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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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Citations
Cites
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Perl, A. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12756 · Cited by 218
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BackgroundKwiatkowski, D. J., Choueiri, T. K., Fay, A. P., Rini, B. I., Thorner, A. R., de Velasco, G., Tyburczy, M. E., Hamieh, L., Albiges, L. K., Agarwal, N., et al. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2631 · Cited by 232
“In addition, mutation or loss of DEPDC5, NPRL2, or NPRL3, which encode protein components of the GATOR1 complex, also lead to high-level activation of mTORC1 (9).”
BackgroundRegulation of YAP by mTOR and autophagy reveals a therapeutic target of tuberous sclerosis complex
Liang, N., Zhang, C., Dill, P., Panasyuk, G., Pion, D., Koka, V., Gallazzini, M., Olson, E. N., Lam, H., Henske, E. P., et al. (2014) · Journal of Experimental Medicine · doi:10.1084/jem.20140341 · Cited by 205
“Several protein complex, such as GATOR1 (DEPC5, Nprl2, Nprl3), GATOR2 (Mios, Seh1l, WDR24, WDR59, Sec13) and Folliculin complex (Folliculin and FNIP1) which have GAP or GEF activities toward Rag GTPase, are identified to be involved in the activation of mTORC1 by amino acids (Bar-Peled et al., 2013; Bar-Peled et al.,…”
Phosphoinositide conversion in endocytosis and the endolysosomal system
Wallroth, A., & Haucke, V. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.000629 · Cited by 195
SAR1B senses leucine levels to regulate mTORC1 signalling
Chen, J., Ou, Y., Luo, R., Wang, J., Wang, D., Guan, J., Li, Y., Xia, P., Chen, P. R., & Liu, Y. (2021) · Nature · doi:10.1038/s41586-021-03768-w · Cited by 226
mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions
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Architecture of the human GATOR1 and GATOR1–Rag GTPases complexes
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Self-citationSZT2 dictates GATOR control of mTORC1 signalling
Peng, M., Yin, N., & Li, M. O. (2017) · Nature · doi:10.1038/nature21378 · Cited by 192
Glutamine and asparagine activate mTORC1 independently of Rag GTPases
Meng, D., Yang, Q., Wang, H., Melick, C. H., Navlani, R., Frank, A. R., & Jewell, J. L. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ac119.011578 · Cited by 242
“Mios (GATOR2) KO HEK293A cells were generated by CRISPR/Cas9 genome editing (56).”
BackgroundStructural basis for the docking of mTORC1 on the lysosomal surface
Rogala, K. B., Gu, X., Kedir, J. F., Abu-Remaileh, M., Bianchi, L. F., Bottino, A. M. S., Dueholm, R., Niehaus, A., Overwijn, D., Fils, A.-C. P., et al. (2019) · Science · doi:10.1126/science.aay0166 · Cited by 214
Self-citationPerl, A., Hanczko, R., Lai, Z.-W., Oaks, Z., Kelly, R., Borsuk, R., Asara, J. M., & Phillips, P. E. (2015) · Metabolomics · doi:10.1007/s11306-015-0772-0 · Cited by 189
“9). mTOR complex 1 (mTORC1), which was measured here via phosphorylation of its downstream substrate, pS6RP, is stimulated by oxidative stress (Sarbassov and Sabatini 2005) and the lysosomal accumulation of amino acids (Bar-Peled et al. 2013).”
BackgroundTRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2 signalling
Wang, B., Jie, Z., Joo, D., Ordureau, A., Liu, P., Gan, W., Guo, J., Zhang, J., North, B. J., Dai, X., et al. (2017) · Nature · doi:10.1038/nature22344 · Cited by 199
A Cellular Mechanism to Detect and Alleviate Reductive Stress
Manford, A. G., Rodríguez-Pérez, F., Shih, K. Y., Shi, Z., Berdan, C. A., Choe, M., Titov, D. V., Nomura, D. K., & Rapé, M. (2020) · Cell · doi:10.1016/j.cell.2020.08.034 · Cited by 205
“The GATOR1 complex was a generous gift from Roberto Zoncu (Lawrence et al., 2019).”
