nm23 is the first identified human metastasis inhibitor gene that encodes a nucleoside diphosphate kinase (NDPK). Despite its medical significance (heart failure, immunity, insulin release and postnatal survival) the molecular mechanisms by which Nm23 exerts its pluripotent roles are still unclear. Particularly, little is known about the roles of
nm23 during devel opment. In this work we focus on the role of
ndk-1, the worm orthologue of
nm23-H1/H2 in Ras-mediated signalling events. Deletion of
ndk-1 results in sterility and protruding vulva phenotype. The EGFR/Ras/MAPK pathway plays a crucial role in the development of the hermaphrodite vulva. To determine the site of action of
ndk-1 in this cascade, we performed an epistasis analysis with vulval determination genes conferring a multivulva phenotype. Our analysis suggests that
ndk-1 acts downstream of
let-60/Ras and upstream of
mpk-1/ERK during vulval development, similar to
ksr-1 and
ksr-2[1]. KSR proteins serve as scaffolds to assemble Raf/MEK/ERK signalling protein complexes, suggesting they are required for the maintenance of the Ras/MAPK cascade. In the development of the gonad the Ras/MAPK cascade is also responsible for meiotic progression during oogenesis. We found that in the gonad of homozygous
ndk-1 mutants, the level of diphosphorylated MAPK is severely reduced, indicatin g that
ndk-1 is necessary for this Ras-dependent process as well. Loss of MAPK activation in the gonad is also characteristic for
ksr-2 mutants[1]. These findings suggest that
ndk-1 functions in Ras-mediated signalling events similar to
ksr-1 and
ksr-2[1]. Although human Ksr-1 and Nm23-H1 were co-immunoprecipitated[2], no in vivo evidence was presented. Since
ksr-1;
ndk-1 and
ksr-2;
ndk-1 double knockouts exhibit synthetic phenotypes, we further investigate the potential interaction of NDK-1 with KSR-1/2 scaffolds in C. elegans. [1]Ohmachi et al. 2002 Curr. Biol. 12, 427-433 [2]Hartsough et al. 2002 J. Biol.Chem. 277, 32389-32399