The Function of NM23-H1/NME1 and Its Homologs in Major Processes Linked to Metastasis

Abstract

Metastasis suppressor genes (MSGs) inhibit different biological processes during metastatic progression without globally influencing development of the primary tumor. The first MSG, NM23 (non-metastatic clone 23, isoform H1) or now called NME1 (stands for nonmetastatic) was identified some decades ago. Since then, ten human NM23 paralogs forming two groups have been discovered. Group I NM23 genes encode enzymes with evolutionarily highly conserved nucleoside diphosphate kinase (NDPK) activity. In this review we summarize how results from NDPKs in model organisms converged on human NM23 studies. Next, we examine the role of NM23-H1 and its homologs within the metastatic cascade, e.g. cell migration and invasion, proliferation and apoptosis. NM23-H1 homologs are well known inhibitors of cell migration. Drosophila studies revealed that AWD, the fly counterpart of NM23-H1 is a negative regulator of cell motility by modulating endocytosis of chemotactic receptors on the surface of migrating cells in cooperation with Shibire/ Dynamin; this mechanism has been recently confirmed by human studies. NM23-H1 inhibits proliferation of tumor cells by phosphorylating the MAPK scaffold, kinase suppressor of Ras (KSR), resulting in suppression of MAPK signalling. This mechanism was also observed with the C. elegans homolog, NDK-1, albeit with an inverse effect on MAPK activation. Both NM23-H1 and NDK-1 promote apoptotic cell death. In addition, NDK-1, NM23-H1 and their mouse counterpart NM23-M1 were shown to promote phagocytosis in an evolutionarily conserved manner. In summary, inhibition of cell migration and proliferation, alongside actions in apoptosis and phagocytosis are all mechanisms through which NM23-H1 acts against metastatic progression.

NME/NM23/NDPK and Histidine Phosphorylation

“…In this way, NME1 overexpressing cells treated with granzyme A are more sensitive to DNA damage [163,164]. In C. elegans and in humans NME promotes the engulfment of apoptotic cells through its interaction with Dynamin1 and 2 [103,165,166]. In the same study, this function was also seen in murine models where NME1 silenced bone marrow-derived macrophages cleared fewer apoptotic thymocytes [166].…”

“…Surprisingly, unlike in humans, NDK-1 activates the Ras/MAPK signaling pathway [54,153]. A possible explanation of this difference is the differential regulation of the KSR scaffold [103]. Nevertheless, these data suggest that NME1 regulates Ras/MAPK signaling through its protein kinase function.…”

“…Whether phosphorylated histidine residues regulate the formation of this complex is still unknown. Studies in Drosophila [26] and mammalian cell lines demonstrate that NME interacts with dynamin 1 to regulate cell migration through the internalization of chemotactic receptors in migrating cells [101][102][103]. Although it is proposed that NME acts through its NDPK function to generate GTP locally for dynamin GTPase function, whether its histidine protein kinase function also plays an important role in this interaction is unknown.…”

“…NME1 can also promote cell death or enhance the engulfing phagocytic capacity of cells [103]. In C. elegans, binding of microRNA mir-35 to NDK-1 modulates the activation of the MAPK pathway resulting in DNA damage-induced apoptosis of germ cells [162].…”

The Impact of Drosophila Awd/NME1/2 Levels on Notch and Wg Signaling Pathways

“…It has been shown that the endocytic function of Awd and its human and C. elegans homologues is involved in the motility of migrating cells. A dosage-dependent effect of Awd/NDK-1 (Nucleoside Diphosphate Kinase-1) has been reported on the migration of tracheal and border cells in Drosophila and of distal tip cells in C. elegans [ 13 ]. Furthermore, a role in the maintenance of genomic stability has also been assigned to both NME1 and Awd [ 14 , 15 ].…”