title: Amino acid deprivation inhibits TORC1 through a GTPase-activating protein complex for the Rag family GTPase Gtr1.
abstract: The Rag family of guanosine triphosphatases (GTPases) regulates eukaryotic cell growth in response to amino acids by activating the target of rapamycin complex 1 (TORC1). In humans, this pathway is often deregulated in cancer. In yeast, amino acids promote binding of GTP (guanosine 5'-triphosphate) to the Rag family GTPase Gtr1, which, in combination with a GDP (guanosine diphosphate)-bound Gtr2, forms the active, TORC1-stimulating GTPase heterodimer. We identified Iml1, which functioned in a complex with Npr2 and Npr3, as a GAP (GTPase-activating protein) for Gtr1. Upon amino acid deprivation, Iml1 transiently interacted with Gtr1 at the vacuolar membrane to stimulate its intrinsic GTPase activity and consequently decrease the activity of TORC1. Our results delineate a potentially conserved mechanism by which the Iml1, Npr2, and Npr3 orthologous proteins in humans may suppress tumor formation.
authors.affiliation: Department of Biology, Division of Biochemistry, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Panchaud
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Péli-Gulli
authors.forename: Claudio
authors.initials: C
authors.lastname: De Virgilio
mesh_terms: D000596:Amino Acids / Q000172:deficiency*; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D015966:Gene Expression Regulation, Fungal / Q000235:genetics / Q000502:physiology*; D006160:Guanosine Triphosphate / Q000378:metabolism; D047468:Immunoprecipitation; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014617:Vacuoles / Q000378:metabolism
chemical_list: D000596:Amino Acids; D020690:GTPase-Activating Proteins; C121262:Gtr1 protein, S cerevisiae; C570233:Iml1 protein, S cerevisiae; D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; C092275:NPR2 protein, S cerevisiae; C543107:NPR3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D006160:Guanosine Triphosphate; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins