The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Open accessAbstract
The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins—a family of four related small guanosine triphosphatases (GTPases)—interact with mTORC1 in an amino acid–sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate–bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.
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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 [23]
In 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 [23]
Rheb 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 [23]
Resistance 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 [23]
Full mTORC1 activation requires its recruitment to the lysosome by heterodimeric Rag GTPases, whereupon GTP-bound Rheb GTPases allosterically activate the kinase.
“Full mTORC1 activation requires its recruitment to the lysosome by heterodimeric Rag GTPases (Sancak et al., 2008), whereupon GTP-bound Rheb GTPases allosterically activate the kinase (Long et al., 2005; Sato et al., 2009)”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sancak et al., 2008
The Rag GTPases and their associated complex, Ragulator, are the essential platform for (m)TORC1 recruitment to the lysosome.
“The Rag GTPases and their associated complex, ‘Ragulator’, are the essential platform for (m)TORC1 recruitment to the lysosome.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sancak et al., 2008
RagA/B, when GTP-bound, and RagC/D, when GDP-bound, recruit RAPTOR, thereby recruiting the mTORC1 kinase complex to late endosomes and lysosomes.
“RagA and RagC regulate mTORC1 in an amino acid-sensitive manner; RagA/B, when GTP-bound, and RagC/D, when GDP-bound, recruit RAPTOR, a core (m)TORC1 component (Sancak et al., 2008), thereby recruiting the kinase complex to late endosomes and lysosomes.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sancak et al., 2008
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- Authors
- Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology (MIT), Nine Cambridge Center, Cambridge, MA 02142, USA.
- Corresponding author
- Sabatini, David M.
- ORCID
- Venue
- Science
- Published
- 2008-06-13
- Volume
- 320
- Issue
- 5882
- Pages
- 1496-1501
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2475333
- OpenAlex
- W2025176940
- Cited by
- 2,773
- References
- 2
- Citations by year
- 2026: 102 · 2025: 116 · 2024: 150 · 2023: 158 · 2022: 181 · 2021: 197 · 2020: 151 · 2019: 162 · 2018: 183 · 2017: 158 · 2016: 170 · 2015: 173 · 2014: 181 · 2013: 134 · 2012: 166
- FWCI
- 53.40
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA103866)
- National Institute of Allergy and Infectious Diseases (AI47389), R01AI047389)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Rag GTPases, raptors, mTORC1, amino acid signaling, Rheb, small GTPases, amino acid starvation, cell growth regulation
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, Amino Acids, Cell Line, Cell Nucleus, Cytoplasm, Guanosine Triphosphate, Humans, Insulin, Leucine, Mutation, Neuropeptides, Phosphorylation, Protein Binding, Protein Kinases, Proteins, Transcription Factors, Signal Transduction, Dimerization, Monomeric GTP-Binding Proteins, Multiprotein Complexes, Adaptor Proteins, Signal Transducing, Mutant Proteins, TOR Serine-Threonine Kinases
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