Rheb promotes cell growth as a component of the insulin/TOR signalling network

Nat Cell Biol. 2003 Jun;5(6):566-71. doi: 10.1038/ncb996.

Abstract

Insulin signalling is a potent stimulator of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin) [corrected]. Recent studies suggest that the tuberous sclerosis complex Tsc1-Tsc2 may couple insulin signalling to Tor activity [corrected]. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Increased levels of Rheb in Drosophila melanogaster promote cell growth and alter cell cycle kinetics in multiple tissues. In mitotic tissues, overexpression of Rheb accelerates passage through G1-S phase without affecting rates of cell division, whereas in endoreplicating tissues, Rheb increases DNA ploidy. Mutation of Rheb suspends larval growth and prevents progression from first to second instar. Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1-Tsc2 and upstream of TOR. Levels of rheb mRNA are rapidly induced in response to protein starvation, and overexpressed Rheb can drive cell growth in starved animals, suggesting a role for Rheb in the nutritional control of cell growth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Division / genetics
  • Cell Division / physiology
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Female
  • Gene Deletion
  • Growth Substances / genetics
  • Growth Substances / metabolism*
  • Insulin / genetics
  • Insulin / metabolism*
  • Interphase
  • Models, Biological
  • Monomeric GTP-Binding Proteins / genetics
  • Monomeric GTP-Binding Proteins / metabolism
  • Monomeric GTP-Binding Proteins / physiology*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism
  • Neuropeptides / physiology*
  • Phosphatidylinositol 3-Kinases
  • Ploidies
  • Protein Kinases
  • Proteins / metabolism
  • Ras Homolog Enriched in Brain Protein
  • Repressor Proteins / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases
  • Transgenes
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Wings, Animal / growth & development

Substances

  • Drosophila Proteins
  • Growth Substances
  • Insulin
  • Neuropeptides
  • Proteins
  • Ras Homolog Enriched in Brain Protein
  • Repressor Proteins
  • Rheb protein, Drosophila
  • Tuberous Sclerosis Complex 1 Protein
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • target of rapamycin protein, Drosophila
  • TOR Serine-Threonine Kinases
  • Monomeric GTP-Binding Proteins