title: Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism.
abstract: The mechanistic target of rapamycin complex 1 (mTORC1) coordinates cell growth with its nutritional, hormonal, energy, and stress status. Amino acids are critical regulators of mTORC1 that permit other inputs to mTORC1 activity. However, the roles of individual amino acids and their interactions in mTORC1 activation are not well understood. Here we demonstrate that activation of mTORC1 by amino acids includes two discrete and separable steps: priming and activation. Sensitizing mTORC1 activation by priming amino acids is a prerequisite for subsequent stimulation of mTORC1 by activating amino acids. Priming is achieved by a group of amino acids that includes l-asparagine, l-glutamine, l-threonine, l-arginine, l-glycine, l-proline, l-serine, l-alanine, and l-glutamic acid. The group of activating amino acids is dominated by l-leucine but also includes l-methionine, l-isoleucine, and l-valine. l-Cysteine predominantly inhibits priming but not the activating step. Priming and activating steps differ in their requirements for amino acid concentration and duration of treatment. Priming and activating amino acids use mechanisms that are distinct both from each other and from growth factor signaling. Neither step requires intact tuberous sclerosis complex of proteins to activate mTORC1. Concerted action of priming and activating amino acids is required to localize mTORC1 to lysosomes and achieve its activation.
authors: From the Department of Pharmacology.|Green Center for Systems Biology, and.|McDermott Center for Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041.
authors: Julia
authors: J
authors: Dyachok
authors: From the Department of Pharmacology.
authors: Svetlana
authors: S
authors: Earnest
authors: From the Department of Pharmacology.|Green Center for Systems Biology, and.
authors: Erica N
authors: EN
authors: Iturraran
authors: From the Department of Pharmacology.
authors: Melanie H
authors: MH
authors: Cobb
authors: From the Department of Pharmacology, Elliott.Ross@UTSouthwestern.edu.|Green Center for Systems Biology, and.
authors: Elliott M
authors: http://orcid.org/0000-0002-0252-8197
authors: EM
authors: Ross
mesh_terms: D000596:Amino Acids / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: S6 kinase; amino acid; cell signaling; lysosome; mTOR complex (mTORC); mammalian target of rapamycin (mTOR); protein kinase