Evidence map›Paper›PMID 40897470›Full record

ArticleLife science alliance2025

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

Takanori Nakamura, Shigeyuki Nada, Masaki Matsumoto, Nuha Loling Othman, Hidetaka Kosako, Kazuki Ikeda, Naohiko Koshikawa, Junya Masumoto, Tatsuya Sawasaki, Mutsuhiro Takekawa and 2 more

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Article in Life science alliance, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

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No citing paper in PubMed yet.

4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Takanori NakamuraDivision of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan nakamura.takanori.cb@ehime-u.ac.jp.ORCID 0000-0002-2915-2257
Shigeyuki NadaDepartment of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.ORCID 0000-0002-1103-6119
Masaki MatsumotoDepartment of Omics and Systems Biology, Niigata University, Niigata, Japan.
Nuha Loling OthmanCenter for Mathematical Modeling and Data Science, Osaka University, Osaka, Japan.
Hidetaka KosakoDivision of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan.ORCID 0000-0003-3228-6368
Kazuki IkedaDepartment of Life Science and Technology, Institute of Science Tokyo, Yokohama, Japan.ORCID 0000-0003-0407-0420
Naohiko KoshikawaDepartment of Life Science and Technology, Institute of Science Tokyo, Yokohama, Japan.
Junya MasumotoDivision of Pathology, Proteo-Science Center and Graduate School of Medicine, Ehime University, Toon, Japan.
Tatsuya SawasakiDivision of Cell-Free Sciences, Proteo-Science Center, Ehime University, Matsuyama, Japan.
Mutsuhiro TakekawaDivision of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.ORCID 0000-0002-8027-3847
Takashi SuzukiCenter for Mathematical Modeling and Data Science, Osaka University, Osaka, Japan suzuki@sigmath.es.osaka-u.ac.jp.
Masato OkadaDepartment of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan okadam@biken.osaka-u.ac.jp.ORCID 0000-0002-0357-0127

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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.

Indexed as

Amino AcidsLysosomesMechanistic Target of Rapamycin Complex 1Protein Phosphatase 2Tuberous Sclerosis Complex 2 ProteinAnimalsHumansInsulinPhosphorylationProto-Oncogene Proteins c-aktSignal TransductionAmino AcidsInsulinMechanistic Target of Rapamycin Complex 1Protein Phosphatase 2Proto-Oncogene Proteins c-aktTSC2 protein, humanTuberous Sclerosis Complex 2 Protein

Identifiers

PMID40897470
PMCPMC12405003

What Socratic holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.