title: Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2.
abstract: TOR complex 1 (TORC1) is a potent anabolic regulator of cellular growth and metabolism. When cells have sufficient amino acids, TORC1 is active due to its lysosomal localization mediated via the Rag GTPases. Upon amino acid removal, the Rag GTPases release TORC1, causing it to become cytoplasmic and inactive. We show here that, upon amino acid removal, the Rag GTPases also recruit TSC2 to the lysosome, where it can act on Rheb. Only when both the Rag GTPases and Rheb are inactive is TORC1 fully released from the lysosome. Upon amino acid withdrawal, cells lacking TSC2 fail to completely release TORC1 from the lysosome, fail to completely inactivate TORC1, and fail to adjust physiologically to amino acid starvation. These data suggest that regulation of TSC2 subcellular localization may be a general mechanism to control its activity and place TSC2 in the amino-acid-sensing pathway to TORC1.
authors: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: k.dimitriadis@dkfz.de.
authors: Constantinos
authors: C
authors: Demetriades
authors: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors: Nikolaos
authors: N
authors: Doumpas
authors: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: a.teleman@dkfz.de.
authors: Aurelio A
authors: AA
authors: Teleman
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D054876:Prenylation; D000076205:Ras Homolog Enriched in Brain Protein; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D007328:Insulin; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D000076205:Ras Homolog Enriched in Brain Protein; D058570:TOR Serine-Threonine Kinases; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; C490211:RHEB protein, human; C000624653:TSC2 protein, human