2025年新着論文 37　細胞情報学分野から論文が発表されました

Amino acid-dependent TSC2 dephosphorylation by lysosome-PP2A regulates mTORC1 signaling transduction

Life Sci Alliance. 2025 Sep 2;8(11):e202503206. doi: 10.26508/lsa.202503206. Print 2025 Nov.

Authors

Takanori Nakamura^{1 2 3 4}, Shigeyuki Nada⁵, Masaki Matsumoto⁶, Nuha Loling Othman⁷, Hidetaka Kosako⁸, Kazuki Ikeda⁹, Naohiko Koshikawa^9 10, Junya Masumoto³, Tatsuya Sawasaki², Mutsuhiro Takekawa^11 12, Takashi Suzuki¹³, Masato Okada^14 15

Affiliations

¹ Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan nakamura.takanori.cb@ehime-u.ac.jp.
² Division of Cell-Free Sciences, Proteo-Science Center, Ehime University, Matsuyama, Japan.
³ Division of Pathology, Proteo-Science Center and Graduate School of Medicine, Ehime University, Toon, Japan.
⁴ Division of Informatics and Computation, Premier Institute for Advanced Studies, Ehime University, Matsuyama, Japan.
⁵ Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
⁶ Department of Omics and Systems Biology, Niigata University, Niigata, Japan.
⁷ Center for Mathematical Modeling and Data Science, Osaka University, Osaka, Japan.
⁸ Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.
⁹ Department of Life Science and Technology, Institute of Science Tokyo, Yokohama, Japan.
¹⁰ Clinical Cancer Proteomics Laboratory, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
¹¹ Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
¹² Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
¹³ Center for Mathematical Modeling and Data Science, Osaka University, Osaka, Japan suzuki@sigmath.es.osaka-u.ac.jp.
¹⁴ Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan okadam@biken.osaka-u.ac.jp.
¹⁵ Center for Advanced Modalities and Drug Delivery System, Osaka University, Osaka, Japan.

Abstract

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.

Conflict of interest statement

The authors declare that they have no conflict of interest.

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カテゴリー: ニュース