The C. elegans PTEN Homolog, DAF-18, Acts in the Insulin Receptor-like Metabolic Signaling Pathway

• Published in: Molecular cell 1998-12, Vol.2 (6), p.887-893
• Main Authors: Ogg, Scott, Ruvkun, Gary
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Caenorhabditis elegans; Caenorhabditis elegans - chemistry; Caenorhabditis elegans - genetics; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins; Epistasis, Genetic; Gene Expression Regulation; Genes, Helminth - genetics; Helminth Proteins - genetics; Helminth Proteins - physiology; Larva - genetics; Molecular Sequence Data; Phenotype; Phosphatidylinositol 3-Kinases; Phosphoric Monoester Hydrolases - genetics; Protein-Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Receptor, Insulin - genetics; Receptor, Insulin - physiology; RNA, Double-Stranded - genetics; RNA, Helminth - genetics; Sequence Homology, Amino Acid; Signal Transduction; Tumor Suppressor Proteins
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/S1097-2765(00)80303-2

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 (PIP 3). DAF-18 PTEN may normally limit AKT-1 and AKT-2 activation by decreasing PIP 3 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.