The JNK MAP kinase (MAPK) pathway plays a pivotal role in the various stress responses of evolutionarily diverse species. In C. elegans, a JNK-like MAPK signaling pathway composed of MLK-1 MAPKKK, MEK-1 MAPKK, and KGB-1 JNK-like MAPK controls stress response. The KGB-1 cascade is inactivated by VHP-1 MAPK phosphatase. The
vhp-1 loss-of-function mutation or expression of constitutively activated MEK-1(SSEE) causes hyperactivation of the KGB-1 pathway, resulting in lethality. However, components mediating this pathway remain unknown. Recently, mapping of the C. elegans interactome network has revealed that MEK-1 physically interacts with SHC-1, an adaptor protein highly homologous to mammalian Shc. We have conducted the genetic and biochemical analysis to elucidate the function of SHC-1 in the KGB-1 cascade. We found that the
shc-1 deletion mutation is defective in activation of KGB-1 and results in hypersensitivity to heavy metals, whose phenotypes are also observed in
mlk-1 and
mek-1 mutants. The
shc-1 mutation can suppress the lethality caused by the
vhp-1 mutation but not that by expression of MEK-1(SSEE). This suggests that SHC-1 acts at the level of MEK-1. Consistent with this possibility, SHC-1 is necessary for activation of MEK-1. Thus, the C. elegans Shc protein plays a critical role in stress response by mediating activation of MEK-1 in the KGB-1 MAPK signaling pathway.