Amino acid–dependent TSC2 dephosphorylation by lysosome–PP2A regulates mTORC1 signaling transduction
The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, composed of amino acid (AA)-sensing (Ragulator/LAMTOR-Rag) and growth factor (GF)-sensing (AKT-TSC1/2-Rheb) axes, pivotally regulates intracellular anabolism and catabolism. mTORC1 deregulation is associated with various metabolic diseases, including cancer and diabetes. As a key regulator of nutrient signaling, mTORC1 integrates a variety of nutrient signals. However, signal integration and crosstalk in the mTORC1 pathway remain incompletely understood. Therefore, in this study, we aimed to understand the complex mTORC1 signaling cascade by constructing an integrated mathematical model of temporal mTORC1 regulation using two AA-sensing and GF-sensing axes. Mathematical simulations and experimental data revealed robust AKT phosphorylation (P-T308/P-S473) after insulin stimulation, regardless of the intracellular AA levels. Conversely, AKT-mediated inhibitory TSC2 phosphorylation (P-T1462) substantially diminished during AA deprivation compared with AA treatment. Furthermore, we highlighted PP2A-mediated TSC2 dephosphorylation during AA removal, ensuring complete mTORC1 activation only upon concurrent AA and GF sensing. Thus, we elucidated mTORC1 signaling dynamics, revealing the complex interplay between AAs and GFs and offering insights into metabolic regulation.
Authors
- Shigeyuki Nada (ORCID: https://orcid.org/0000-0002-1103-6119)
- Tatsuya Sawasaki (ORCID: https://orcid.org/0000-0002-7952-0556)
- Nuha Loling Othman (ORCID: https://orcid.org/0000-0002-5889-812X)
- Masaki Matsumoto (ORCID: https://orcid.org/0000-0002-6987-0288)
- Hidetaka Kosako (ORCID: https://orcid.org/0000-0003-3228-6368)
- Takashi Suzuki (ORCID: https://orcid.org/0000-0002-0203-5587)
- Junya Masumoto (ORCID: https://orcid.org/0000-0003-0847-0456)
- Takanori Nakamura (ORCID: https://orcid.org/0000-0002-2915-2257)
- Mutsuhiro Takekawa (ORCID: https://orcid.org/0000-0002-8027-3847)
- Masato Okada (ORCID: https://orcid.org/0000-0002-0357-0127)
- Naohiko Koshikawa (ORCID: https://orcid.org/0000-0002-4539-888X)
- Kazuki Ikeda (ORCID: https://orcid.org/0000-0003-0407-0420)
Institutions
- Canon (Japan) (JP)
- Kanagawa Prefectural Hospital Organization (JP)
- Matsuyama University (JP)
- Institute for Advanced Medical Research (US)
- Ehime University (JP)
- Tokushima College of Technology (JP)
- Niigata University (JP)
- The University of Tokyo (JP)
- Premier University (BD)
- Tokushima University (JP)
- The University of Osaka (JP)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2025-09-02
- DOI
- https://doi.org/10.26508/lsa.202503206
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- Princess Takamatsu Cancer Research Fund
- Japan Society for the Promotion of Science
- Core Research for Evolutional Science and Technology