Regulation of dauer larva development in Caenorhabditis elegans by daf-18, a homologue of the tumour suppressor PTEN

Curr Biol. 1999 Mar 25;9(6):329-32. doi: 10.1016/s0960-9822(99)80143-2.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans Proteins*
  • Catalysis
  • DNA, Complementary / genetics
  • Genes, Helminth*
  • Genes, Tumor Suppressor*
  • Helminth Proteins / genetics
  • Helminth Proteins / physiology*
  • Humans
  • Larva / growth & development
  • Longevity / genetics
  • Membrane Lipids / metabolism
  • Multigene Family
  • PTEN Phosphohydrolase
  • Phosphatidylinositol 3-Kinases*
  • Phosphatidylinositol Phosphates / metabolism
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphorylation
  • Receptor, Insulin / genetics
  • Receptor, Insulin / physiology
  • Tumor Suppressor Proteins*

Substances

  • Caenorhabditis elegans Proteins
  • DAF-18 protein, C elegans
  • DNA, Complementary
  • Helminth Proteins
  • Membrane Lipids
  • Phosphatidylinositol Phosphates
  • Tumor Suppressor Proteins
  • phosphatidylinositol 3,4,5-triphosphate
  • Phosphatidylinositol 3-Kinases
  • AGE-1 protein, C elegans
  • DAF-2 protein, C elegans
  • Receptor, Insulin
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human