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A Tumor Suppressor Complex with GAP Activity for the Rag GTPases That Signal Amino Acid Sufficiency to mTORC1
Open accessAbstract
Limiting mTORC1: The mTORC1 protein kinase complex has important functions linking metabolism to cell growth and its functions are disrupted in common diseases, including cancer and diabetes. Bar-Peled et al. (p. 1100 ; see the Perspective by Shaw ) discovered regulatory components that help turn down signaling by mTORC1 when cells are deprived of amino acids. Two complexes of proteins, GATOR1 and GATOR2, have opposite effects on activity and cellular localization of mTORC1. Components of the GATOR1 complex negatively regulate mTORC1 and appear to function as tumor supressors. Cancers with loss of GATOR1 function may be particularly amenable to therapeutic strategies that limit activity of mTORC1.
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“These include CG12090, the Drosophila ortholog of mammalian DEPDC5, which was found to be part of the GATOR1 complex that inhibits the Tor pathway during the protracted course of our studies.”
From Functional unknomics: Systematic screening of conserved genes of unknown function (2023) · cites this paper as [54]
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In the citing paper
“WDR59 and WDR24 are both subunits of GATOR2 complex, which functions as a positive regulator of amino‐acid‐mediated mTORC1 activation (Bar‐Peled et al., 2013), and WDR24 modulates mTOR through the previously described changes in lysosome cellular positioning and dynamics (Korolchuk et al., 2011) and thus indirectly modulates autophagic flux (Cai et al., 2016).”
From Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging ( SOMMA ) (2024) · cites this paper as Bar‐Peled et al., 2013
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“Mutants in GATOR1 subunits promote cell growth by increasing Tor activity [54,55].”
From Functional unknomics: Systematic screening of conserved genes of unknown function (2023) · cites this paper as [54]
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“At the Ragulator, the Rag heterodimer interacts with GATOR (GAP Activity Towards Rags), an octomeric complex that controls the activity of the Rag proteins [22].”
From Using Molecular Biology to Maximize Concurrent Training (2014) · cites this paper as [22]
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“One of the best described systems for regulating the nucleotide binding status of the Rag GTPases is the activity of the GATOR complexes. GATOR1 functions as a GAP for RagA and RagB, while GATOR2 acts to inhibit the activity of GATOR1 167,168.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [168]
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“One of the best described systems for regulating the nucleotide binding status of the Rag GTPases is the activity of the GATOR complexes. GATOR1 functions as a GAP for RagA and RagB, while GATOR2 acts to inhibit the activity of GATOR1 167,168.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [168]
In the citing paper
“Upstream regulation of the Rag GTPases is more baroque, featuring at least four large protein complexes including: GATOR1, a GAP for RagA/RagB/Gtr1 (Neklesa and Davis, 2009; Bar-Peled et al., 2013; Panchaud et al., 2013a); FLCN-FNIP (Lst4-Lst7 in yeast), a GAP for RagC/RagD/Gtr2 (Péli-Gulli et al., 2015; Petit et al., 2013; Tsun et al., 2013); GATOR2, an inhibitor of GATOR1 (Bar-Peled et al., 2013”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Bar-Peled et al., 2013
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“Previous studies functionally characterized NPRL2 and its molecular mechanism in cancer cells ( Liu et al., 2015b ; Bar-Peled et al., 2013 ), but the role of NPRL2 in modulating the TME and its association with immune cells in tumors has not been previously studied.”
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“While one study identi fi ed loss of function mutations in the GATOR1 complex components in some solid malignancies 35 , GATOR1 has not previously been reported to suppress Myc-driven hematological malignancies.”
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“21 Baldassari et al. 22 re-ported that 64% of patients with GATOR1-encoding gene variants inherited these variants from asymptomatic parents, and 10% of patients presented with IESS.”
