Abstract
An insulin receptor-like signaling pathway regulates
Caenorhabditis elegans
metabolism, development, and longevity. Inactivation of the insulin receptor homolog DAF-2, the AGE-1 PI3K, or the AKT-1 and AKT-2 kinases causes a developmental arrest at the dauer stage. A null mutation in the
daf-16
Fork head transcription factor alleviates the requirement for signaling through this pathway. We show here that a loss-of-function mutation in
pdk-1
, the
C. elegans
homolog of the mammalian Akt/PKB kinase PDK1, results in constitutive arrest at the dauer stage and increased life span; these phenotypes are suppressed by a loss of function mutation in
daf-16
. An activating mutation in
pdk-1
or overexpression of wild-type
pdk-1
relieves the requirement for AGE-1 PI3K signaling. Therefore,
pdk-1
activity is both necessary and sufficient to propagate AGE-1 PI3K signals in the DAF-2 insulin receptor-like signaling pathway. The activating mutation in
pdk-1
requires
akt-1
and
akt-2
gene activity in order to suppress the dauer arrest phenotype of
age-1
. This indicates that the major function of
C. elegans
PDK1 is to transduce signals from AGE-1 to AKT-1 and AKT-2. The activating
pdk-1
mutation is located in a conserved region of the kinase domain; the equivalent amino acid substitution in human PDK1 activates its kinase activity toward mammalian Akt/PKB.