Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN.
The tumour suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancer types [1] [2] [3] [4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndromes called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN encodes a dual-specificity phosphatase that inhibits cell spreading and migration partly by inhibiting integrin-mediated signalling [5] [6] [7]. Furthermore, PTEN regulates the levels of phosphatidylinositol 3,4,5-trisphosphate (PIP3) by specifically dephosphorylating position 3 on the inositol ring [8]. We report here that the dauer formation gene daf-18 is the Caenorhabditis elegans homologue of PTEN. DAF-18 is a component of the insulin-like signalling pathway controlling entry into diapause and adult longevity that is regulated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. Others have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Similarly, we show that inactivation of daf-18 by RNA-mediated interference mimics this suppression, and that a wild-type daf-18 transgene rescues the dauer defect. These results indicate that PTEN/daf-18 antagonizes the DAF-2-AGE-1 pathway, perhaps by catalyzing dephosphorylation of the PIP3 generated by AGE-1. These data further support the notion that mutations of PTEN contribute to the development of human neoplasia through an aberrant activation of the PI 3-kinase signalling cascade.
Rouault
J P
JP
Unité INSERM U453, Centre Léon Bérard, 69373 Lyon Cedex 08, France.
Kuwabara
P E
PE
Sinilnikova
O M
OM
Duret
L
L
Thierry-Mieg
D
D
Billaud
M
M
D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins; D002384:Catalysis; D018076:DNA, Complementary / Q000235:genetics; D017238:Genes, Helminth; D016147:Genes, Tumor Suppressor; D015801:Helminth Proteins / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007814:Larva / Q000254:growth & development; D008136:Longevity / Q000235:genetics; D008563:Membrane Lipids / Q000378:metabolism; D005810:Multigene Family; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000235:genetics / Q000502:physiology; D025521:Tumor Suppressor Proteins
D029742:Caenorhabditis elegans Proteins; C116661:DAF-18 protein, C elegans; D018076:DNA, Complementary; D015801:Helminth Proteins; D008563:Membrane Lipids; D018129:Phosphatidylinositol Phosphates; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D019869:Phosphatidylinositol 3-Kinases; C100662:AGE-1 protein, C elegans; C107483:DAF-2 protein, C elegans; D011972:Receptor, Insulin; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human