Structural insights into cholesterol sensing by the LYCHOS-mTORC1 pathway
Yu, S., Ding, J.-H., Wang, J.-L., Wang, W.-Z., Zuo, P., Yang, A., Dai, Z.-L., Yin, Y.-X., Sun, J.-P., & Liang, L. (2025) · Nature Communications · doi:10.1038/s41467-025-61966-w · Cited by 6
Li, Z., Guan, Y., Gao, J., Zhu, L., Zeng, Z., Jing, Q., Wan, Q., Fan, Q., Ren, X., Pei, H., et al. (2025) · Oncogene · doi:10.1038/s41388-025-03320-4 · Cited by 3
“Amino acids, including branched-chain amino acids (BCAAs), affect the binding of the sensor protein to the GATOR complex (including GATOR1 and GATOR2), which controls GTP loading of Rag GTPase to regulate the lysosomal localization of mTORC1 [6].”
New insights into GATOR2-dependent interactions and its conformational changes in amino acid sensing
Yang, C., Sun, X., & Wu, G. (2024) · Bioscience Reports · doi:10.1042/bsr20240038 · Cited by 6
“Given that GATOR2 negatively regulates GATOR1 in response to amino acids [12,44], the dynamics of GATOR2 may also play a role in the regulation of GATOR1.”
Yang, S., Ting, C., & Lilly, M. A. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.01.012 · Cited by 7
Rbpms2 promotes female fate upstream of the nutrient sensing Gator2 complex component, Mios
Wilson, M. L., Romano, S. N., Khatri, N., Aharon, D., Liu, Y., Kaufman, O., Draper, B., & Marlow, F. L. (2024) · bioRxiv · doi:10.1101/2024.01.25.577235 · Cited by 6
“In cancer cells, Gator2, inhibits Gator1, thus activating mTORC1 44 .”
Resveratrol Promotes Gluconeogenesis by Inhibiting SESN2-mTORC2-AKT Pathway in Calf Hepatocytes
Wang, G., Qin, S., Geng, H., Zheng, Y., Li, R., Xia, C., Chen, L., Yao, J., & Deng, L. (2023) · Journal of Nutrition · doi:10.1016/j.tjnut.2023.05.005 · Cited by 6
Clinical and genetic features of GATOR1 complex-associated epilepsy
Yin, K., Lei, X.-X., Yan, Z.-F., Yang, Y.-J., Deng, Q.-Q., Lu, Q., Zhang, X., Wang, M.-Y., & Liu, Q. (2023) · Journal of Medical Genetics · doi:10.1136/jmg-2021-108364 · Cited by 6
Coordinated Regulation of Myelination by Growth Factor and Amino-acid Signaling Pathways
Yang, Z., Yu, Z., & Xiao, B. (2022) · Neuroscience Bulletin · doi:10.1007/s12264-022-00967-x · Cited by 6
“Also surprising is that the requirement of MIOS/GATOR2 in amino-acid signaling to mTORC1 is cell-type-specific: genetic deletion of Mios in neural stem cells does not affect mTORC1 activity in neurons, but selectively impairs it in the oligodendrocyte lineage.”
BackgroundInfluentialMorales, J., Allegakoen, D., García, J. A., Kwong, K., Sahu, P., Fajardo, D. A., Pan, Y., Horlbeck, M., Weissman, J., Gustafson, W., et al. (2022) · JCI Insight · doi:10.1172/jci.insight.162207 · Cited by 6
“mTORC1 to the lysosomal membrane in response to aa abundance (6).”
BackgroundYulink, predicted from evolutionary analysis, is involved in cardiac function
Kuo, M.-W., Tsai, H., Wang, S., Chen, Y., Yu, A. L.-T., & Yu, J. (2021) · Journal of Biomedical Science · doi:10.1186/s12929-020-00701-7 · Cited by 8
“Later, it was found as a subunit of GATOR2 complex proteins in HEK-293T cells and inhibition of GATOR2 suppressed mTORC1 signaling and GATOR2 negatively regulated GATOR1 [2].”
