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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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“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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Cites
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“Moreover, many regulators of RagA/B have been identified, and these include the SLC38A9 functioning as the guanosine exchange factor (GEF) of RagA/B,(128) Sestrin2 identified as the guanine nucleotide dissociation inhibitor (GDI) of RagA/B,(129) and the GATOR1 complex acting as a GTPaseactivating protein (GAP) to RagA…”
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“Human mutations in DEPDC5, a component of the GATOR complex, have been linked to both epilepsy with cerebral malformations and nonlesional epilepsy (Bar-Peled et al., 2013; Dibbens et al., 2013; Scheffer et al., 2014).”
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InfluentialSLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
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“Studies in mammalian cells led to the identification of the GATOR1 complex as the GAP that inactivates RagA/B. Depletion of any of the three GATOR1 subunits leads to constitutive lysosomal localization and to activation of mTORC1 irrespective of amino acid status (Bar-Peled et al. 2013).”
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“…mg HA-GST-RagCD181N and 16 mg HA-RagB; 8 mg HA-GST-RagC and 16 mg HA-RagB; GATOR1: 4 mg FLAGDEPDC5 and 8 mg myc-NPRL2 and 8 mg myc-NPRL3 isoform 1 (Bar-Peled et al., 2013); FLCN-FNIP1: 8 mg FLAG-FNIP1 and 16 mg HA-FLCN; FLCNFNIP2: 8 mg FLAG-FNIP2 and 16 mg HA-FLCN; FLCN(DN-term)-FNIP2: 8 mg…”
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“Akt phosphorylates and inhibits the GTPase-activating protein (GAP) tuberosclerosis complex 2 (TSC2), which forms a complex with the scaffolding protein TSC1 that negatively controls the small GTPase Rheb, a key regulator of the mTORC1 complex (120, 121).”
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Sestrins inhibit mTORC1 kinase activation through the GATOR complex
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“RagA:RagB is active in its GTP-bound form, and GATOR1 can regulate RagA:RagB by stimulating its GTPase activity (Bar-Peled et al., 2013).”
BackgroundInfluentialmTOR in Brain Physiology and Pathologies
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“mTORC1 activation due to mutations in DEPDC5 [a component of the GATOR1 complex which negatively controls mTORC1 activity (18)] has also been implicated in a majority of cases of autosomal dominant familial focal epilepsies with variable foci (FFEVF) (63).”
BackgroundActivation of mTOR (mechanistic target of rapamycin) in rheumatic diseases
Perl, A. (2015) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2015.172 · Cited by 348
Regulation of Autophagy by mTOR Signaling Pathway
Wang, Y., & Zhang, H. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-981-15-0602-4_3 · Cited by 363
A systems study reveals concurrent activation of AMPK and mTOR by amino acids
Dalle Pezze, P., Ruf, S., Sonntag, A. G., Langelaar-Makkinje, M., Hall, P., Heberle, A. M., Razquin Navas, P., van Eunen, K., Tölle, R. C., Schwarz, J. J., et al. (2016) · Nature Communications · doi:10.1038/ncomms13254 · Cited by 148
KICSTOR recruits GATOR1 to the lysosome and is necessary for nutrients to regulate mTORC1
Wolfson, R. L., Chantranupong, L., Wyant, G. A., Gu, X., Orozco, J. M., Shen, K., Condon, K. J., Petri, S., Kedir, J. F., Scaria, S. M., et al. (2017) · Nature · doi:10.1038/nature21423 · Cited by 345
Self-citationSLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity
Guo, C., You, Z., Shi, H., Sun, Y., Du, X., Palacios, G. F., Guy, C. S., Yuan, S., Chapman, N. M., Lim, S. A., et al. (2023) · Nature · doi:10.1038/s41586-023-06299-8 · Cited by 325
Mechanism of arginine sensing by CASTOR1 upstream of mTORC1
Saxton, R. A., Chantranupong, L., Knockenhauer, K. E., Schwartz, T. U., & Sabatini, D. M. (2016) · Nature · doi:10.1038/nature19079 · Cited by 308
Self-citationNutrient-Sensing Mechanisms across Evolution
Chantranupong, L., Wolfson, R. L., & Sabatini, D. M. (2015) · Cell · doi:10.1016/j.cell.2015.02.041 · Cited by 324
“Ragulator binds the Rag GTPases to the lysosome and also has nucleotide exchange activity for RagA/B (Bar-Peled et al., 2012; Sancak et al., 2010), but the function of the v-ATPase in the pathway is unknown.”
