Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability

BEUGNET, Anne; TEE, Andrew R.; TAYLOR, Peter M.; PROUD, Christopher G.

doi:10.1042/bj20021266

Cited by 307PI3K/AKT/mTOR signaling in cancerRNA and protein synthesis mechanismsMuscle metabolism and nutrition

Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability

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BEUGNET, Anne, TEE, Andrew R., TAYLOR, Peter M., PROUD, Christopher G.·2003·Biochemical Journal

DOI 10.1042/bj20021266PMC PMC1223408

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Abstract

In mammalian cells, amino acids affect the phosphorylation state and function of several proteins involved in mRNA translation that are regulated via the rapamycin-sensitive mTOR (mammalian target of rapamycin) pathway. These include ribosomal protein S6 kinase, S6K1, and eukaryotic initiation factor 4E-binding protein, 4E-BP1. Amino acids, especially branched-chain amino acids, such as leucine, promote phosphorylation of 4E-BP1 and S6K1, and permit insulin to further increase their phosphorylation. However, it is not clear whether these effects are exerted by extracellular or intracellular amino acids. Inhibition of protein synthesis is expected to increase the intracellular level of amino acids, whereas inhibiting proteolysis has the opposite effect. We show in the present study that inhibition of protein synthesis by any of several protein synthesis inhibitors tested allows insulin to regulate 4E-BP1 or S6K1 in amino-acid-deprived cells, as does the addition of amino acids to the medium. In particular, insulin activates S6K1 and promotes initiation factor complex assembly in amino-acid-deprived cells treated with protein synthesis inhibitors, but cannot do so in the absence of these compounds. Their effects occur at concentrations commensurate with their inhibition of protein synthesis and are not due to activation of stress-activated kinase cascades. Inhibition of protein breakdown (autophagy) impairs the ability of insulin to regulate 4E-BP1 or S6K1 under such conditions. These and other data presented in the current study are consistent with the idea that it is intracellular amino acid levels that regulate mTOR signalling.

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Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks
Magnuson, B., Ekim, B., & Fingar, D. C. (2012) · Biochemical Journal · doi:10.1042/bj20110892 · Cited by 1,015 · see citing works
Glucose exerts a permissive effect on the regulation of the initiation factor 4E binding protein 4E-BP1
Patel, J. V., Xuemin, W. A. N. G., & Proud, C. G. (2001) · Biochemical Journal · doi:10.1042/bj3580497 · Cited by 24 · see citing works
Self-citation
The immunosuppressant tributyltin oxide blocks the mTOR pathway, like rapamycin, albeit by a different mechanism
Osman, A. M., & Loveren, H. V. (2013) · Journal of Applied Toxicology · doi:10.1002/jat.2966 · Cited by 4 · see citing works
p53/TAp63 and AKT Regulate Mammalian Target of Rapamycin Complex 1 (mTORC1) Signaling through Two Independent Parallel Pathways in the Presence of DNA Damage
Cam, M., Bid, H. K., Xiao, L., Zambetti, G. P., Houghton, P. J., & Çam, H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.530303 · Cited by 58 · see citing works

Authors: BEUGNET, A., TEE, A. R., TAYLOR, P. M., & PROUD, C. G.
Affiliations: University of Dundee (GB)
ORCID: BEUGNET, Anne
TEE, Andrew R.
TAYLOR, Peter M.
PROUD, Christopher G.
Venue: Biochemical Journal
Publisher: Portland Press Ltd.
Published: 2003-06-01
Volume: 372
Issue: 2
Pages: 555-566
ISSN: 0264-6021 (ISSN-L)
1470-8728
DOI: 10.1042/bj20021266
PMC: PMC1223408
OpenAlex: W2018938558
Cited by: 307
References: 63
Citations by year: 2026: 4 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 13 · 2019: 9 · 2018: 9 · 2017: 16 · 2016: 24 · 2015: 18 · 2014: 13 · 2013: 9 · 2012: 18
FWCI: 6.10
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Biochemical Journal (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Discovery Research Portal (University of Dundee) (publishedVersion)
ePrints Soton (University of Southampton) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
Keywords: mTOR signaling, intracellular amino acids, amino acid availability, 4E-BP1, S6K1, S6K, mRNA translation regulation, insulin signaling, protein synthesis inhibitors, autophagy, amino acid starvation, branched-chain amino acids, leucine
MeSH terms: Adenine, Amino Acids, Animals, Anisomycin, Carrier Proteins, Cycloheximide, Enzyme Inhibitors, Gene Expression Regulation, Cricetinae, Immunosuppressive Agents, Insulin, Peptide Initiation Factors, Phosphoproteins, Phosphorylation, Protein Kinases, Protein Synthesis Inhibitors, Blotting, Western, Signal Transduction, CHO Cells, Ribosomal Protein S6 Kinases, Sirolimus, Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase Kinases, JNK Mitogen-Activated Protein Kinases, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 4, TOR Serine-Threonine Kinases

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Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability

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