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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.
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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“DEPDC5 (Disheveled, Eg10 and Pleckstrin Domain containing proteins) is a gene that encodes a protein structurally-related to Gap Activity Toward Rags 1 (GATOR1), which is an important negative modulator of mammalian target of Rapamycin (mTOR) Complex 1 (mTORC1) that regulates various cell functions (Bar-Peled et al.,…”
BackgroundFLCN Maintains the Leucine Level in Lysosome to Stimulate mTORC1
Wu, X., Zhao, L., Chen, Z. J., Ji, X., Qiao, X., Jin, Y., & Liu, W. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157100 · Cited by 26
Sekiguchi, T., Kamada, Y., Furuno, N., Funakoshi, M., & Kobayashi, H. (2014) · Genes to Cells · doi:10.1111/gtc.12145 · Cited by 23
Targeting the PI3K/Akt/mTOR Pathway in Malignancy: Rationale and Clinical Outlook
Cho, D. (2014) · BioDrugs · doi:10.1007/s40259-014-0090-5 · Cited by 23
mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes
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Pathogenesis of diabesity‐induced kidney disease: role of kidney nutrient sensing
Hinden, L., Kogot‐Levin, A., Tam, J., & Leibowitz, G. (2021) · FEBS Journal · doi:10.1111/febs.15790 · Cited by 27
Luo, S.-J., Shao, L., Chen, Z., Hu, D., Jiang, L., & Tang, W. (2020) · Experimental Cell Research · doi:10.1016/j.yexcr.2020.111981 · Cited by 22
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“Upon starvation, activation of GTPase activity of RagA/B [9] facilitates Rag A degradation [10], whereby the mTOR-Ragulator complex dissociates and relieves the tonic phosphorylation of TFEB family members.”
BackgroundDENN domain-containing protein FAM45A regulates the homeostasis of late/multivesicular endosomes
Zhang, J., Zhang, K., Qi, L., Hu, Q., Shen, Z., Liu, B., Deng, J., Zhang, C., & Zhang, Y. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.02.006 · Cited by 29
Tumor suppressor NPRL2 induces ROS production and DNA damage response
Ma, Y., Silveri, L., LaCava, J., & Dokudovskaya, S. (2017) · Scientific Reports · doi:10.1038/s41598-017-15497-0 · Cited by 35
Liu, M., Clarke, C., Salama, M. F., Choi, Y.-O.-J., Obeid, L., & Hannun, Y. (2017) · PLoS ONE · doi:10.1371/journal.pone.0184818 · Cited by 22
GATOR1 regulates nitrogenic cataplerotic reactions of the mitochondrial TCA cycle
Chen, J., Sutter, B. M., Shi, L., & Tu, B. P. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2478 · Cited by 31
Feng, Z.-Y., Cao, K., Sun, H., & Liu, X.-W. (2024) · Apoptosis · doi:10.1007/s10495-024-02009-5 · Cited by 21
“SEH1 like nucleoporin (SEH1L), part of a nuclear pore complex (NPC), plays important roles in mTORC1 regula - tion as an inhibitor of the Rag GTPases [ 23 ].”
BackgroundMangione, M. C., Wen, J., & Cao, D. J. (2023) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2023.10.011 · Cited by 20
Piwarski, S. A., & Salisbury, T. B. (2023) · Biochemical Pharmacology · doi:10.1016/j.bcp.2023.115771 · Cited by 25
Yuskaitis, C. J., Modasia, J. B., Schrötter, S., Rossitto, L.-A. M., Groff, K. J., Morici, C., Mithal, D. S., Chakrabarty, R. P., Chandel, N. S., Manning, B. D., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111278 · Cited by 29
mTOR Signaling in the Inner Ear as Potential Target to Treat Hearing Loss
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“GATOR2 complex Negatively regulates GATOR1 to activate mTORC1 [36]”
BackgroundInfluentialParallel and population-specific gene regulatory evolution in cold-adapted fly populations
Huang, Y., Lack, J., Hoppel, G. T., & Pool, J. (2021) · Genetics · doi:10.1093/genetics/iyab077 · Cited by 21
GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels
Kanno, A., Asahara, S.-I., Furubayashi, A., Masuda, K., Yoshitomi, R., Suzuki, E., Takai, T., Kimura-Koyanagi, M., Matsuda, T., Bartolomé, A., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.128820 · Cited by 24
Sestrins are Gatekeepers in the Way from Stress to Aging and Disease
Dalina, A. A., Kovaleva, I. E., & Budanov, A. V. (2018) · Molecular Biology · doi:10.1134/s0026893318060043 · Cited by 20
Aminoacylation of Proteins: New Targets for the Old ARSenal.
Jafarnejad, S. M., Kim, S.-H., & Sonenberg, N. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.12.012 · Cited by 21
Eichner, R., Fernández‐Sáiz, V., Targosz, B., & Bassermann, F. C. (2018) · International review of cytology · doi:10.1016/bs.ircmb.2018.06.001 · Cited by 27
The Role of mTORC1 Pathway and Autophagy in Resistance to Platinum-Based Chemotherapeutics
Pan, Z., Zhang, H. T., & Dokudovskaya, S. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241310651 · Cited by 26
“Notably, a low expression of NPRL2, one of the GATOR1 components, in different types of lung cancers is correlated with cisplatin resistance [74,75].”