InfluentialSelf-citationGrowing knowledge of the mTOR signaling network
Huang, K., & Fingar, D. C. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.09.011 · Cited by 310
Amino acid-dependent control of mTORC1 signaling: a variety of regulatory modes
Takahara, T., Amemiya, Y., Sugiyama, R., Maki, M., & Shibata, H. (2020) · Journal of Biomedical Science · doi:10.1186/s12929-020-00679-2 · Cited by 300
“The addition of amino acids triggers the shift of Rag GTPases to their active nucleotide-bound state, i.e., the GTP-bound form of RagA/B and the GDP-bound form of RagC/D. Active Rag GTPases can bind to Raptor and thereby recruit mTORC1 on the lysosomal surface, where Rheb, a direct activator of mTORC1, is also believe…”
BackgroundInfluentialThe role of mammalian target of rapamycin (mTOR) in insulin signaling
Yoon, M.-S. (2017) · Nutrients · doi:10.3390/nu9111176 · Cited by 300
The hidden genetics of epilepsy—a clinically important new paradigm
Thomas, R. H., & Berkovic, S. F. (2014) · Nature Reviews Neurology · doi:10.1038/nrneurol.2014.62 · Cited by 300
Nutrient regulation of mTORC1 at a glance
Condon, K. J., & Sabatini, D. M. (2019) · Journal of Cell Science · doi:10.1242/jcs.222570 · Cited by 342
Self-citationLim, C.-Y., Davis, O. B., Shin, H. R., Zhang, J., Berdan, C. A., Jiang, X., Counihan, J. L., Ory, D. S., Nomura, D. K., & Zoncu, R. (2019) · Nature Cell Biology · doi:10.1038/s41556-019-0391-5 · Cited by 312
Molecular logic of mTORC1 signalling as a metabolic rheostat
Valvezan, A. J., & Manning, B. D. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0038-7 · Cited by 310
Signaling Pathways Involved in the Regulation of mRNA Translation
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“GAP activity toward Rags 1 (GATOR1) is a heterotrimeric complex comprising of Nprl3, Nprl2, and DEPDC5, which acts as a RagA/B GAP and inhibits mTORC1 (81).”
BackgroundFamilial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
Baulac, S., Ishida, S., Marsan, E., Miquel, C., Biraben, A., Nguyen, D., Nordli, D., Cossette, P., Nguyen, S., Lambrecq, V., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24368 · Cited by 279
“The finding that DEPDC5 is associated with FCD in the context of inherited focal epilepsy agrees with evidence that DEPDC5 acts as an mTORC1 inhibitor.(16) The role of DEPDC5 in the mTORC1 cascade is particularly attractive for 2 main reasons: (1) other genes encoding inhibitors of mTORC1 have been shown to cause brai…”
BackgroundRab1A Is an mTORC1 Activator and a Colorectal Oncogene
Thomas, J. D., Zhang, Y.-J., Wei, Y.-H., Cho, J.-H., Morris, L. E., Wang, H.-Y., & Zheng, X. F. S. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.09.008 · Cited by 278
“A recent study implicated GATOR, the GTPase-activating protein (GAP) for Rag A/RagB as potential tumor suppressor (Bar-Peled et al., 2013).”
Phosphatidylinositol 3-phosphates—at the interface between cell signalling and membrane traffic
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“The recruitment of mTORC1 to the lysosome, where it will be activated, is mediated via the cellular amino acid status (Sancak et al , 2008; Zoncu et al , 2011a; Bar-Peled et al , 2013).”
