Florence Solari et al. (2002) European Worm Meeting "The human PTEN tumor suppressor regulates diapause and longevity in Caenorhabditis elegans."

Florence Solari, Marc Billaud, Angelique Bourbon-Piffaut

[European Worm Meeting, 2002]

The tumor suppressor gene PTEN (also called MMAC1 or TEP1) is somatically mutated in a variety of cancers. In addition, germline mutations of PTEN are responsible for two dominantly inherited cancer syndromes called Cowden disease and Bannayan-Zonana syndrome. PTEN encodes a protein which displays both a dual-specificity protein phosphatase and a lipid phosphatase activities. PTEN antagonizes phosphatidylinositol-3 kinase (PI3K) by catalyzing the hydrolysis of the phosphate on position D3 of phosphatidylinositol (3, 4, 5) triphosphate (PIP3). We and others have recently shown that DAF-18, the orthologue of PTEN in C. elegans, is a component of the insulin-like signalling pathway that controls the entry into dauer and adult longevity. Daf-18 mutants are dauer defective and have a shorter lifespan than wild type worms. Although PTEN and DAF-18 proteins share the highest homology within the catalytic domain, they do not exhibit a marked similarity outside this region. Notably, the C-terminus of PTEN, which mediates interaction with PDZ domain proteins and regulates the protein stability, is not conserved in DAF-18. We now report that PTEN can substitute to DAF-18 in C.elegans and we are using the nematode to uncover the mode of regulation of PTEN.

Florence Solari et al. (2003) International Worm Meeting "The human tumor suppressor PTEN regulates longevity and dauer formation in Caenorhabditis elegans"

ANDREW ML CHAN, ANGELIQUE BOURBON, INGRID MASSE, BERNARD PAYRASTRE, Gary Ruvkun, Patrick Hu, Florence Solari, Marc Billaud

[International Worm Meeting, 2003]

The PTEN tumor suppressor is a dual-specificity phosphatase that dephosphorylates phosphatidylinositol 3, 4, 5 triphosphate (PIP3) and protein substrates. PTEN function is modulated by its carboxy terminal region which contained several clustered phosphorylation sites and a PDZ-binding motif. Although PTEN growth suppression effect is well demonstrated, its additional biological roles are less well understood. DAF-18, a Caenorhabditis elegans homolog PTEN, is a component of the insulin/IGF-I signalling pathway that controls entry at the dauer larval stage and adult longevity. To explore in a model organism the ability of human PTEN to regulate the insulin signalling cascade and its possible involvement in the mechanisms of aging, we undertook a study of PTEN function in C.elegans. We now report, that PTEN expression can substitute for DAF-18 and restores the dauer and longevity phenotypes in mutant worms devoided of DAF-18. Furthermore, we provide genetic and biochemical evidence that entry in the dauer stage and lifespan depends on PTEN-mediated regulation of PIP3 levels. Finally, we established that the phosphorylation sites of the PTEN tail and the PDZ-binding motif are necessary for PTEN ability to control the transduction of the insulin/IGF-I signal. These results demonstrate that PTEN negatively regulates the insulin/IGF pathway in C.elegans, thus raising the possibility that PTEN acts similarly in mammals and may be also involved in the aging process.