ArticleNature cell biology2024
Spatial and functional separation of mTORC1 signalling in response to different amino acid sources.
Article in Nature cell biology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed.
- Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors.The Biochemical journal · 2026Article
- mTORC1-TFEB/TFE3 signaling is associated with bile acid diversification during hepatic metabolic adaptation.Science advances · 2026Article
- The hallmarks of protein and amino acid restriction in aging and longevity.Cell press blue · 2026Article
- Global cellular responses to lysosomal damage.Current biology : CB · 2026Review
- Autophagy and metabolic homeostasis: Exploration in obesity‑related metabolic diseases (Review).International journal of molecular medicine · 2026Review
- GRASP55 maintains lysosome function by controlling sorting of lysosomal enzymes at the Golgi.EMBO reports · 2026Article
- 4E-BP1 acts as a molecular rheostat balancing regenerative healing and fibrotic scarring.Experimental & molecular medicine · 2026Article
- mTORC1-signaling switches megalin function from endocytosis to cell cycle progression.Cellular and molecular life sciences : CMLS · 2026Article
- A TerminaTOR of mTORC1 signaling.Nature chemical biology · 2026Article
- Genetically targeted mTORC1 inhibitor reveals transcriptional control by nuclear mTORC1.Nature chemical biology · 2026Article
- From Growth Trajectory to Functional Decline: Age-Contextualized Nutritional Strategies for Muscle Vulnerability. A Narrative Review.Nutrients · 2026Review
- Viral-host interactions mediated by the mTOR signaling pathway.Cell insight · 2026Review
- Lysosomal phosphoinositide turnover acts upstream of RagGTPase-mTORC1 and controls muscle growth.Nature metabolism · 2026Article
- Lactobacillus plantarum (LPsca12) enhances growth phenotype and muscle nutrition in abalone (Haliotis discus hannai) by modulating microbial function and metabolism through the Amino Acid-Driven Gut-Muscle Axis.Animal microbiome · 2026Article
- The lysosomal LAMTOR-Rag complex functions as a checkpoint for antiviral interferon production.The EMBO journal · 2026Article
- Peripheral lysosome levels dictate mTORC1 inactivation even when catabolically impaired.Cell communication and signaling : CCS · 2026Article
- A time-resolved high-throughput screening of fission yeast deletion mutants for oxidative stress resistance.Microbial cell (Graz, Austria) · 2026Article
- Lysosomes as chemical and metabolic organizers of central nervous system injury and repair.Frontiers in chemistry · 2026Review
- Mechanisms of mTORC1 and GCN2 amino acid sensing pathways in tumorigenesis and metastatic progression (Review).International journal of molecular medicine · 2026Review
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
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. Here, by using multiple pharmacological and genetic means to perturb the lysosomal AA-sensing and protein recycling machineries, we describe the spatial separation of mTORC1 regulation and downstream functions in mammalian cells, with lysosomal and non-lysosomal mTORC1 phosphorylating distinct substrates in response to different AA sources. Moreover, we reveal that a fraction of mTOR localizes at lysosomes owing to basal lysosomal proteolysis that locally supplies new AAs, even in cells grown in the presence of extracellular nutrients, whereas cytoplasmic mTORC1 is regulated by exogenous AAs. Overall, our study substantially expands our knowledge about the topology of mTORC1 regulation by AAs and hints at the existence of distinct, Rag- and lysosome-independent mechanisms that control its activity at other subcellular locations. Given the importance of mTORC1 signalling and AA sensing for human ageing and disease, our findings will probably pave the way towards the identification of function-specific mTORC1 regulators and thus highlight more effective targets for drug discovery against conditions with dysregulated mTORC1 activity in the future.
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