Metformin as an Anticancer Agent
Vancura, A., Bu, P., Bhagwat, M., Zeng, J., & Vancurova, I. (2018) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2018.07.006 · Cited by 274
The lysosome as a command-and-control center for cellular metabolism
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“Npr3) GAT OR1 DEP DC5, Nprl2, Nprl3 GAP for Rag-A/B Down Dokudovskaya and Rout, 2011; Bar-Peled et al., 2013; Panchaud et al., 2013”
BackgroundDefinition and diagnostic criteria of sleep-related hypermotor epilepsy
Tinuper, P., Bisulli, F., Cross, J. H., Hesdorffer, D., Kahane, P., Nobili, L., Provini, F., Scheffer, I., Tassi, L., Vignatelli, L., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002666 · Cited by 274
Lysosomes as coordinators of cellular catabolism, metabolic signalling and organ physiology
Settembre, C., & Perera, R. M. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00676-x · Cited by 303
Signaling pathways in cancer metabolism: mechanisms and therapeutic targets
You, M., Xie, Z., Zhang, N., Zhang, Y., Xiao, D., Liu, S., Zhuang, W., Li, L., & Tao, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01442-3 · Cited by 317
“Interestingly, the study found that when the amino acid adequacy is low, a protein subcomplex called GTPaseactivating target of rapamycin 1(GATOR1) has been shown to inactivate the rag heterodimer complex, thereby inhibiting the ability of RAG GTPase heterodimer to recruit mTORC1 on the surface of the enzyme body.(314…”
BackgroundAmino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9
Jung, J., Genau, H. M., & Behrends, C. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00125-15 · Cited by 266
“While the GATOR1 (GAP activity toward Rags) complex exhibits GAP activity toward RagA/B (21), FLCN (folliculin) and its interacting partners, FNIP1 (folliculin-interacting protein 1) and FNIP2, act on RagC/D (20).”
BackgroundInfluentialMcConnell, M. J., Moran, J. V., Abyzov, A., Akbarian, S., Bae, T., Cortes-Ciriano, I., Erwin, J. A., Fasching, L., Flasch, D. A., Freed, D., et al. (2017) · Science · doi:10.1126/science.aal1641 · Cited by 262
“DEPDC5 (109, 110) PI3K-AKT-mTOR Epilepsy with FCD mTORC1”
Chemical Proteomics Identifies Druggable Vulnerabilities in a Genetically Defined Cancer
Bar-Peled, L., Kemper, E. K., Suciu, R. M., Vinogradova, E. V., Backus, K. M., Horning, B. D., Paul, T. A., Ichu, T.-A., Svensson, R. U., Olucha, J., et al. (2017) · Cell · doi:10.1016/j.cell.2017.08.051 · Cited by 262
“Oligonucleotides See Table S5 N/A N/A Recombinant DNA pLKO.1:shGFP (Bar-Peled et al., 2013) N/A pLKO.1:shNRF2_1 Sigma-Aldrich TRCN0000284998 (Continued on next page) e2 Cell 171, 1–14.e1–e12, October 19, 2017 Please cite this article in press as: Bar-Peled et al., Chemical Proteomics Identifies…”
Self-citationGoul, C., Peruzzo, R., & Zoncu, R. (2023) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-023-00641-8 · Cited by 280
“The cryo-electron microscopy (cryo-EM) structure of human GATOR1 in complex with the Rag heterodimer shows that as the Arg78-containing loop of NPRL2 is inserted in the nucleotide-binding pocket of RagA, an additional interaction is established between RagC and DEPDC5 (ref.”
BackgroundInfluentialWatch What You (Self-) Eat: Autophagic Mechanisms that Modulate Metabolism
Lahiri, V., Hawkins, W. D., & Klionsky, D. J. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.03.003 · Cited by 287
“, 2016) family proteins, which, in response to cytosolic leucine and arginine, respectively, modulate RRAG activity through the GTPase activating proteins GATOR1 and GATOR2 (Bar-Peled et al., 2013; Panchaud et al., 2013).”
