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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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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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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Figlia, G., Müller, S., Cortizo, F. G., Neff, M., Klinke, G., Poschet, G., & Teleman, A. A. (2025) · The EMBO Journal · doi:10.1038/s44318-025-00505-1 · Cited by 16
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InfluentialPib2 is a cysteine sensor involved in TORC1 activation in Saccharomyces cerevisiae.
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“It encodes a subunit protein of the Gap Activity TOward Rags 1 (GATOR1) complex, which has been characterized as a suppressor of the mechanistic target of the rapamycin complex 1 (mTORC1) pathway (Bar‐Peled et al., 2013; J. Chen, Ou, et al., 2018).”
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InfluentialDai, W.-T., Wang, Q.-J., Zou, Y.-X., White, R., Liu, J.-X., & Liu, H.-Y. (2017) · Journal of Dairy Science · doi:10.3168/jds.2016-12366 · Cited by 17
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“the Rag GAP GATOR1, thereby leading to increased RagA/B GTP loading and subsequent mTOCR1 activation (Figure 2).[63,64] Study”
BackgroundLeucine retention in lysosomes is regulated by starvation
Bandyopadhyay, U., Todorova, P., Pavlova, N., Tada, Y., Thompson, C., Finley, L. W. S., & Overholtzer, M. (2022) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2114912119 · Cited by 16
“Further investigation of the mTORC1 pathway through knockout (KO) of Depdc5, which encodes a component of the Gator1 complex that inhibits mTORC1 during leucine starvation (16), knockdown of SESTRIN2, which blocks leucine sensing by mTORC1 (17), or KO of tuberous sclerosis 2 (Tsc2), which also leads to constitutive mT…”
BackgroundAmino acid sensory complex proteins in mTORC1 and macroautophagy regulation
Seibert, M., Kurrle, N., Schnütgen, F., & Serve, H. L. (2021) · Matrix Biology · doi:10.1016/j.matbio.2021.01.001 · Cited by 18
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“, GTPase-activating proteins toward Rags 1 (GATOR1) complex [9]]; guanine nucleotide exchange factors that facilitate GDP dissociation (e.”
BackgroundThe structure of the human LACTB filament reveals the mechanisms of assembly and membrane binding
Bennett, J. A., Steward, L. R., Rudolph, J., Voss, A. P., & Aydin, H. (2022) · PLOS Biology · doi:10.1371/journal.pbio.3001899 · Cited by 16
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“To address this issue, we performed co-immunoprecipitation (Co-IP) experiment using an expression plasmid encoding FLAGWDR24, a component of GATOR2 complex.(25) Amino acid depletion increased Sestrin2 proteins co-immunoprecipitated with FLAG-WDR24 proteins and reduced the p-S6K levels, while the following amino acid r…”
MethodBranched-chain amino acids in muscle growth: mechanisms, physiological functions, and applications
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“3, intracellular BCAA activate mTORC1 signaling through the GATOR regulatory network, with Sestrin2 acting as the primary Leu sensor [54].”
Targeting mTOR Kinase for Cancer Treatment: A Comprehensive Review With Clinical Insights
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Nucleoporin Seh1 maintains Schwann cell homeostasis by regulating genome stability and necroptosis
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“DEPDC5 is a subunit of the GATOR1 complex, which functions as an inhibitor of the mTORC1 signaling pathway.(57) Finally, we identified one sample with a COL4A5–COL4A6 deletion and significant upregulation of IRS4.”
BackgroundDietary Energy Modulation and Autophagy: Exploiting Metabolic Vulnerabilities to Starve Cancer
Cozzo, A. J., Coleman, M. F., Pearce, J. B., Pfeil, A. J., Etigunta, S. K., & Hursting, S. D. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.590192 · Cited by 55
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“DEPDC5 is a protein in the GATOR1 complex that upregulates amino acid-dependent Rag signaling [22].”
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InfluentialHigh expression of NPRL2 is linked to poor prognosis in patients with prostate cancer
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“…of their activation during the course of this tumor ’ s treatment: MAPK ( SPRY3 ) (Cabrita and Christofori 2008), PI3K (DEPDC5) (Cabrita and Christofori 2008; Bar-Peled et al. 2013), and WNT ( KREMEN2 , NET1 , GPR124 ) (Orlow et al. 1987; Mao et al. 2002; Posokhova et al. 2015; Wei et al. 2017).”
