Regulation of TORC1 by Rag GTPases in nutrient response
Open accessAbstract
TORC1 (target of rapamycin complex 1) has a crucial role in the regulation of cell growth and size. A wide range of signals, including amino acids, is known to activate TORC1. Here, we report the identification of Rag GTPases as activators of TORC1 in response to amino acid signals. Knockdown of Rag gene expression suppressed the stimulatory effect of amino acids on TORC1 in Drosophila melanogaster S2 cells. Expression of constitutively active (GTP-bound) Rag in mammalian cells activated TORC1 in the absence of amino acids, whereas expression of dominant-negative Rag blocked the stimulatory effects of amino acids on TORC1. Genetic studies in Drosophila also show that Rag GTPases regulate cell growth, autophagy and animal viability during starvation. Our studies establish a function of Rag GTPases in TORC1 activation in response to amino acid signals.
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This complex molecular process explains both the load-dependent activation of mTOR and the effects of amino acid consumption on protein synthesis and muscle hypertrophy.
“This complex molecular process explains both the load-dependent activation of mTOR (more activation of the RxRxx kinase [14]) and the effects of amino acid consumption (increased movement of mTOR to the lysosome and its activator Rheb [23, 24]) on protein synthesis and, finally, muscle hypertrophy [25, 26].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [24]
The Introduction (page unavailable) says TORC1 promotes protein synthesis and cell growth, and the Discussion reports Rag-dependent changes in Drosophila cell size. Those findings support a general link between amino-acid signaling, TORC1 and growth, but the paper does not establish muscle hypertrophy, the outcome for which this citation is offered. (LLM, conf=0.86)
Experimental — accuracy not yet measuredRheb is located on the lysosome, so the net effect of leucine is to bring mTOR to its activator.
“As discussed above, the activator of mTOR, Rheb, is also located on the lysosome, so the net effect of leucine is to bring mTOR to its activator.”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [24]
The Introduction and Results identify Rheb as an activator of TORC1, and the Discussion proposes that Rag may regulate the localization of TORC1 pathway components. But the Discussion presents localization only as a possibility; our copy does not establish that Rheb is on lysosomes or that leucine brings mTOR to it (pages unavailable). (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the presence of amino acids, the Rags are activated and recruit mTORC1 to the lysosome by binding to raptor.
“In the presence of amino acids, the Rags are activated and recruit mTORC1 to the lysosome by binding to raptor [23, 24].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [24]
The Results section ('Rag GTPases regulate amino acid response'; page unavailable) shows that Rag GTPases promote mTORC1 signaling in response to amino acids. The Discussion (page unavailable) raises localization of TORC1 components only as a possibility; our copy does not establish recruitment to lysosomes, binding to raptor, or direct activation of the Rags by amino acids. (LLM, conf=0.87)
Experimental — accuracy not yet measuredResistance exercise activates mTORC1 through activation of an RxRxx-directed kinase that phosphorylates and moves TSC2 away from the lysosome, while enhanced amino acid uptake moves mTOR to the lysosome where it can be activated by GTP-bound Rheb.
“Together, these data suggest that resistance exercise activates mTORC1 through the activation of an RxRxx-directed kinase that phosphorylates and moves the inhibitor TSC2 away from the lysosome (Fig. 2). At the same time, by regulating LAT1, enhanced amino acid uptake moves mTOR to the lysosome where it can be activated by GTP-bound Rheb.”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [24]
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- Authors
- Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P., & Guan, K.-L.
- Affiliations
- University of California San Diego (US)
- University of Minnesota (US)
- Corresponding author
- Neufeld, Thomas P.
- Guan, Kun-Liang
- Venue
- Nature Cell Biology
- Published
- 2008-07-06
- Volume
- 10
- Issue
- 8
- Pages
- 935-945
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC2711503
- OpenAlex
- W2004582874
- Cited by
- 1,349
- References
- 48
- Citations by year
- 2026: 37 · 2025: 51 · 2024: 62 · 2023: 76 · 2022: 74 · 2021: 86 · 2020: 74 · 2019: 81 · 2018: 77 · 2017: 71 · 2016: 75 · 2015: 84 · 2014: 89 · 2013: 77 · 2012: 99
- FWCI
- 32.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA108941, R01CA108941)
- National Institute of General Medical Sciences (GM62694, R01GM062694, GM62509, R01GM062509)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TORC1, Rag GTPases, amino acid signaling, TOR signaling, cell growth regulation, autophagy, starvation, Drosophila melanogaster, cell size control
- MeSH terms
- Amino Acids, Animals, Autophagy, Cell Line, Drosophila melanogaster, Food, Humans, Protein Kinases, Signal Transduction, Phosphatidylinositol 3-Kinases, Monomeric GTP-Binding Proteins, Drosophila Proteins, RNA, Small Interfering, Cell Size, Cell Proliferation, TOR Serine-Threonine Kinases
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