Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor.
A neurosecretory pathway regulates a reversible developmental arrest and metabolic shift at the Caenorhabditis elegans dauer larval stage. Defects in an insulin-like signaling pathway cause arrest at the dauer stage. We show here that two C. elegans Akt/PKB homologs, akt-1 and akt-2, transduce insulin receptor-like signals that inhibit dauer arrest and that AKT-1 and AKT-2 signaling are indispensable for insulin receptor-like signaling in C. elegans. A loss-of-function mutation in the Fork head transcription factor DAF-16 relieves the requirement for Akt/PKB signaling, which indicates that AKT-1 and AKT-2 function primarily to antagonize DAF-16. This is the first evidence that the major target of Akt/PKB signaling is a transcription factor. An activating mutation in akt-1, revealed by a genetic screen, as well as increased dosage of wild-type akt-1 relieves the requirement for signaling from AGE-1 PI3K, which acts downstream of the DAF-2 insulin/IGF-1 receptor homolog. This demonstrates that Akt/PKB activity is not necessarily dependent on AGE-1 PI3K activity. akt-1 and akt-2 are expressed in overlapping patterns in the nervous system and in tissues that are remodeled during dauer formation.
Paradis
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S
Department of Molecular Biology, Massachusetts General Hospital (MGH) and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114 USA.
Ruvkun
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D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D015971:Gene Expression Regulation, Enzymologic; D015801:Helminth Proteins / Q000378:metabolism*; D008017:Life Expectancy; D008969:Molecular Sequence Data; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; D051858:Forkhead Transcription Factors; D015801:Helminth Proteins; D015513:Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D014157:Transcription Factors; C108831:daf-16 protein, C elegans; C100662:AGE-1 protein, C elegans; C107483:DAF-2 protein, C elegans; C494915:akt-1 protein, C elegans; C494916:akt-2 protein, C elegans