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.
Highlights
NM23-H1 was the first identified metastasis suppressor, which displays a nucleoside diphosphate kinase (NDPK) and histidine protein kinase activity
In the human breast carcinoma cell line MDA-MB435 and in HEK293 cells NM23-H1 has been shown to phosphorylate KSR1 on Ser392 [14,15,17], and NM23H1 overexpression in those cells resulted in reduced levels of MAPK signaling
NDPKs might attenuate Ras/ERK signaling through phosphorylation of Kinase suppressor of Ras (KSR) scaffolds
Summary
NM23-H1 ( known as NME1) was the first identified metastasis suppressor, which displays a nucleoside diphosphate kinase (NDPK) and histidine protein kinase activity. The scaffold protein KSR (kinase suppressor of Ras) helps in Raf activation, and contributes to the sequential phosphorylation steps of the MAPK cascade by bringing together MAPK components, Raf, MEK and ERK/MAPK. KSR provides a scaffold, which facilitates the phosphorylation steps in the MAPK cascade in order to execute signal transduction downstream of Ras. The domain structure of KSR proteins is similar to that of Raf family members indicating their possible common origin (reviewed in [41]).
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