BackgroundInfluentialThe mTORC1 Signaling Network Senses Changes in Cellular Purine Nucleotide Levels
Hoxhaj, G., Hallett, J. E. H., Timson, R. C., Ilagan, E., Yuan, M., Asara, J. M., Ben‐Sahra, I., & Manning, B. D. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.10.029 · Cited by 203
“siRNAmediated knockdown or CRISPR–Cas9 knockout of the GATOR1 component DEPDC5, a critical negative regulator of the amino acid-sensing Rag pathway (Bar-Peled et al., 2013), did not substantially influence mTORC1 inhibition in response to MTX treatment (Figure 5A, S5B, and S5C), but did render cells partially resistan…”
BackgroundInhibition of the Mechanistic Target of Rapamycin (mTOR)–Rapamycin and BeyondPreprint
Lamming, D. W. (2016) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a025924 · Cited by 205
“The regulation of the Rag/ragulator complex has been a subject of intensive investigation, resulting in the identification of the additional upstream regulators of mTORC1 signaling, including the GATOR1/2 complex and Sestrin1–Sestrin3 (Bar-Peled et al. 2013; Chantranupong et al. 2014).”
BackgroundSomatic Mutations in the MTOR gene cause focal cortical dysplasia type II b
Nakashima, M., Saitsu, H., Takei, N., Tohyama, J., Kato, M., Kitaura, H., Shiina, M., Shirozu, H., Masuda, H., Watanabe, K., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24444 · Cited by 198
“Gator1 has GTPaseactivating activity for RagA/B and thus suppresses mTORC1 activity in static and low-amino-acid conditions.(39) Therefore, loss of function in PTEN and Gator1 may cause mTOR activation.”
BackgroundLocalization of mTORC2 activity inside cells
Ebner, M., Sinkovics, B., Szczygieł, M., Ribeiro, D. W., & Yudushkin, I. A. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201610060 · Cited by 214
“Indeed, activation of mTORC1 by amino acids is dependent on its association with the lysosomal membranes (Sancak et al., 2008, 2010; Bar-Peled et al., 2013).”
Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia
Weckhuysen, S., Marsan, E., Lambrecq, V., Marchal, C., Morin‐Brureau, M., An-Gourfinkel, I., Baulac, M., Fohlen, M., Zetchi, C. K., Seeck, M., et al. (2016) · Epilepsia · doi:10.1111/epi.13391 · Cited by 181
“In vitro and in yeast, DEPDC5 acts as an inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1).(11,12) mTORC1 has a serine-threonine kinase activity that phosphorylates several downstream proteins regulating essential cellular functions like protein synthesis, cell growth, migration, and proliferation.”
BackgroundTOR Complexes and the Maintenance of Cellular Homeostasis
Eltschinger, S., & Loewith, R. (2015) · Trends in Cell Biology · doi:10.1016/j.tcb.2015.10.003 · Cited by 193
“SEACIT and GATOR1 are themselves regulated by SEACAT and GATOR2, respectively [21,93].”
BackgroundRecurrent mTORC1-activating RRAGC mutations in follicular lymphoma
Okosun, J., Wolfson, R. L., Wang, J., Araf, S., Wilkins, L., Castellano, B. M., Escudero‐Ibarz, L., Seraihi, A. A., Richter, J., Bernhart, S. H., et al. (2015) · Nature Genetics · doi:10.1038/ng.3473 · Cited by 220
Self-citationControl of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity
Carroll, B., Maetzel, D., Maddocks, O. D., Otten, G., Ratcliff, M., Smith, G. R., Dunlop, E. A., Passos, J. F., Davies, O. R., Jaenisch, R., et al. (2016) · eLife · doi:10.7554/elife.11058 · Cited by 183
“…factor (GEF) to activate the Rag GTPases and works in opposition to the GTPase-activating protein (GAP) complex, GATOR1 ( Bar-Peled et al., 2012 ; Bar-Peled et al., 2013 ; Panchaud et al., 2013 ) to ensure the tight control of Rag GTPases and therefore mTORC1 activity. mTORC1 localization to the…”
Sestrin2 inhibits mTORC1 through modulation of GATOR complexes
Kim, J. S., Ro, S., Kim, M.-J., Park, H., Semple, I. A., Park, H., Cho, U., Wang, W., Guan, K., Karin, M., et al. (2015) · Scientific Reports · doi:10.1038/srep09502 · Cited by 180
mTOR signaling in stem and progenitor cells
Meng, D., Frank, A. R., & Jewell, J. L. (2018) · Development · doi:10.1242/dev.152595 · Cited by 201
“Studies in yeast have also demonstrated that glutamine, the preferred nitrogen source for yeast, can sustain TORC1 activity independent of Gtr1, the yeast homolog of mammalian RagA/B (Stracka et al., 2014).”