BackgroundRibosomal Protein S6 Phosphorylation
Meyuhas, O. (2015) · International review of cytology · doi:10.1016/bs.ircmb.2015.07.006 · Cited by 296
“In contrast, the pentameric complex, GATOR1, inhibits the mTORC1 pathway by functioning as a GAP for RagA, whereas the trimeric complex, GATOR2 negatively regulates GATOR1 (Bar-Peled et al., 2013).”
BackgroundEmerging Roles for the Lysosome in Lipid Metabolism
Thelen, A. M., & Zoncu, R. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.07.006 · Cited by 275
Ricos, M. G., Hodgson, B. L., Pippucci, T., Saidin, A., Ong, Y. S., Heron, S. E., Licchetta, L., Bisulli, F., Bayly, M. A., Hughes, J., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24547 · Cited by 246
“This complex has been shown to act as a GAP (GTPase-activating protein) for the RagA/B GTPases, which control mTORC1 (mammalian target of rapamycin complex 1) activity.(5) mammalian target of rapamycin (mTOR) is a master regulator of cell growth, and deregulation of mTOR signaling has been associated with multiple dis…”
BackgroundMirzaa, G., Campbell, C., Solovieff, N., Goold, C. P., Jansen, L., Menon, S., Timms, A., Conti, V., Biag, J., Adams, C., et al. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.0363 · Cited by 246
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Amino Acid Sensing by mTORC1: Intracellular Transporters Mark the Spot
Goberdhan, D. C. I., WILSON, C. G., & Harris, A. L. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.03.013 · Cited by 257
“For example, components of GATOR1 (Figure 2), which negatively regulates amino acid sensing, act as tumor suppressors (Bar-Peled et al., 2013), and RagC mutations have recently been linked to follicular lymphoma (Okosun”
BackgroundRegulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A
Wong, P.-M., Feng, Y., Wang, J., Shi, R., & Jiang, X. (2015) · Nature Communications · doi:10.1038/ncomms9048 · Cited by 239
The vacuolar-type H+-ATPase at a glance – more than a proton pump
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“Components of the mTORC1 pathway – the Ragulator complex (comprising LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5) and the Ras-related GTP-binding proteins (RRAGA, RRAGB, RRAGC and RRAGD; hereafter referred to as Rag GTPases) – localize to the lysosomal membrane in an inactive form (see poster panel ‘Amino-acid- ind…”
BackgroundInfluentialMolecular regulation of autophagy machinery by mTOR‐dependent and ‐independent pathways
Al‐Bari, M. A. A., & Xu, P. (2020) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14305 · Cited by 269
Translational reprogramming in cellular stress response
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Quantitative analysis of T cell proteomes and environmental sensors during T cell differentiation
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Harpur, B., Kent, C. F., Molodtsova, D., Lebon, J., Alqarni, A., Owayss, A., & Zayed, A. (2014) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.1315506111 · Cited by 229
“Vg in turn regulates the central insulin/Tor growth pathway (49) and both of the bee’s insulin receptors and the Depdc5 gene—part of a complex which sensitizes Tor signaling to cellular amino acid levels (50)—are under positive selection.”
BackgroundScheffer, I. E., Heron, S. E., Regan, B. M., Mandelstam, S. A., Crompton, D. E., Hodgson, B. L., Licchetta, L., Provini, F., Bisulli, F., Vadlamudi, L., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24126 · Cited by 234
“However, under conditions of amino acid deprivation, GATOR1 inhibits mTORC1 activation by acting as a GTPase activating protein for Rag GTPases.11 Activation of the mTORC1 pathway leads to increased synthesis of proteins and lipids to generate new cell membranes, increased cellular metabolism, and energy production.”
BackgroundInfluentialPeng, M., Yin, N., & Li, M. O. (2014) · Cell · doi:10.1016/j.cell.2014.08.038 · Cited by 220
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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