BackgroundZeng, N., Prodhan, U. K., D’Souza, R. F., Ramzan, F., Mitchell, S. M., Sharma, P., Knowles, S. O., Roy, N. C., Sjödin, A. M., Wagner, K., et al. (2019) · The journal of nutrition health & aging · doi:10.1007/s12603-019-1171-4 · Cited by 9
Cестрины – шлагбаумы на путях от стресса к старению и болезням
Dalina, A. A., Kovaleva, I. E., & Budanov, A. V. (2018) · Molecular Biology · doi:10.1134/s0026898418060046 · Cited by 15
Hierarchical organization of the human cell from a cancer coessentiality network
Kim, E., Dede, M., Lenoir, W. F., Wang, G., Srinivasan, S., Colic, M., & Hart, T. (2018) · bioRxiv · doi:10.1101/328880 · Cited by 6
“…of essential Rag GTPase activity (Bar-Peled et al., 2013) and is therefore absent from our network, but essential suppression of GATOR-1 by GATOR-2 (Bar-Peled et al., 2013; Wei et al., 2014) is reflected by the strong linkage of the GATOR-2 complex to both the Ragulator and mTOR complexes.”
BackgroundInfluentialApelt, L., Knockenhauer, K., Leksa, N., Benlasfer, N., Schwartz, T., & Stelzl, U. (2016) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m115.054627 · Cited by 6
“complex where these proteins have an additional role (66).”
BackgroundIffland, P. H., & Crino, P. (2016) · Epilepsy Currents · doi:10.5698/1535-7511-16.3.158 · Cited by 6
“GATOR1 regulates mTOR in response to changes in amino acid levels by modulating the localization of mTORC1 to the lysosomal surface by activating the RAG GTPases on the lysosomal membrane; leucine and arginine are of particular importance in this mechanism (27).”
BackgroundRegulatory role of Wdr24 in autophagy activity during zebrafish embryogenesis
Kim, Y.-I., Nam, I., Um, J., & Choe, S.-K. (2018) · Molecular & Cellular Toxicology · doi:10.1007/s13273-019-0010-3 · Cited by 6
mTORC1 in the Control of Myogenesis and Adult Skeletal Muscle Mass
Wallace, M. A., Hughes, D. C., & Baar, K. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-802733-2.00025-6 · Cited by 9
Xiang, J., Wang, T., Tian, S., Li, J., Luo, M., Wang, Y., Du, A., Chen, X., Tian, F., Wang, L., et al. (2026) · Nature Cell Biology · doi:10.1038/s41556-026-01926-8 · Cited by 5
“A moderate decrease of two GATOR1 subunits, DEPDC5 and NPRL3, was likely due to the fact that cells missing a GATOR1 component have reduced expression of the remaining complex components 7 .”
InfluentialArchitecture of the human KICSTOR and GATOR1–KICSTOR complexes
Teng, F., Zeng, H., Mai, X., Chen, S., Wang, L., Feng, Z., Tian, S., Wang, S., Stjepanović, G., Lim, C.-Y., et al. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01693-4 · Cited by 6
“Two GTPase-activating protein (GAP) complexes have been characterized as part of the core nutrient-sensing machinery, the GATOR1 complex and the FLCN–FNIP2 complex, which stimulate GTP hydrolysis by RagA/B and RagC/D, respectively 10,11 .”
Targeting autophagy in dysfunctional tumor vasculature
Lin, Q., Cai, B., Ke, R., Ni, X., Wan, X., Chen, L., Huang, T., Shan, X., & Wang, B. (2025) · iScience · doi:10.1016/j.isci.2025.114084 · Cited by 5
“135 This system enables TECs to rapidly adapt to the dynamic changes in nutrient availability characteristic of tumor blood vessels.”
