Cited by 208Autophagy in Disease and TherapyPI3K/AKT/mTOR signaling in cancerMuscle metabolism and nutrition

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Amino Acids and Insulin Control Autophagic Proteolysis through Different Signaling Pathways in Relation to mTOR in Isolated Rat Hepatocytes

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Kanazawa, Takumi, Taneike, Ikue, Akaishi, Ryuichiro, Yoshizawa, Fumiaki, Furuya, Norihiko, Fujimura, Shinobu, Kadowaki, Motoni·2004·Journal of Biological Chemistry

DOI 10.1074/jbc.m306337200

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Abstract

Autophagy, a major bulk proteolytic pathway, contributes to intracellular protein turnover, together with protein synthesis. Both are subject to dynamic control by amino acids and insulin. The mechanisms of signaling and cross-talk of their physiological anabolic effects remain elusive. Recent studies established that amino acids and insulin induce p70 S6 kinase (p70(S6k)) phosphorylation by mTOR, involved in translational control of protein synthesis. Here, the signaling mechanisms of amino acids and insulin in macroautophagy in relation to mTOR were investigated. In isolated rat hepatocytes, both regulatory amino acids (RegAA) and insulin coordinately activated p70(S6k) phosphorylation, which was completely blocked by rapamycin, an mTOR inhibitor. However, rapamycin blocked proteolytic suppression by insulin, but did not block inhibition by RegAA. These contrasting results suggest that insulin controls autophagy through the mTOR pathway, but amino acids do not. Furthermore, micropermeabilization with Saccharomyces aureus alpha-toxin completely deprived hepatocytes of proteolytic responsiveness to RegAA and insulin, but still maintained p70(S6k) phosphorylation by RegAA. In contrast, Leu(8)-MAP, a non-transportable leucine analogue, did not mimic the effect of leucine on p70(S6k) phosphorylation, but maintained the activity on proteolysis. Finally, BCH, a System L-specific amino acid, did not affect proteolytic suppression or mTOR activation by leucine. All the results indicate that mTOR is not common to the signaling mechanisms of amino acids and insulin in autophagy, and that the amino acid signaling starts extracellularly with their "receptor(s)," probably other than transporters, and is mediated through a novel route distinct from the mTOR pathway employed by insulin.

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Authors: Kanazawa, T., Taneike, I., Akaishi, R., Yoshizawa, F., Furuya, N., Fujimura, S., & Kadowaki, M.
Affiliations: Niigata University (JP)
Utsunomiya University (JP)
Corresponding author: Kadowaki, Motoni
ORCID: Yoshizawa, Fumiaki
Furuya, Norihiko
Fujimura, Shinobu
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2004-02
Volume: 279
Issue: 9
Pages: 8452-8459
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m306337200
OpenAlex: W2054125361
Cited by: 208
References: 57
Citations by year: 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 5 · 2021: 7 · 2020: 6 · 2019: 13 · 2018: 5 · 2017: 10 · 2016: 7 · 2015: 8 · 2014: 16 · 2013: 12 · 2012: 9
FWCI: 12.69
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6100 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
Health Sciences › Nursing › Nutrition and Dietetics › Muscle metabolism and nutrition
Keywords: autophagy, amino acids, insulin, mTOR, p70 S6 kinase, hepatocytes, leucine, rapamycin, protein turnover, amino acid signaling, alpha-toxin, BCH
MeSH terms: Amino Acids, Amino Acids, Cyclic, Animals, Bacterial Toxins, Cell Membrane, Enzyme Inhibitors, Hemolysin Proteins, Insulin, Leucine, Male, Peptide Hydrolases, Phosphorylation, Protein Kinases, Signal Transduction, Rats, Wistar, Sirolimus, Hepatocytes, Ribosomal Protein S6 Kinases, 70-kDa, Protein Kinase Inhibitors, Rats, TOR Serine-Threonine Kinases

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Amino Acids and Insulin Control Autophagic Proteolysis through Different Signaling Pathways in Relation to mTOR in Isolated Rat Hepatocytes

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