Amino acids regulate mTORC1 by an obligate two-step mechanism

Julia Dyachok, Svetlana Earnest, Erica N. Iturraran, Melanie H. Cobb, Elliott M. Ross

Research output: Contribution to journalArticle

10 Citations (Scopus)

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 ofindividual 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.

Original languageEnglish (US)
Pages (from-to)22414-22426
Number of pages13
JournalJournal of Biological Chemistry
Volume291
Issue number43
DOIs
StatePublished - Oct 21 2016

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Amino Acids
Chemical activation
Aminoacylation
mechanistic target of rapamycin complex 1
Tuberous Sclerosis
Isoleucine
Asparagine
Valine
Threonine
Lysosomes
Glutamine
Cell growth
Proline
Leucine
Alanine
Methionine
Glycine
Serine
Cysteine
Arginine

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Amino acids regulate mTORC1 by an obligate two-step mechanism. / Dyachok, Julia; Earnest, Svetlana; Iturraran, Erica N.; Cobb, Melanie H.; Ross, Elliott M.

In: Journal of Biological Chemistry, Vol. 291, No. 43, 21.10.2016, p. 22414-22426.

Research output: Contribution to journalArticle

Dyachok, Julia ; Earnest, Svetlana ; Iturraran, Erica N. ; Cobb, Melanie H. ; Ross, Elliott M. / Amino acids regulate mTORC1 by an obligate two-step mechanism. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 43. pp. 22414-22426.
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