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“…components of this pathway, including inactivating mutations in DEPDC5, NPRL2, and NPRL3, and an activating mutation (Y35N) in RHEB have been shown to lead to strong mTORC1 activation in vitro, including analysis of cancer cell lines in some cases (Bar-Peled et al., 2013; Grabiner et al., 2014).”
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“UA Inhibits Leucine-stimulated mTORC1 Signaling by Disrupting mTOR Lysosomal Localization The small GTPase Rag has been shown to be critical for leucine-stimulated mTORC1 activation [16,35].”
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“Specifically, GATOR1 (GAP activity towards Rags 1) negatively regulates mTORC1 activity through GTP hydrolysis of RAG A/B (Ras-related GTP-binding protein A and B) and RAG C/D (Ras-related GTP-binding protein C and D), which can also be regulated by the Ragulator complex, the lysosomal bound proteins LAMTOR 1/2/3/4/5…”
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“The guanine nucleotide status of Rag GTPases is regulated by certain amino acids and the LE v-ATPase and involves different lysosomal scaffolds, such as Ragulator [33–35], GATOR1 [36, 37], Sestrin2 [38], Folliculin (FLCN/FNIP2) [39–41], and the lysosomal transporter SLC38A9 [28, 42, 43].”
BackgroundGenetic updates on paroxysmal dyskinesias
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BackgroundPolarization and asymmetry in T cell metabolism
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“The protein product of this gene is part of the GATOR1 complex, a repressor of mTOR signaling.(6) Although most cases of FCD-II are not familial, de novo mutations in DEPDC5 and other mTOR pathway genes are known”
BackgroundAutophagy: Biology and Diseases: Clinical Science
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“GATOR1 activates the GTPase RagA/B, thus inhibiting mTORC1 activity under static and low amino acid conditions (Bar-Peled et al. 2013).”
BackgroundStructure of the lysosomal KICSTOR-GATOR1-SAMTOR nutrient-sensing supercomplex
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“158098 complex (26), folliculin (27), the KICSTOR complex (28), and solute carrier family 38 member 9 (SLC38A9) (29).”
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“rupt Rag function and made mTORC1 hyperactive and insensitive to nutrient starvation.(24) Furthermore, some patients with colon cancers show low levels of Sestrin2, sug-”
BackgroundA Genome-Wide siRNA Screen in Mammalian Cells for Regulators of S6 Phosphorylation
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“The GATOR 1 complex (nprl2/nprl3/DEPDC5) is reported to be a negative regulator of amino acid-stimulated, Rag dependent mTORC1 activation, whose inhibitory effect is relieved by the GATOR2 complex (Sec13/Mios/WDR24/ WDR59/SEH1L) [30].”
BackgroundAl-Anazi, M., Matou-Nasri, S., Abdo, A. A., Sanai, F., Khan, M., Albenmousa, A., Al-ashgar, H., Khalaf, N., Al-Ahdal, M., & Al-Qahtani, A. (2014) · BMC Infectious Diseases · doi:10.1186/s12879-014-0632-y · Cited by 13
“Thus far, the only cell function of DEPDC5 mentioned was to block mTOR pathway [18].”
BackgroundSignal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12
Fine-tuning AMPK in physiology and disease using point-mutant mouse models
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Lysosomes, curcumin, and anti-tumor effects: how are they linked?
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“Loss of GTPase activating protein for RAGA (GATOR1) has been identified in multiple tumors (Bar-Peled et al., 2013).”
BackgroundMathur, P., Santos, C. D. B., Lachuer, H., Patat, J., Latgé, B., Radvanyi, F., Goud, B., & Schauer, K. (2023) · Communications Biology · doi:10.1038/s42003-023-04501-1 · Cited by 16
NPRL2 Inhibition of mTORC1 Controls Sodium Channel Expression and Brain Amino Acid Homeostasis
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GATOR2 complex–mediated amino acid signaling regulates brain myelination
Yu, Z., Yang, Z., Ren, G., Wang, Y., Luo, X., Zhu, F., Yu, S.-Y., Jia, L., Chen, M.-N., Worley, P., et al. (2022) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.2110917119 · Cited by 12
“Amino acid starvation and refeeding experiments were conducted based on the previous study (27).”
