title: Metabolism. Differential regulation of mTORC1 by leucine and glutamine.
abstract: The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) integrates environmental and intracellular signals to regulate cell growth. Amino acids stimulate mTORC1 activation at the lysosome in a manner thought to be dependent on the Rag small guanosine triphosphatases (GTPases), the Ragulator complex, and the vacuolar H(+)-adenosine triphosphatase (v-ATPase). We report that leucine and glutamine stimulate mTORC1 by Rag GTPase-dependent and -independent mechanisms, respectively. Glutamine promoted mTORC1 translocation to the lysosome in RagA and RagB knockout cells and required the v-ATPase but not the Ragulator. Furthermore, we identified the adenosine diphosphate ribosylation factor-1 GTPase to be required for mTORC1 activation and lysosomal localization by glutamine. Our results uncover a signaling cascade to mTORC1 activation independent of the Rag GTPases and suggest that mTORC1 is differentially regulated by specific amino acids.
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Jewell
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Young Chul
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Russell
authors.affiliation: Children's Hospital and Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China.
authors.forename: Fa-Xing
authors.initials: FX
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Hyun Woo
authors.initials: HW
authors.lastname: Park
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Plouffe
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Tagliabracci
authors.affiliation: Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA. kuguan@ucsd.edu.
authors.forename: Kun-Liang
authors.initials: KL
authors.lastname: Guan
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D005973:Glutamine / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007930:Leucine / Q000378:metabolism*; D008247:Lysosomes / Q000201:enzymology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D021381:Protein Transport; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D020823:ADP-Ribosylation Factor 1; D048868:Adaptor Proteins, Signal Transducing; D005973:Glutamine; D007930:Leucine; D000076222:Mechanistic Target of Rapamycin Complex 1; D020559:Monomeric GTP-Binding Proteins; D046912:Multiprotein Complexes; D000076223:Regulatory-Associated Protein of mTOR; D058570:TOR Serine-Threonine Kinases; C000589375:Rraga protein, Mouse; C540162:Rptor protein, mouse; C484342:RRAGA protein, human; C484345:RRAGB protein, human; C000589376:Rragb protein, Mouse