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The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway
Open accessAbstract
Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Here, we show that CASTOR1, a previously uncharacterized protein, interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. Collectively, these results establish CASTOR1 as an arginine sensor for the mTORC1 pathway.
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“The CASTOR proteins function similarly; when arginine levels are low, the CASTOR proteins bind to and inhibit GATOR2. When arginine levels are high, CASTOR proteins bind to arginine and release GATOR2, which allows the recruitment of mTORC1 to the lysosome170,171.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [171]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“The CASTOR proteins function similarly; when arginine levels are low, the CASTOR proteins bind to and inhibit GATOR2. When arginine levels are high, CASTOR proteins bind to arginine and release GATOR2, which allows the recruitment of mTORC1 to the lysosome170,171.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [171]
Experimental — accuracy not yet measuredIn the citing paper
“WDR24 and SEH1L are known to form a minimal complex sufficient for interaction with SESN2 (Parmigiani et al., 2014), and these GATOR2 components, with the addition of MIOS, were also identified as sufficient to bind CASTOR1 (Chantranupong et al., 2016; Gai et al., 2016b).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Chantranupong et al., 2016
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Cites
Boussif, O., Lezoualc’h, F., Zanta, M. A., Djavaheri‐Mergny, M., Scherman, D., DEMENEIX, B. A., & Behr, J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.16.7297 · Cited by 6,256
Arginine metabolism: nitric oxide and beyond
WU, G., & MORRIS, S. M. (1998) · Biochemical Journal · doi:10.1042/bj3360001 · Cited by 2,811
The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., & Sabatini, D. M. (2008) · Science · doi:10.1126/science.1157535 · Cited by 2,773
Self-citationSancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M. (2010) · Cell · doi:10.1016/j.cell.2010.02.024 · Cited by 2,464 · cited 3×
“…a complex interplay between multiple distinct factors, including Ragulator, which serves as a lysosomal scaffold for RagA/B (Bar-Peled et al., 2012; Sancak et al., 2010); FLCN/FNIP2, a GAP for RagC/D (Petit et al., 2013; Tsun et al., 2013); and GATOR1, a GAP for RagA/B and a critical negative…”
Self-citationZoncu, R., Bar-Peled, L., Efeyan, A., Wang, S., Sancak, Y., & Sabatini, D. M. (2011) · Science · doi:10.1126/science.1207056 · Cited by 1,673
Self-citationThe BioPlex network: a systematic exploration of the human interactome
Huttlin, E. L., Ting, L., Bruckner, R. J., Gebreab, F., Gygi, M. P., Szpyt, J., Tam, S., Zarraga, G., Colby, G., Baltier, K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.06.043 · Cited by 1,425 · cited 3×
“To identify potential GATOR2binding partners, we interrogated BioPlex, a database of human protein-protein interactions generated from immunoprecipitation followed by mass spectrometry of 2,594 proteins stably expressed in HEK293T cells (Huttlin et al., 2015).”
InfluentialSelf-citationHara, K., Yonezawa, K., Weng, Q.-P., Kozlowski, M. T., BELHAM, C. M., & Avruch, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14484 · Cited by 1,370
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-citationBar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080 · cited 3×
“The GATOR2 complex, which has five subunits (mios, WDR24, WDR59, sec13, seh1L), acts upstream or parallel to GATOR1 and is a key positive regulator of the mTORC1 pathway, although its molecular function is unknown (Bar-Peled et al., 2013).”
Self-citationRagulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1
Bar-Peled, L., Schweitzer, L. D., Zoncu, R., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.07.032 · Cited by 918 · cited 3×
“Amino acid availability controls the nucleotide state of the Rags, and this regulation depends on a complex interplay between multiple distinct factors, including Ragulator, which serves as a lysosomal scaffold for RagA/B (Bar-Peled et al., 2012; Sancak et al., 2010); FLCN/FNIP2, a GAP for RagC/D (Petit et al., 2013;…”
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mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
Self-citationmTOR at the nexus of nutrition, growth, ageing and disease
Liu, G. Y., & Sabatini, D. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0199-y · Cited by 2,737
Self-citationFrom Krebs to clinic: glutamine metabolism to cancer therapy
Altman, B. J., Stine, Z. E., & Dang, C. V. (2016) · Nature Reviews Cancer · doi:10.1038/nrc.2016.71 · Cited by 2,119
Reprogramming of fatty acid metabolism in cancer
Koundouros, N., & Poulogiannis, G. (2019) · British Journal of Cancer · doi:10.1038/s41416-019-0650-z · Cited by 1,669
Architecture of the human interactome defines protein communities and disease networks
Huttlin, E. L., Bruckner, R. J., Paulo, J. A., Cannon, J. R., Ting, L., Baltier, K., Colby, G., Gebreab, F., Gygi, M. P., Parzen, H., et al. (2017) · Nature · doi:10.1038/nature22366 · Cited by 1,437
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Metadata
- Authors
- 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.
- Affiliations
- Broad Institute (US)
- Harvard University (US)
- Corresponding author
- Sabatini, David M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 165
- Issue
- 1
- Pages
- 153-164
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4808398
- OpenAlex
- W2293646973
- Cited by
- 843
- References
- 52
- Citations by year
- 2026: 64 · 2025: 81 · 2024: 77 · 2023: 105 · 2022: 78 · 2021: 102 · 2020: 95 · 2019: 57 · 2018: 73 · 2017: 67 · 2016: 43
- FWCI
- 41.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- US NIH (R01CA103866, AI47389)
- Department of Defense (W81XWH-07-0448)
- John Reed UROP Fund
- National Defense Science & Engineering Graduate Fellowship
- NIH (F31 CA180271, F31 CA189437, U41 HG006673, GM095567)
- 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, arginine sensing, arginine deprivation, GATOR2, GATOR1, Rag GTPases, amino acid signaling, arginine binding, protein complex dissociation, homodimerization, heterodimerization
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Arginine, Carrier Proteins, Humans, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Protein Multimerization, HEK293 Cells, TOR Serine-Threonine Kinases
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