The insulin/IGF-1 pathway controls a number of physiological processes in the nematode worm Caenorhabditis elegans, including development, aging and stress response. We previously found that the Akt/PKB ortholog AKT-1 dampens the apoptotic response to genotoxic stress in the germline by negatively regulating the
p53-like transcription factor CEP-1. Here, we report unexpected rearrangements to the insulin/IGF-1 pathway, whereby the insulin-like receptor DAF-2 and 3-phosphoinositide-dependent protein kinase PDK-1 oppose AKT-1 to promote DNA damage-induced apoptosis. While DNA damage does not affect phosphorylation at the PDK-1 site Thr350/Thr308 of AKT-1, it increased phosphorylation at Ser517/Ser473. Although ablation of
daf-2 or
pdk-1 completely suppressed
akt-1-dependent apoptosis, the transcriptional activation of CEP-1 was unaffected, suggesting that
daf-2 and
pdk-1 act independently or downstream of
cep-1 and
akt-1. Ablation of the
akt-1 paralog
akt-2 or the downstream target of the insulin/IGF-1 pathway
daf-16 (a FOXO transcription factor) restored sensitivity to damage-induced apoptosis in
daf-2 and
pdk-1 mutants. In addition,
daf-2 and
pdk-1 mutants have reduced levels of phospho-MPK-1/ERK in their germ cells, indicating that the insulin/IGF-1 pathway promotes Ras signaling in the germline. Ablation of the Ras effector
gla-3, a negative regulator of
mpk-1, restored sensitivity to apoptosis in
daf-2 mutants, suggesting that
gla-3 acts downstream of
daf-2. In addition, the hypersensitivity of
let-60/Ras gain-of-function mutants to damage-induced apoptosis was suppressed to wild-type levels by ablation of
daf-2. Thus, insulin/IGF-1 signaling selectively engages AKT-2/DAF-16 to promote DNA damage-induced germ cell apoptosis downstream of CEP-1 through the Ras pathway.