An insulin-like signaling pathway, from the DAF-2 insulin receptor homologue, the AGE-1 phosphoinositide 3-kinase, the AKT-1/AKT-2 serine/threonine protein kinases to the DAF-16 Fork head transcription factor, regulates the metabolism, development and life span of Caenorhabditis elegans. DAF-2 insulin receptor is likely to signal via the AGE-1 PI 3-kinase which generates lipid second messengers (PI-3,4-P 2 and PI-3,4,5-P 3 ) that activate the Akt kinases. The Akt kinases act redundantly to antagonize the activity of DAF-16 FKHR (Paradis and Ruvkun, 1998). AKT-1 can directly phosphorylate DAF-16 in vitro and AKT-1/AKT-2 are likely to directly antagonize DAF-16 FKHR in vivo. Inhibition of
daf-18 gene activity bypasses the normal requirement for AGE-1 PI 3-kinase and partially bypasses the need for DAF-2 insulin receptor signaling. Using RNA interference, we have demonstrated that the suppression of
age-1 mutations by a
daf-18 mutation depends on AKT-1/AKT-2 signaling. This suggests that DAF-18 acts between the AGE-1 PI 3-kinase and the Akt kinases. Our molecular characterization revealed that
daf-18 encodes a homologue of the human tumor suppressor PTEN (MMAC1/TEP1). PTEN has both tyrosine phosphatase activity and 3-phosphatase activity towards PI-3,4-P 2 and PI-3,4,5-P 3 (Maehama and Dixon, 1998). DAF-18 PTEN likely antagonizes AGE-1 PI 3-kinase and limits AKT-1 and AKT-2 activation by dephosphorylating AGE-1 PI 3-kinase generated lipid second messengers. DAF-18 PTEN may act to modulate or down regulate DAF-2 insulin receptor/AGE-1 PI 3-kinase signaling and/or isolate distinct PI 3-kinase signaling complexes. The action of
daf-18/PTEN in this metabolic control pathway suggests that PTEN may modulate mammalian insulin signaling and may be variant in diabetic pedigrees. These results also suggest a mechanism by which human PTEN suppresses tumor formation by limiting cell growth and survival signals through Akt. Maehama, T. and Dixon, J.E. (1998). J. Biol. Chem. 273:13375-13378. Paradis, S. and Ruvkun, R. (1998). Genes Dev. 12:2488-2498.