Hassan, F., Slone, C., McDonald, R. J., Dueber, J. C., Ashraf, A. M., Windon, M., Fackelmayer, O. J., Lee, C. Y., Bocklage, T. J., & Allison, D. (2025) · Current Oncology · doi:10.3390/curroncol32040224 · Cited by 5
“Its loss disrupts the balance between anabolic and catabolic processes, largely due to its role as a GTPase-activating protein for Rag GTPases involved in nutrient signaling [31–33].”
Anglès, F., Gupta, V., Wang, C., & Balch, W. E. (2024) · Scientific Reports · doi:10.1038/s41598-024-60687-2 · Cited by 5
OTUD3 suppresses the mTORC1 signaling by deubiquitinating KPTN
Li, J., Yang, D., Lin, Y., Xu, W., Zhao, S.-M., & Wang, C.-J. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1337732 · Cited by 5
Bagh, M. B., Appu, A. P., Sadhukhan, T., Mondal, A., Plavelil, N., Raghavankutty, M., Supran, A. M., Sadhukhan, S., Liu, A., & Mukherjee, A. B. (2024) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2024.105641 · Cited by 7
“Notably, the Rag GTPases tethered to the lysosomal membrane by a Rag GTPase/Ragulator scaffold brings mTORC1 to the lysosomal surface where its signaling pathway is activated.”
BackgroundInfluentialTai, Y.-T., Fukuda, T., Morozumi, Y., Hirai, H., Oda, A. H., Kamada, Y., Akikusa, Y., Kanki, T., Ohta, K., & Shiozaki, K. (2023) · Molecular and Cellular Biology · doi:10.1080/10985549.2023.2282349 · Cited by 5
Coen, P., Huo, Z., Tranah, G. J., Barnes, H., Cawthon, P., Hepple, R., Toledo, F., Evans, D. S., Fernández, O. S., Cuervo, A., et al. (2023) · medRxiv · doi:10.1101/2023.11.04.23297979 · Cited by 5
“WDR59 and WDR24 are both subunits of GATOR2 complex which functions as a positive regulator of amino-acid-mediated mTORC1 activation (Bar-Peled et al. 2013) and WDR24 modulates mTOR through the previously described changes in lysosome cellular positioning and dynamics (Korolchuk et al. 2011), and…”
BackgroundPetri, B. J., Piell, K. M., Wahlang, B., Head, K. Z., Rouchka, E. C., Park, J. W., Hwang, J. Y., Banerjee, M., Cave, M. C., & Klinge, C. M. (2023) · Environmental Toxicology and Pharmacology · doi:10.1016/j.etap.2023.104260 · Cited by 7
Westphal, D., Meinhardt, M., Grützmann, K., Schöne, L., Steininger, J., Neuhaus, L. T., Wiegel, M., Schrimpf, D., Aust, D. E., Schröck, E., et al. (2023) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2023.01.011 · Cited by 17
Cabral-Fernandes, L., Goyal, S., Farahvash, A., Tsalikis, J., Philpott, D., & Girardin, S. (2022) · Molecular and Cellular Biology · doi:10.1128/mcb.00241-22 · Cited by 5
“of RagA/B GTPases, leading to the inactivation of mTORC1 (35).”
BackgroundBehavioral And Physiological Analysis In A Zebrafish Model Of Epilepsy.
de Calbiac, H., Dăbâcan, A., Muresan, R., Kabashi, E., & Ciura, S. (2021) · Journal of Visualized Experiments · doi:10.3791/58837 · Cited by 5
Gonzalez-Estevez, A., Verrico, A., Orniacki, C., Reina-San-Martin, B., & Doye, V. (2021) · Journal of Cell Science · doi:10.1242/jcs.258340 · Cited by 5
Main insights of genome wide association studies into HCV-related HCC
Moaz, I., Abdallah, A., Yousef, M., & Ezzat, S. (2020) · Egyptian Liver Journal · doi:10.1186/s43066-019-0013-8 · Cited by 5
Conceptualizing Eukaryotic Metabolic Sensing and Signaling
Laxman, S. (2017) · Journal of the Indian Institute of Science · doi:10.1007/s41745-016-0013-1 · Cited by 5
Twists and turns—How we stepped into and had fun in the “boring” lipid field
Han, M. (2015) · Science China Life Sciences · doi:10.1007/s11427-015-4949-6 · Cited by 5
Rag Ubiquitination Recruits a GATOR1: Attenuation of Amino Acid-Induced mTORC1 Signaling.
