The DOI matches its Crossref record; 112 of the 112 references it cites were found in a registry or an index.
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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In the citing paper
“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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Citations
Cites
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509 · cited 1×
“In skeletal muscle, glucose import is suppressed and skeletal muscle waste ensues as a consequence (reviewed in [75]).”
Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing
Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1113205 · Cited by 7,774 · cited 1×
“In addition, it is intriguing that only a very few mutations in mTOR have been found in human sporadic cancers [100,101].”
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227 · cited 2×
“Furthermore, aberrant mTORC1 potently suppresses autophagy, which may play a role in tumor suppression [62,63,79].”
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941 · cited 1×
“The mTOR kinase nucleates two distinct core complexes that have different kinase specificity and distinct protein partners (reviewed in [2]).”
Self-citationTSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914 · cited 8×
“The DNA damage response, a signal cascade that is initiated by the detection of DNA double-strand breaks and other genetic insults, culminates in activation of the tumor suppressor transcription factor p53, which transactivates AMPK and TSC2, contributing to mTORC1 inhibition [13,14].”
BackgroundInfluentialAMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint
Gwinn, D. M., Shackelford, D. B., Egan, D. F., Mihaylova, M. M., Mery, A., Vasquez, D. S., Turk, B. E., & Shaw, R. J. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.03.003 · Cited by 3,849 · cited 2×
“In parallel, AMPK phosphorylates Raptor [12], leading to direct inhibition of mTORC1, possibly through structural destabilization of the complex.”
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice
Harrison, D. E., Strong, R., Sharp, Z. D., Nelson, J. F., Astle, C. M., Flurkey, K., Nadon, N. L., Wilkinson, J. E., Frenkel, K., Carter, C. S., et al. (2009) · Nature · doi:10.1038/nature08221 · Cited by 3,766 · cited 1×
“Manipulating mTORC1 activity in this way may also prove important for anti-aging purposes, as suggested by the fact that rapamycin delays aging in mammals [106,107].”
BackgroundTemsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma
Hudes, G. R., Carducci, M. A., Tomczak, P., Dutcher, J. P., Figlin, R. A., Kapoor, A., Starosławska, E., Sosman, J. A., McDermott, D. F., Bodrogi, I., et al. (2007) · New England Journal of Medicine · doi:10.1056/nejmoa066838 · Cited by 3,645 · cited 1×
“Despite minimal side effects and outstanding pharmacokinetics, rapamycin has efficacy against only a few pathologies associated with high levels of mTORC1 activity, such as renal cell carcinoma [102] and tuberous sclerosis [103–105].”
Autophagy and the Integrated Stress Response
Kroemer, G., Mariño, G., & Levine, B. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.023 · Cited by 3,506 · cited 2×
“Moreover, it was observed that amino acid withdrawal from cells and organisms triggered autophagy, a process of cellular self-eating where pre-existing proteins and organelles are broken down into simpler metabolites via lysosomal degradation [21].”
Cited by
Sorted by citations
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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