Authors: Paradis S; Ailion M; Toker A; Thomas JH; Ruvkun G
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.
Keywords: Alanine; Alleles; Amino Acid Sequence; Animals; Caenorhabditis elegans/*enzymology/genetics/*physiology; *Caenorhabditis elegans Proteins; Enzyme Activation; Gene Expression Regulation, Enzymologic; Green Fluorescent Proteins; Helminth Proteins/*metabolism; Humans; Luminescent Proteins/genetics; Molecular Sequence Data; Mutagenesis; Phenotype; Phosphatidylinositol 3-Kinases/*metabolism; Protein-Serine-Threonine Kinases/genetics/*metabolism; Proto-Oncogene Proteins/genetics; Proto-Oncogene Proteins c-akt; Receptor, Insulin/genetics/metabolism; Sequence Homology, Amino Acid; *Signal Transduction; Valine|
Journal: Genes & development Volume: 13 Issue: 11 Pages: 1438-52 Date: June 11, 1999 PMID: 10364160 |
Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G (1999) A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes & development 13: 1438-52.
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