Fingar, D. (2015) · Molecules and Cells · doi:10.1016/j.molcel.2015.05.029 · Cited by 5
“The heterotrimeric GATOR1 complex opposes the action of the ragulator complex by functioning as a GAP for RagA/B (Bar-Peled et al., 2013).”
BackgroundChild, N. D., & Benarroch, E. E. (2014) · Neurology · doi:10.1212/wnl.0000000000000922 · Cited by 17
“The GAP activity towards Rags (GATOR) complex regulates Rag signaling; GATOR1 has GAP activity for Rag, thus inhibiting mTORC1 signaling.(30)”
BackgroundAutophagy and amino acids with their metabolites
mammals, M. I. R. T. T. L. S. I. A. A.-R. C. R. G. T. (. H. F. O. T. L. A. T. K. P. I. T. T. O. M. T. T. L. M. B. A. A. I., found, F. R. G. H. B., RagA, N., RagB, RagC, and RagD [53, 5. U. O. S. G., conditions, R. G. H. N. L. A. A. T. F. A. H. T. C. R. O. R. W. E. R. O. R. T. G. O. G. S. I. R. A. R. B. A. A. R. B. T. G. A. R. B. T. G. I. A. A.-D., conditions, W. R. B. T. G. A. R. B. T. G. I. A. A.-R., mTORC1, T. L. S. B. T. A. S. O. T. R. H. T. A. R. H. B. W. R. I., hence, T. L. T. T. L. O. M. T. T. L. M. [. R. G. L. A. L. A., et al. (2015) · Integrative Food Nutrition and Metabolism · doi:10.15761/ifnm.1000119 · Cited by 3
“In GATOR2, Mios is necessary for the activation of mTORC1 by amino acids [60].”
Background
Metadata
- Authors
- Bar-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.
- Affiliations
- Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA.
- Whitehead Institute for Biomedical Research (US)
- Broad Institute (US)
- Johns Hopkins University (US)
- Corresponding author
- Chantranupong, Lynne
- Sabatini, David M.
- ORCID
- Venue
- Science
- Published
- 2013-05-31
- Volume
- 340
- Issue
- 6136
- Pages
- 1100-1106
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3728654
- OpenAlex
- W1519230612
- Cited by
- 1,080
- References
- 32
- Citations by year
- 2026: 40 · 2025: 79 · 2024: 88 · 2023: 89 · 2022: 97 · 2021: 85 · 2020: 91 · 2019: 77 · 2018: 88 · 2017: 83 · 2016: 84 · 2015: 87 · 2014: 69 · 2013: 21
- FWCI
- 38.94
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- PMC
- Funders
- Howard Hughes Medical Institute
- National Cancer Institute (CA103866, R01CA103866, R01CA129105, F31CA180271, U24CA143867, P30CA014051)
- National Institute of Allergy and Infectious Diseases (R37AI047389, 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- GATOR1, GATOR2, mTORC1, Rag GTPases, GTPase-activating protein, amino acid signaling, lysosomal translocation, DEPDC5, NPRL2, NPRL3, MIO, Sec13, rapamycin sensitivity, amino acid starvation, cancer
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acids, Carrier Proteins, Humans, Lysosomes, Mutation, Neoplasms, Nuclear Proteins, Proteins, Monomeric GTP-Binding Proteins, GTPase-Activating Proteins, Tumor Suppressor Proteins, RNA, Small Interfering, Cell Line, Tumor, Multiprotein Complexes, HEK293 Cells, TOR Serine-Threonine Kinases
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