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Amino acids and mTORC1: from lysosomes to disease
Open accessAbstract
The mechanistic target of rapamycin (mTOR) kinase controls growth and metabolism, and its deregulation underlies the pathogenesis of many diseases, including cancer, neurodegeneration, and diabetes. mTOR complex 1 (mTORC1) integrates signals arising from nutrients, energy, and growth factors, but how exactly these signals are propagated await to be fully understood. Recent findings have placed the lysosome, a key mediator of cellular catabolism, at the core of mTORC1 regulation by amino acids. A multiprotein complex that includes the Rag GTPases, Ragulator, and the v-ATPase forms an amino acid-sensing machinery on the lysosomal surface that affects the decision between cell growth and catabolism at multiple levels. The involvement of a catabolic organelle in growth signaling may have important implications for our understanding of mTORC1-related pathologies.
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“The activation of the pro-aging and pro-cancer mTOR pathways is modulated by energy intake but also by a cocktail of different essential amino acids, with the branched-chain amino acids leucine and isoleucine playing a fundamental role (82).”
From Health Benefits of the Mediterranean Diet: Metabolic and Molecular Mechanisms (2018) · cites this paper as [82]
In the citing paper
“AMPK has a direct inhibitory action on raptor, the adaptor protein for mTORC1, and can also stimulate the tuberous sclerosis complex TSC1/2 (164).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [164]
In the citing paper
“More recent research has identified a Ragulator-RAG GTPases multiprotein complex associated with the lysosomal surface that regulates mTOR activity by controlling its sub-cellular location, recruiting it to the lysosome (164).”
From Placental Origins of Chronic Disease (2016) · cites this paper as [164]
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Cites
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Metadata
- Authors
- Efeyan, A., Zoncu, R., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Corresponding author
- Zoncu, Roberto
- Sabatini, David M.
- Venue
- Trends in Molecular Medicine
- Publisher
- Elsevier BV
- Published
- 2012-09
- Volume
- 18
- Issue
- 9
- Pages
- 524-533
- ISSN
- 1471-4914 (ISSN-L)
- PMC
- PMC3432651
- OpenAlex
- W2059716825
- Cited by
- 436
- References
- 112
- Citations by year
- 2026: 13 · 2025: 8 · 2024: 14 · 2023: 21 · 2022: 22 · 2021: 36 · 2020: 34 · 2019: 29 · 2018: 29 · 2017: 36 · 2016: 50 · 2015: 60 · 2014: 52 · 2013: 31 · 2012: 1
- FWCI
- 4.20
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Trends in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Howard Hughes Medical Institute
- Ellison Medical Foundation
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
- National Institutes of Health (CA129105)
- National Cancer Institute (R01CA103866, R01CA129105)
- National Institute of Allergy and Infectious Diseases (R37AI047389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTORC1, amino acid signaling, lysosomes, Rag GTPases, Ragulator complex, V-ATPase, nutrient sensing, cancer, neurodegeneration, diabetes mellitus
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acids, Diabetes Mellitus, Humans, Lysosomes, Neoplasms, Neurodegenerative Diseases, Multiprotein Complexes, TOR Serine-Threonine Kinases
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