Spatial and functional separation of mTORC1 signalling in response to different amino acid sources
What this study shows
mTORC1 regulation and downstream substrate phosphorylation are spatially separated: lysosomal mTORC1 (fed by local lysosomal proteolysis) and cytoplasmic mTORC1 (fed by exogenous amino acids) phosphorylate distinct substrates depending on amino acid source, challenging the single lysosomal-hub model.
Abstract
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Amino acid (AA) availability is a robust determinant of cell growth through controlling mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity. According to the predominant model in the field, AA sufficiency drives the recruitment and activation of mTORC1 on the lysosomal surface by the heterodimeric Rag GTPases, from where it coordinates the majority of cellular processes. Importantly, however, the teleonomy of the proposed lysosomal regulation of mTORC1 and where mTORC1 acts on its effector proteins remain enigmatic.
Read the full abstract on PubMed →At a glance
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| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human cells (HEK293FT, WI-26 SV40 lung fibroblasts) + mouse MEFs (WT and RagA/B-KO)) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human cells (HEK293FT, WI-26 SV40 lung fibroblasts) + mouse MEFs (WT and RagA/B-KO) |
| Journal | Nature Cell Biology |
| Year | 2024 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1038/s41556-024-01523-7 · PMID 39385049 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
Pathway relations
Supports
Lysosome required-for mTORC1Strongest evidence: M (Molecular — cells, biochemistry, structure) · settled in the literature · Status: Proposed
plausible in people, not shown directly
Scoped to amino-acid-driven activation. Live BRET imaging in this corpus (BOU2020) resolves mTOR activity in the cytosol, at the lysosome, in the nucleus and near mitochondria, so mTOR signalling is measurably not one pool. This map draws…
People in the Atlas
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First author of the study showing that lysosomal and cytoplasmic pools of mTORC1 respond to different amino acid sources and phosphorylate different substrates.
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Showed as a postdoc in Aurelio Teleman's lab that starvation and other stresses pull TSC2 to the lysosome to switch mTORC1 off. His group, at the Max Planck Institute for Biology of Ageing in Cologne from 2017 and at ERIBA in Groningen since 2025, studies how cells sense nutrients and stress through mTORC1 and how this changes with age
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Co-author on two Demetriades-lab mTORC1 papers from Cologne: the spatial split of mTORC1 signalling by amino acid source and malonyl-CoA as a direct mTORC1 inhibitor.
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PhD student who co-authored the 2024 study showing that mTORC1 does different jobs at the lysosome and away from it, and first author of a 2026 review on why mTORC1 is better seen as a substrate-selective kinase than an on/off switch
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First author of the 'Rag dimer code' study showing that the four Rag GTPase paralogues are not interchangeable: RagC/D sets substrate choice and RagA/B sets the response to amino acid withdrawal.
More: 5 other authors
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Co-author on two Demetriades-lab studies of amino acid sensing by mTORC1: the Rag GTPase dimer code and the spatial split of mTORC1 signalling.
No profile yet: Angelidaki DD, Elkis Y, Artoni F, Kovacevic-Sarmiento M
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | Pharmacological and genetic perturbation of lysosomal amino-acid sensing (Rag pathway) and lysosomal proteolysis |
| Target | Lysosomal vs non-lysosomal mTORC1 pools |
| Model | Human cell lines (HEK293FT, WI-26 SV40 fibroblasts); mouse embryonic fibroblasts (WT, RagA/B-KO) |
| Effect | Lysosomal mTORC1 is fed by local lysosomal proteolysis and cytoplasmic mTORC1 by external amino acids, and the two phosphorylate distinct substrates. |
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