C. elegans ksr-1 and ksr-2 Have Both Unique and Redundant Functions and Are Required for MPK-1 ERK Phosphorylation

Abstract

Kinase Suppressor of Ras (KSR) is a conserved protein that positively regulates Ras signaling and may function as a scaffold for Raf, MEK, and ERK. However, the precise role of KSR is not well understood, and some observations have suggested that KSR might act in a parallel pathway. In C. elegans, ksr-1 is only required for a specific Ras-mediated process (sex myoblast migration) and is a nonessential positive regulator of other Ras-mediated developmental events. We report the existence of a second C. elegans ksr gene, ksr-2, which is required for Ras-mediated signaling during germline meiotic progression and functions redundantly with ksr-1 during development of the excretory system, hermaphrodite vulva, and male spicules. Thus, while the ksr-1 and ksr-2 genes are individually required only for specific Ras-dependent processes, together these two genes appear necessary for most aspects of Ras-mediated signaling in C. elegans. The finding that ksr-2; ksr-1 double mutants have strong ras-like phenotypes and severely reduced or absent levels of diphosphorylated MPK-1 ERK strongly supports models where KSR acts to promote the activation or maintenance of the Raf/MEK/ERK kinase cascade.

The Caenorhabditis elegans ekl (Enhancer of ksr-1 Lethality) Genes Include Putative Components of a Germline Small RNA Pathway

“…In C. elegans, as in mammals, KSR is encoded by two paralogous genes, ksr-1 and ksr-2, which have both overlapping and unique functions (Ohmachi et al 2002;Channavajhala et al 2003). For example, ksr-1 and ksr-2 are redundantly required for Ras-ERK-dependent specification of vulval and excretory duct cell fates, while ksr-1 alone is required for Ras-ERK-dependent sex myoblast migration, and ksr-2 alone is required for Ras-ERK-dependent germline meiotic progression.…”

Conferring specificity on the ubiquitous Raf/MEK signalling pathway

“…Gene knockout experiments in the worm C. elegans, which like mammals has two KSR genes, has revealed overlapping as well as some specific functions for the two KSR genes. However, when both genes were removed, ERK activation was severely compromised and the phenotype was similar to disabling the let-60 Ras gene (Ohmachi et al, 2002). Knocking out KSR1 in mice did not result in any gross abnormalities, although ERK activation in response to growth factors was modestly attenuated and the T-cell response to antigen was impeded.…”

Nucleoside diphosphate kinases (NDPKs) in animal development

“…These data suggest that NDK-1 is necessary for full activation of MAPK signaling in somatic tissues of the worm. Because the scaffold proteins KSR-1/KSR-2 (kinase suppressor of Ras) are indispensable for MAPK activation [64], and because several studies on human cell lines have linked NM23's function to KSR scaffolds [65,66], ndk-1(-);ksr-1(-) and ndk-1(-)ksr-2(-) double knockouts were generated to test potential genetic interactions between ndk-1 and ksr genes. In these double mutants, ndk-1 single-mutant phenotypes were enhanced.…”