BackgroundInfluentialSestrin2 and mitochondrial quality control: Potential impact in myogenic differentiation
Piochi, L. F., Machado, I. F., Palmeira, C. M., & Rolo, A. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101309 · Cited by 21
Sin1-mediated mTOR signaling in cell growth, metabolism and immune response
Ruan, C., Ouyang, X., Liu, H., Li, S., Jin, J., Tang, W., Xia, Y., & Su, B. (2019) · National Science Review · doi:10.1093/nsr/nwz171 · Cited by 26
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Multilayered regulation of TORC1-body formation in budding yeast
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Chen, Y., Xu, W., Jin, H., Zhang, M., Liu, S., Liu, Y., & Zhang, H. (2024) · ACS Nano · doi:10.1021/acsnano.4c08083 · Cited by 19
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“A major regulatory complex is GATOR1, composed of Nprl2, Nprl3 and DEPDC5 (8).”
Advances in the regulatory mechanisms of mTOR in necroptosis
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“Loss-of-function variants of the GATOR1 subunits DEPDC5, NPRL2, and NPRL3 in FCDIIa result in constitutive activation of mTORC1 [3, 4, 58] and are likely similar to that mediated by activating MTOR variants.”
BackgroundmTOR Signaling Pathway in Bone Diseases Associated with Hyperglycemia
Wang, S., Wang, J., Wang, S., Tao, R., Yi, J., Chen, M., & Zhao, Z. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24119198 · Cited by 21
Sestrin2 Signaling Pathway Regulates Podocyte Biology and Protects against Diabetic Nephropathy
Ala, M. (2023) · Journal of Diabetes Research · doi:10.1155/2023/8776878 · Cited by 22
“Similarly, GATOR2/GATOR1/RagB regulates mTORC1 based on amino acid availability [19].”
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“To be specific, the lysosomal positioning is necessary for mTORC1 activation, which is mainly mediated bymultiple factors, such as SESN2 (Chantranupong et al., 2014; Saxton et al., 2016; Wolfson et al., 2016), KICSTOR/SZT2 (Bar-Peled et al., 2013; Shen et al., 2018; Wolfson et al., 2017), GATOR2-GATOR1 (comprising NPR…”
Schrötter, S., Yuskaitis, C. J., MacArthur, M. R., Mitchell, S. J., Hosios, A. M., Osipovich, M., Torrence, M. E., Mitchell, J. R., Hoxhaj, G., Şahin, M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110824 · Cited by 19
Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy
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“NPRL3, encoding the nitrogen permease regulator–like 3 protein, forms a complex with NPRL2 and DEPDC5 to form the GATOR1 complex, a key negative regulator of the mTOR pathway.(38)”
BackgroundSeh1 targets GATOR2 and Nup153 to mitotic chromosomes
Platani, M., Samejima, I., Samejima, K., Kanemaki, M. T., & Earnshaw, W. (2018) · Journal of Cell Science · doi:10.1242/jcs.213140 · Cited by 19
Epilepsy: Old Syndromes, New Genes
Weckhuysen, S., & Korff, C. M. (2014) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-014-0447-7 · Cited by 21
Secretome translation shaped by lysosomes and lunapark-marked ER junctions
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“…whether secretome mRNAs exhibit preferential translation in spatially restricted ER subdomains—potentially governed by compartmentalized translation-related factors 10–12 —or whether they are translated non-selectively across the continuous ER network remains an unresolved and compelling question.”
A conserved N-terminal motif of CUL3 contributes to assembly and E3 ligase activity of CRL3KLHL22
Wang, W., Liang, L., Dai, Z., Zuo, P., Yu, S., Lu, Y., Ding, D., Chen, H., Shan, H., Jin, Y., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48045-2 · Cited by 17
“In contrast, the BTB-containing Kelch-like protein 22 (KLHL22) plays important roles in mitosis, T-cell activity and amino acid sensing 19 – 21 .”
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“mTORc1 activity is also modulated by the availability of amino acids (particularly leucine), which are sensed through the GATOR complexes and RAG GTPase (31, 32).”
BackgroundJeong, A., & Wong, M. (2017) · Journal of Child Neurology · doi:10.1177/0883073817696814 · Cited by 18
“DEPDC5 is an upstream negative regulator of mTORC1 that forms part of the GATOR1 complex, which is activated under conditions of amino acid deprivation and acts as a negative regulator of the mTORC1 pathway.(56) Many of the upstream and downstream components of the mTOR pathway have now been identified as having genet…”
BackgroundInsulin–InsR signaling drives multipotent progenitor differentiation toward lymphoid lineages
Xia, P., Wang, S., Du, Y., Huang, G., Satoh, T., Akira, S., & Fan, Z. (2015) · The Journal of Experimental Medicine · doi:10.1084/jem.20150618 · Cited by 20
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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