disturb epithelial integrity and suggested that an optimal dosage of AWD is needed to balance demand and supply of adherens junction components in follicular cells. 49 …”

“…ndk-1 gene leads to normal U-shaped gonad arms, half dosage of ndk-1 present in heterozygotes results in extra turns and overshoots of migrating gonad arms, and in response to excess NDK-1 incompletely elongated, J-shaped gonad arms are developed (Table 1). In Drosophila during tracheal morphogenesis, homozygous awd − /awd − loss-of-function mutants and awd+/awd − heterozygotes show also different phenotypes: in homozygotes a complete disruption of tracheal tubules, whereas in heterozygotes ectopic branch migration was observed, 49 Table 1). In our opinion, a parallel can be drawn between DTC migration phenotypes in the nematode and tracheal migration phenotypes in the fruit fly: complete absence of the NDPK homolog results in incomplete migration, but presence of half dosage of NDPK causes ectopic migration in both models (eg, extra gonadal turns in the worm and ectopic tracheal branches in the fly, see Table 1).…”

“…44 Different tracheal phenotypes were observed in case of awd homozygotes and heterozygotes: in the former case a complete disruption of tracheal tubules, whereas in the latter case ectopic branch migration was noted. 44,49 In homozygotes complete loss-of AWD resulted in over accumulation of surface receptor and delayed migration, which is the net outcome of random movement of the cells as a consequence of lack of directional cues due to symmetrical signal activation of the receptor. In heterozygotes the former severe phenotype is rarely seen, in the majority of cases the overall tracheal network is developed often with ectopic branches.…”

Proteomic Characterization of Plasma Cells from Patients with Multiple Myeloma

“…Unfortunately, there have been few consensus mechanistic explanations for this critical function because of the numerous molecular functions ascribed to these proteins, including nucleoside diphosphate kinase, protein kinase, nuclease, transcription factor, growth factor, among others [45]. At present, it is not yet clear what molecular activity of NME is involved in multiple myeloma and such information will be of ultimate importance for the NME studies in general.…”

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

“…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.…”