BackgroundMethodInfluentialTyrosine phosphorylation of DEPTOR functions as a molecular switch to activate mTOR signaling
Gagné, L. M., Morin, N., Lavoie, N., Bisson, N., Lambert, J.-P., Mallette, F. A., & Huot, M.-É. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.101291 · Cited by 12
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The TORC1 inhibitor Nprl2 protects age-related digestive function in Drosophila
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“In Drosophila and mammals, depleting any of the GATOR1 or TSC complex components results in a dramatic increase in TORC1 activity and cell size [13, 14].”
BackgroundZhao, L., Ji, X., Zhang, X., Li, L., Jin, Y., & Liu, W. (2018) · Journal of Cell Science · doi:10.1242/jcs.218792 · Cited by 14
“Proton-assisted amino acid transporter PAT1 complexes with Rag GTPases and activates TORC1 on late endosomal and lysosomal membranes.”
BackgroundInfluentialZeng, N., D’Souza, R. F., Sorrenson, B., Merry, T. L., Barnett, M. P. G., Mitchell, C. J., & Cameron‐Smith, D. (2018) · European Journal of Applied Physiology · doi:10.1007/s00421-018-3853-8 · Cited by 13
“2010), where GATOR2 activates mTORC1 by inhibiting GATOR1 following increased AA exposure (Bar-Peled et al. 2013).”
Kwon, O., Kwak, D., Ha, S. H., Jeon, H., Park, M., Chang, Y., Suh, P., & Ryu, S. H. (2017) · Cellular Signalling · doi:10.1016/j.cellsig.2017.01.015 · Cited by 12
“However, the inactive form of Rag GTPase, which contains GDP-bound Rag A or Rag B, is generated by the GATOR complex, a GAP complex of Rag GTPases, under conditions of starvation [9-12].”
Amino acid-dependent NPRL2 interaction with Raptor determines mTOR Complex 1 activation
Kwak, S. S., Kang, K. H., Kim, S., Lee, S., Lee, J., Kim, J. W., Byun, B., Meadows, G. G., & Joe, C. O. (2015) · Cellular Signalling · doi:10.1016/j.cellsig.2015.11.008 · Cited by 15
Nutrient sensing lost in cancer
Menon, S., & Manning, B. D. (2013) · Nature · doi:10.1038/498444a · Cited by 10
Evolutionary mining of skyline clusters of attributed graph data
Dhifli, W., Karabadji, N. E., & Elati, M. (2020) · Information Sciences · doi:10.1016/j.ins.2018.09.053 · Cited by 12
Lysosomes as hubs of metabolic sensing and cellular homeostasis
Jain, A., & Zoncu, R. (2026) · Molecular Cell · doi:10.1016/j.molcel.2026.01.011 · Cited by 15
Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex
Su, M.-Y., Teng, F., Wang, S., Mai, X., Zeng, H., Li, J., Song, X., Wang, X., & Stjepanović, G. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116088 · Cited by 11
Structural basis for mTORC1 regulation by the CASTOR1–GATOR2 complex
Jansen, R. M., Maghe, C., Tapia, K., Wu, S., Yang, S., Ren, X., Zoncu, R., & Hurley, J. H. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01635-0 · Cited by 14
“When cytosolic amino acid levels are low, the Rag–Ragulator complex is inactivated by the GTPase-activating protein (GAP) GATOR1, which promotes GTP hydrolysis by RagA or RagB 13 .”
InfluentialWu, Y.-C., Wang, W.-T., Yang, M.-C., Su, Y.-T., Yeh, J., Hsu, J.-H., & Wu, J.-R. (2023) · Biological Research · doi:10.1186/s40659-023-00480-z · Cited by 11
“…contains a highly conserved domain, MIOS (missing oocyte, gene ID: 33399), which was revealed to participate in the regulation of mTOR signaling [11]. mTOR signaling plays critical roles in cell migration, cell proliferation and energy homeostasis in PASMCs in PAH [12]; however, whether YULINK…”
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RAGA prevents tumor immune evasion of LUAD by promoting CD47 lysosome degradation
Zhang, L., Yu, J., Zheng, M., Zhen, H., Xie, Q., Zhang, C., Zhou, Z., & Jin, G. (2023) · Communications Biology · doi:10.1038/s42003-023-04581-z · Cited by 12
Hu, J.-J., Gao, X., Chen, L., Kan, Y.-L., Du, Z., Xin, S., Ji, W.-K., Yu, Q., & Cao, L.-R. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2022.1054567 · Cited by 11
“NPRL3, NPRL2, and DEPDC5 form the GATOR1 complex, which controls the activity of the mTORC1 signaling pathway (Bar-Peled et al., 2013).”
