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 [1-4]. In addition, germline mutation of PTEN is responsible for two dominantly inherited, related cancer syndrom es called Cowden disease and Bannayan-Ruvalcaba-Riley syndrome [4]. PTEN en codes a dual-specificity phosphatase that inhibits cell spreading and migra tion partly by inhibiting integrin-mediated signalling [5-7]. 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 ele gans homologue of PTEN. DAF-18 is a component of the insulin-like signallin g pathway controlling entry into diapause and adult longevity that is regul ated by the DAF-2 receptor tyrosine kinase and the AGE-1 PI 3-kinase [9]. O thers have shown that mutation of daf-18 suppresses the life extension and constitutive dauer formation associated with daf-2 or age-1 mutants. Simila rly. we show that inactivation of daf-18 by RNA mediated interference mimic s 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 contri bute to the development of human neoplasia through an aberrant activation o f the PI 3-kinase signalling cascade.