Abstract
An insulin-like signaling pathway, from the DAF-2 receptor, the AGE-1 phosphoinositide 3-kinase, and the AKT-1/AKT-2 serine/threonine kinases to the DAF-16 Fork head transcription factor, regulates the metabolism, development, and life span of Caenorhabditis elegans. Inhibition of daf-18 gene activity bypasses the normal requirement for AGE-1 and partially bypasses the need for DAF-2 signaling. The suppression of age-1 mutations by a daf-18 mutation depends on AKT-1/AKT-2 signaling, showing that DAF-18 acts between AGE-1 and the AKT input to DAF-16 transcriptional regulation. daf-18 encodes a homolog of the human tumor suppressor PTEN (MMAC1/TEP1), which has 3-phosphatase activity toward phosphatidylinositol 3,4,5-trisphosphate (PIP3). DAF-18 PTEN may normally limit AKT-1 and AKT-2 activation by decreasing PIP3 levels. The action of daf-18 in this metabolic control pathway suggests that mammalian PTEN may modulate insulin signaling and may be variant in diabetic pedigrees.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Amino Acid Sequence
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Animals
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Base Sequence
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Caenorhabditis elegans / chemistry
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Caenorhabditis elegans / genetics
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Caenorhabditis elegans / physiology*
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Caenorhabditis elegans Proteins*
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Epistasis, Genetic
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Gene Expression Regulation
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Genes, Helminth / genetics
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Helminth Proteins / genetics
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Helminth Proteins / physiology*
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Larva / genetics
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Molecular Sequence Data
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PTEN Phosphohydrolase
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Phenotype
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Phosphatidylinositol 3-Kinases*
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Phosphoric Monoester Hydrolases / genetics*
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Protein Serine-Threonine Kinases / genetics
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins c-akt
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RNA, Double-Stranded / genetics
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RNA, Helminth / genetics
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Receptor, Insulin / genetics
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Receptor, Insulin / physiology*
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Sequence Homology, Amino Acid
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Signal Transduction
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Tumor Suppressor Proteins*
Substances
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Caenorhabditis elegans Proteins
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DAF-18 protein, C elegans
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Helminth Proteins
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Proto-Oncogene Proteins
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RNA, Double-Stranded
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RNA, Helminth
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Tumor Suppressor Proteins
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AGE-1 protein, C elegans
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DAF-2 protein, C elegans
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Receptor, Insulin
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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akt-1 protein, C elegans
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akt-2 protein, C elegans
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Phosphoric Monoester Hydrolases
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PTEN Phosphohydrolase