BackgroundWang, Y.-C., Tsai, M.-C., Chen, Y., Hsieh, P.-M., Hung, C.-M., Lin, H.-Y., Hsu, Y.-C., Yeh, J., Hsiao, P.-J., Su, Y., et al. (2022) · Hepatology Communications · doi:10.1002/hep4.2019 · Cited by 11
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“Importantly, the GATOR1 complex is a regulator of the mTOR pathway [36], and its actions can be blocked by inhibiting mTOR complex 1 activity [37].”
BackgroundExperimental Approaches in Delineating mTOR Signaling
Qian, J., Su, S., & Liu, P. (2020) · Genes · doi:10.3390/genes11070738 · Cited by 17
“In brief, 30 million of HEK293T cells stably expressing individual GATOR2 components or Rags, including Flag-tagged p18, p14, HBXIP, c7orf59, and RagB, were used for Flag-immunoprecipitations under nonheated conditions and eluted by Flag peptides (Flag-METAP2 was used as a negative control) [59].”
BackgroundInfluentialNegative regulation of amino acid signaling by MAPK-regulated 4F2hc/Girdin complex
Weng, L., Han, Y., Enomoto, A., Kitaura, Y., Nagamori, S., Kanai, Y., Asai, N., An, J., Takagishi, M., Asai, M., et al. (2018) · PLoS Biology · doi:10.1371/journal.pbio.2005090 · Cited by 13
GATORs Take a Bite Out of mTOR
Shaw, R. J. (2013) · Science · doi:10.1126/science.1240315 · Cited by 15
mTOR pathway diseases: challenges and opportunities from bench to bedside and the mTOR node
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Cryo-EM reveals cholesterol binding in the lysosomal GPCR-like protein LYCHOS
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Longin domain GAP complexes in nutrient signalling, membrane traffic and neurodegeneration
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“GATOR1, plays an important role as a positive regulator of the mTORC1 pathway.([64]) Furthermore, mTORC1 is a master regulator of cell growth and is particularly sensitive to”
BackgroundEndosomal v-ATPase as a Sensor Determining Myocardial Substrate Preference
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The SZT2 Interactome Unravels New Functions of the KICSTOR Complex
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Sleep related hyper motor epilepsy (SHE): a unique syndrome with heterogeneous genetic etiologies
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DEPDC5 takes a second hit in familial focal epilepsy
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“As DEPDC5 is part of the GATOR1 complex, which negatively regulates mammalian target of rapamycin complex 1 (mTORC1) (6), the stage was set for a second-hit mechanism of cortical dysplasia, as has been found for cortical tubers that result from mutations of the tuberous sclerosis ( TSC ) gene.”
Charting Developmental Dissolution of Pluripotency
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PRAS40 alleviates neurotoxic prion peptide‐induced apoptosis via mTOR‐AKT signaling
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“When the level of amino acids becomes high, GATOR2 is thought to inhibit the GAP activity of GATOR1, thus activating mTORC1 signaling [12, 13].”
BackgroundTORC1 autonomously controls its spatial partitioning via the Rag GTPase tether Tco89
Nicastro, R., Gulli, M., Caligaris, M., Jaquenoud, M., Dokládal, L., Alba, J., Tripodi, F., Pillet, B., Brunner, M., Stumpe, M., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115683 · Cited by 10
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mTORC1 signaling and diabetic kidney disease
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“Other than SLC38A9, all other Leu-and Arg-binding proteins interact with and inhibit Gap Activity Toward Rags 2 (GATOR2), the protein complex that inhibits GATOR1, the GAP complex toward Rag A/B [35].”
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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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