The metastasis suppressor Nm23 as a modulator of Ras/ERK signaling

Abstract

NM23-H1 (also known as NME1) was the first identified metastasis suppressor, which displays a nucleoside diphosphate kinase (NDPK) and histidine protein kinase activity. NDPKs are linked to many processes, such as cell migration, proliferation, differentiation, but the exact mechanism whereby NM23-H1 inhibits the metastatic potential of cancer cells remains elusive. However, some recent data suggest that NM23-H1 may exert its anti-metastatic effect by blocking Ras/ERK signaling. In mammalian cell lines NDPK-mediated attenuation of Ras/ERK signaling occurs through phosphorylation (thus inactivation) of KSR (kinase suppressor of Ras) scaffolds. In this review I summarize our knowledge about KSR's function and its regulation in mammals and in C. elegans. Genetic studies in the nematode contributed substantially to our understanding of the function and regulation of the Ras pathway (i.e. KSR's discovery is also linked to the nematode). Components of the RTK/Ras/ERK pathway seem to be highly conserved between mammals and worms. NDK-1, the worm homolog of NM23-H1 affects Ras/MAPK signaling at the level of KSRs, and a functional interaction between NDK-1/NDPK and KSRs was first demonstrated in the worm in vivo. However, NDK-1 is a factor, which is necessary for proper MAPK activation, thus it activates rather than suppresses Ras/MAPK signaling in the worm. The contradiction between results in mammalian cell lines and in the worm regarding NDPKs' effect exerted on the outcome of Ras signaling might be resolved, if we better understand the function, structure and regulation of KSR scaffolds.

Keywords: Kinase; Kinase suppressor of Ras (KSR); Metastasis inhibitor; Nm23; Nucleoside-diphosphate kinase (NDPK); Ras/ERK signaling; Scaffold.

Figure 1

Domain organization of the worm KSR proteins related to murine KSR1. KSR proteins consist of five conserved areas (CA): CA1 (KSR-specific domain), CA2 (proline-rich region), CA3 (cysteine-rich region), CA4 (serine/threonine-rich region), CA5 (kinase-like domain). C. elegans (C.e.) KSR-1 and KSR-2A lack the CA1 domain. Worm KSR-1 lacks the CA2 domain, whereas in KSR-2A the CA4 domain with the FXFP motif (ERK/MAPK docking site) is absent. 14-3-3 binding sites Ser297 (S*) and Ser392 (S* marked red) located on either side of the CA3 domain in the mouse protein (mKSR1) are absent in the worm proteins.

Figure 2

Scaffolds of the Raf/MEK/ERK cascade and regulation of KSR in mammals and in the nematode. SOC-2/SUR-8, CNK/CNK-1 and KSR are scaffolds of the Raf/MEK/ERK cascade. SOC-2/SUR-8 and CNK/CNK-1 are thought to facilitate Raf activation [52,53]. KSR assembles Raf/MEK/ERK complexes and functions downstream of Raf. A) Protein interactions in mammals [22]. C-TAK1 and Nm23-H1 phosphorylate Ser392 of mammalian KSR, while PP2A is able to dephosphorylate the same residue. B) Genetic interactions in C. elegans. PAR-1 inhibits, while SUR-6/PP2A activates KSR-1. NDK-1 activates Ras signaling at the level of KSRs. The molecular mechanisms are not known. The regulation of KSR-2 remains to be determined. The mammalian proteins and their nematode homologs are labeled by the same color.

Figure 3

EGL-17/FGF, a known MAPK target shows reduced expression in ndk-1(−) mutant background. The vulva of wild-type hermaphrodites develops from a subset of epidermal blast cells, called vulval precursor cells (VPCs). P(5–7).p VPCs undergo three rounds of cell division and give rise to 22 vulval cells. The vulva at mid-L4 larval stage is composed of 22 cells, which can be grouped into seven cell types (vulA, B1, B2, C, D, E and F). These cells are the great-granddaughters of P5.p-P7.p VPCs (grey filled circles: primary lineages; white circles: secondary lineages). EGL-17/FGF is a known MAPK target, which is expressed in all daughters (P6p.x) and granddaughters (P6p.xx) of P6.p in the L3 stage in wild-type animals. EGL-17/FGF expression was reduced in P6p.xx cells (red triangle) in ndk-1(−) mutants suggesting that Ras/MAPK signaling is inhibited in the absence of NDK-1 [18].