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Amino Acids Regulate mTORC1 by an Obligate Two-step Mechanism
Julia Dyachok1,2,3, Svetlana Earnest1, Erica N Iturraran1,2
1From the Department of Pharmacology.
The Journal of Biological Chemistry
|September 3, 2016
Summary
Amino acids regulate cell growth via the mechanistic target of rapamycin complex 1 (mTORC1) in two distinct steps: priming and activation. Specific amino acids prime mTORC1, while others, like leucine, activate it for full function.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular signals for growth.
- Amino acids are key regulators of mTORC1, but their specific roles and interactions are unclear.
Purpose of the Study:
- To elucidate the distinct roles of individual amino acids in mTORC1 activation.
- To differentiate the mechanisms of amino acid-mediated mTORC1 priming and activation.
Main Methods:
- Investigated the effects of various amino acids on mTORC1 signaling.
- Analyzed the requirements for amino acid concentration and treatment duration for each step.
- Examined the involvement of tuberous sclerosis complex proteins.
Main Results:
- Amino acid-mediated mTORC1 activation involves two separable steps: priming and activation.
- Priming amino acids (e.g., asparagine, glutamine) sensitize mTORC1, while activating amino acids (e.g., leucine, isoleucine) stimulate it.
- Priming and activation utilize distinct mechanisms and have different concentration/duration requirements; l-cysteine inhibits priming.
Conclusions:
- Amino acid regulation of mTORC1 is a two-step process involving distinct priming and activation phases.
- These steps are mechanistically separate from each other and from growth factor signaling.
- Coordinated action of priming and activating amino acids is essential for lysosomal localization and activation of mTORC1.
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