nm23-H1(currently
nme1), the first identified metastasis inhibitor, encodes a nucleoside diphosphate kinase (NDPK). Despite the wide biological significance of NDPK deletion (heart failure, defective immunity, insulin release and postnatal survival) the molecular mechanisms by which Nm23-H1 exerts its pluripotent roles are still unclear. Here, we focus on the role of
ndk-1 (which corresponds to F25H2.5), the Caenorhabditis elegans orthologue of
nm23-H1/H2 in Ras-mediated signaling events during development. Deletion of
ndk-1 results in a protruding vulva phenotype.
ndk-1 null mutants display a severely reduced diphosphorylated MAPK level in somatic tissues, indicating defects in Ras/ERK signaling. Therefore we examined the interaction of
ndk-1 and the EGFR/Ras/MAPK pathway that is central to vulval development. Reduced expression of the Ras/MAPK target gene
egl-17(FGF) in the
ndk-1 null mutant background further suggests that NDK-1 is needed for full Ras/MAPK activation. Our epistasis analysis demonstrates that
ndk-1 acts downstream of
let-60/Ras and upstream of
mpk-1/ERK during vulval development, at the level of kinase suppressor of Ras (ksr). KSR-1 and KSR-2 proteins act as scaffolds to approximate Ras/MAPK components permitting downstream signaling. Mechanistically we show that NDK-1 binds physically to KSR-2, and we suggest that NDK-1/NDPK activates Ras/MAPK signaling through modification of the KSR-2 scaffold during vulval development in C. elegans. This study provides the first in vivo evidence for the significance of the NDPK/KSR interaction and could provide a model system to understand the pleiotropic effects of NDPK in human diseases.