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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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Ku-0063794 is a specific inhibitor of the mammalian target of rapamycin (mTOR)
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“In light of these results, it is noteworthy that the yeast vacuole contains multiple transporters that ferry amino acids between the lumen and the cytoplasm (reviewed in [51,55]).”
BackgroundThe Vam6 GEF Controls TORC1 by Activating the EGO Complex
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BackgroundRheb Binding to Mammalian Target of Rapamycin (mTOR) Is Regulated by Amino Acid Sufficiency
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Novel G Proteins, Rag C and Rag D, Interact with GTP-binding Proteins, Rag A and Rag B*
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“These small GTPases, the Rags, belong to the Ras superfamily and are quite unusual: they exist as heterodimers where the highly similar RagA and RagB bind to either RagC or RagD, which are also similar to one another [27], leading to four possible dimer combinations.”
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Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer
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“In addition, it is intriguing that only a very few mutations in mTOR have been found in human sporadic cancers [100,101].”
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InfluentialSirolimus Therapy in Tuberous Sclerosis or Sporadic Lymphangioleiomyomatosis
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“Interestingly, a partial loss of function of LAMTOR2 in humans underlies the first identified disease of hypoactive mTORC1 signaling, characterized by stunted growth, immunodeficiency, and albinism [42] (Box 2 and Figure 2).”
Localization of Rheb to the endomembrane is critical for its signaling function
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“Among its many targets, AMPK directly phosphorylates TSC2 [10,11]; but in contrast to Akt, AMPK-dependent phosphorylation of TSC2 stimulates the GTPase activity of TSC, inhibiting Rheb.”
BackgroundInfluentialDynamic aspects of vacuolar and cytosolic amino acid pools of Saccharomyces cerevisiae
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“Basic amino acids arginine, lysine, and histidine preferentially accumulate in the vacuole, whereas they are relatively less abundant in the cytoplasm [52].”
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An Activating Mutation of AKT2 and Human Hypoglycemia
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“Interestingly, somatic mutations in the Akt2 gene do not cause cancer, but are the cause of a syndrome characterized by severe hypoglycemia, asymmetrical growth, and increased adiposity [99].”
A Family of Yeast Proteins Mediating Bidirectional Vacuolar Amino Acid Transport
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Class III PI-3-kinase activates phospholipase D in an amino acid–sensing mTORC1 pathway
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The Late Endosome is Essential for mTORC1 Signaling
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“Among its many targets, AMPK directly phosphorylates TSC2 [10,11]; but in contrast to Akt, AMPK-dependent phosphorylation of TSC2 stimulates the GTPase activity of TSC, inhibiting Rheb.”
InfluentialSTRADα deficiency results in aberrant mTORC1 signaling during corticogenesis in humans and mice
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“Even more intriguingly, the recently reported crystal structure of the Gtr1–Gtr2 C-terminal domain displays a remarkable similarity to both the Ego2–3 and the LAMTOR2–3 dimer [48], and the same structural feature is predicted to exist in the Cterminal domain of the mammalian RagA–RagC heterodimer.”
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“Many prokaryotes possess proteins dedicated to sensing amino acids, which allow them to couple nutrient availability to the regulation of multiple physiological processes [16,17].”
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“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript crystal structure of Ego2–3 was recently solved and found to be very similar to that of LAMTOR2–3 [46,47].”
ResultRagA is a functional homologue of S. cerevisiae Gtr1p involved in the Ran/Gsp1-GTPase pathway
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“Remarkably, many of these genes were membrane traffic regulators, including lipid kinases such as the type III PI3-Kinase Vps34 as well as small GTPases and endosomal tethering complexes [36,37].”
BackgroundAttractant Signaling by an Aspartate Chemoreceptor Dimer with a Single Cytoplasmic Domain
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“Many prokaryotes possess proteins dedicated to sensing amino acids, which allow them to couple nutrient availability to the regulation of multiple physiological processes [16,17].”
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“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript crystal structure of Ego2–3 was recently solved and found to be very similar to that of LAMTOR2–3 [46,47].”
Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin
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Signals from the lysosome: a control centre for cellular clearance and energy metabolism
Settembre, C., Fraldi, A., Medina, D. L., & Ballabio, A. (2013) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3565 · Cited by 1,755
Sestrin2 is a leucine sensor for the mTORC1 pathway
Wolfson, R. L., Chantranupong, L., Saxton, R. A., Shen, K., Scaria, S. M., Cantor, J. R., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aab2674 · Cited by 1,306
Self-citationPromoting Health and Longevity through Diet: From Model Organisms to Humans
Fontana, L., & Partridge, L. (2015) · Cell · doi:10.1016/j.cell.2015.02.020 · Cited by 1,245
“Dietary protein intake is an important regulator of the IGF-1/mTOR network (Efeyan et al, 2012).”
InfluentialNutrient-sensing mechanisms and pathways
Efeyan, A., Comb, W. C., & Sabatini, D. M. (2015) · Nature · doi:10.1038/nature14190 · Cited by 1,110
Self-citationThe CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway
Chantranupong, L., Scaria, S. M., Saxton, R. A., Gygi, M. P., Shen, K., Wyant, G. A., Wang, T., Harper, J. W., Gygi, S. P., & Sabatini, D. M. (2016) · Cell · doi:10.1016/j.cell.2016.02.035 · Cited by 843
“…effects stem at least in part from the ability of arginine to activate mTORC1, a master growth controller that integrates diverse environmental inputs to coordinate many anabolic and catabolic processes in cells (Ban et al., 2004; Dibble and Manning, 2013; Efeyan et al., 2012; Hara et al., 1998).”
Self-citation
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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