The human tumour suppressor PTEN regulates longevity and dauer formation in Caenorhabditis elegans.
The PTEN tumour suppressor is a phosphatase that dephosphorylates phosphatidylinositol 3, 4, 5 triphosphate (PIP3) and protein substrates. PTEN function is modulated by its carboxy-terminal region, which contains several clustered phosphorylation sites and a PDZ-binding motif (PDZbm). Although PTEN growth suppression effect is well demonstrated, its additional biological roles are less well understood. DAF-18, a Caenorhabditis elegans homologue PTEN, is a component of the insulin/IGF-I signalling pathway that controls entry to the dauer larval stage and adult longevity. To further explore the role of PTEN in the insulin signalling cascade and its possible involvement in the mechanisms of ageing, we undertook a study of PTEN function in C. elegans. We now report that human PTEN can substitute for DAF-18 and restores the dauer and longevity phenotypes in worms devoid of DAF-18. Furthermore, we provide genetic and biochemical evidence that dauer and lifespan control depends on PTEN-mediated regulation of PIP3 levels. Finally, we established that phosphorylation sites in the C-terminus of PTEN and its PDZbm are necessary for PTEN control of the insulin/IGF-I pathway. These results demonstrate that PTEN negatively regulates the insulin/IGF pathway in a whole organism and raise the hypothesis that PTEN may be involved in mammalian ageing.
Solari
Florence
F
Laboratoire Génétique et cancer, FRE 2692 CNRS, Université Claude Bernard Lyon 1, Domaine Rockefeller, 8 avenue Rockefeller, 69373 Cedex 08, Lyon, France.
Bourbon-Piffaut
Angélique
A
Masse
Ingrid
I
Payrastre
Bernard
B
Chan
Andrew M-L
AM
Billaud
Marc
M
D000375:Aging / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D009154:Mutation; D051059:PTEN Phosphohydrolase; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D029742:Caenorhabditis elegans Proteins; C116661:DAF-18 protein, C elegans; D007328:Insulin; D018129:Phosphatidylinositol Phosphates; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D007334:Insulin-Like Growth Factor I; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human