Modulation of small GTPase activity by NME proteins

Abstract

NME proteins are reported to influence signal transduction activity of small GTPases from the Ras superfamily by diverse mechanisms in addition to their generic NDP kinase activity, which replenishes the cytoplasmic pool of GTP. Comprehensive evidence shows that NME proteins modulate the activity of Ras GTPases, in particular members of the Rho family, via binding to their major activators GEFs. Direct interaction between several NMEs and Ras GTPases were also indicated in vitro and in vivo. These modes of regulation are mainly independent of the NME's kinase activity. NMEs also modulate the Ras-mediated signal transduction by interfering with the formation of a Ras signaling complex at the plasma membrane. In several examples, NMEs were proposed to perform the role of GAP proteins by promoting hydrolysis of the bound GTP, but this activity still requires additional verification. Early suggestions that NMEs can activate small GTPases by direct phosphorylation of the bound GDP, or by high-rate loading of GTP onto a closely apposed GTPase, were largely dismissed. In this review article, we survey and put into perspective published examples of identified and hypothetical mechanisms of Ras signaling modulation by NME proteins. We also point out involvement of NMEs in the transcriptional regulation of components of Ras GTPases-mediated signal transduction pathways, and reciprocal regulation of NME function by small GTPases, particularly related to NME's binding to membranes.

The Subcellular Localization and Oligomerization Preferences of NME1/NME2 upon Radiation-Induced DNA Damage

“…Numerous studies reported NME1 and NME2 to be associated with a number of different binding/interacting partners [34]. Both proteins have been found to interact with dynamin [24], while NME1 additionally interacts with PRUNE 1 (Prune Exopolyphosphatase 1) [35], STRAP (Serine/Threonine Kinase Receptor Associated Protein) [36], MIF (Macrophage Migration Inhibitory Factor) [37], VHL (Von Hippel-Lindau) tumor suppressor [38], tumor virus-encoded oncoprotein EBNA 1-3C (Epstein-Barr Nuclear Antigen 1-3C) [39], and a number of small GTPases [40]. NME2 was reported to interact with MDM2 (Mouse Double Minute 2 Homolog) [41], TRF1 (Telomeric Repeat Binding Factor 1) [42], ICAP1α (Integrin Cytoplasmic Domain-Associated Protein 1α) [21], and several other proteins.…”

Characterization of MRCK(a) Autophosphorylation and its Role in the Actomyosin Cytoskeleton Complex

“…NDPK proteins have been shown to modulate Rho GTPases that are bound to their GEFs such as Tiam-1, Dbl-1 and Lbc of Ras, which relies directly on the protein-protein interaction of NME with GEFs (Filić et al, 2018). This was further shown by performing a two-way coimmunoprecipitation using HEK293T cells and mouse brain extracts, which had showed that NME1 and Tiam1 associate with each other, which was completely independent of NDPK kinase activity.…”

“…GTPases in order to regulate them. In fact, inhibition of signaling downstream of Ras was shown to be caused be NME1 (Filić et al, 2018). Examples include upregulation of regulators of Gprotein signaling families and KSR, which is a scaffold for Ras/Raf/MEK/ERK signaling pathways, by NME1.…”

A young researcher’s guide to NME/Nm23/NDP Kinase

“…In the recent years, the most thoroughly investigated members of the NME family, NME1 and NME2 have both been reported to interact with dynamin (37). Additionally, NME1 seems to interact with prune (38), MIF (39), p53/STRAP (40), WHL (41,42) and a number of small GTPase interacting proteins (43). NME2 has been reported to interact with TRF1 (44), MDM2 (45), ICAP1a (46) and several others.…”