BackgroundInfluentialParallel shRNA and CRISPR-Cas9 screens enable antiviral drug target identification
Deans, R. M., Morgens, D. W., Ökesli, A., Pillay, S., Horlbeck, M. A., Kampmann, M., Gilbert, L. A., Li, A., Mateo, R., Smith, M. A., et al. (2016) · Nature Chemical Biology · doi:10.1038/nchembio.2050 · Cited by 182
Regulation of autophagy by amino acids and MTOR-dependent signal transduction
Meijer, A. J., Lorin, S., Blommaart, E. F. C., & Codogno, P. (2014) · Amino Acids · doi:10.1007/s00726-014-1765-4 · Cited by 203
“As follic- ulin, GATOR-1 acts as a GTPase-activating protein but in this case toward RagA and RagB, not RagC and D, and thereby suppresses MTORC1 activity (Bar-Peled et al. 2013).”
BackgroundCovalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition
Chung, C. Y., Shin, H. R., Berdan, C. A., Ford, B., Ward, C. C., Olzmann, J. A., Zoncu, R., & Nomura, D. K. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0308-4 · Cited by 182
The lysosome: a crucial hub for AMPK and mTORC1 signalling
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Ong, P. S., Wang, L. Z., Dai, X., Tseng, S. H., Loo, S. J., & Sethi, G. (2016) · Frontiers in Pharmacology · doi:10.3389/fphar.2016.00395 · Cited by 162
“In a similar manner, loss of function mutations in GATOR1, a negative regulator of Rag GTPases which activate mTORC1 following amino acid stimulation, renders a hyperactive mTORC1 in tumor cells (Bar-Peled et al., 2013).”
BackgroundSex‐ and tissue‐specific changes in mTOR signaling with age in C57 BL /6J mice
Baar, E. L., Carbajal, K. A., Ong, I. M., & Lamming, D. W. (2016) · Aging Cell · doi:10.1111/acel.12425 · Cited by 177
Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex
Lawrence, R. E., Fromm, S. A., Fu, Y., Yokom, A. L., Kim, D. J., Thelen, A. M., Young, L. N., Lim, C.-Y., Samelson, A. J., Hurley, J. H., et al. (2019) · Science · doi:10.1126/science.aax0364 · Cited by 192
Getting ready for building: signaling and autophagosome biogenesis
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“GATOR-1 is a GAP for RagA/RagB, mediating mTORC1 sensitivity to amino acids [25].”
Gremke, N., Polo, P., Dort, A., Schneikert, J., Elmshäuser, S., Brehm, C. U., Klingmüller, U., Schmitt, A., Reinhardt, H. C., Timofeev, O. N., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18504-7 · Cited by 192
Amino acid metabolism, transport and signalling in the liver revisited
Paulusma, C. C., Lamers, W. H., Bröer, S., & van de Graaf, S. F. J. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115074 · Cited by 185
Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy
Marsan, E., & Baulac, S. (2018) · Neuropathology and Applied Neurobiology · doi:10.1111/nan.12463 · Cited by 162
mTORC1 and Nutrient Homeostasis: The Central Role of the Lysosome
Rabanal‐Ruiz, Y., & Korolchuk, V. I. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19030818 · Cited by 178
“The formation of heterodimeric complexes RagA/B-RagC/D is important for their stability and allows the normal activation of mTORC1 [55–57].”
BackgroundInfluentialGuan, B., Krokowski, D., Majumder, M., Schmotzer, C. L., Kimball, S. R., Merrick, W. C., Koromilas, A. E., & Hatzoglou, M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.543215 · Cited by 161
“Interestingly, increased system L activity can lead to increased intracellular levels of Leu, which along with other factors becomes a nutrient sensing mechanism that activates mTORC1 on lysosomal membranes (31, 32).”
BackgroundBalestrini, S., & Sisodiya, S. M. (2017) · Neuroscience Letters · doi:10.1016/j.neulet.2017.01.014 · Cited by 158
mTOR signaling in tumorigenesis
Xu, K. L., Liu, P., & Wei, W. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.10.007 · Cited by 167
Péli-Gulli, M.-P., Sardu, A., Panchaud, N., Raucci, S., & De Virgilio, C. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.08.059 · Cited by 157
Principles and functions of metabolic compartmentalization
Bar‐Peled, L., & Kory, N. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00645-2 · Cited by 194
Self-citationLysosome: The metabolic signaling hub
Lamming, D. W., & Bar‐Peled, L. (2019) · Traffic · doi:10.1111/tra.12617 · Cited by 173
“The nucleotide loading state of RagA and RagB are also controlled by the GATOR complexes.(61,62) GATOR1, which consists of the pro-”
BackgroundSelf-citationThe expanding role of mTOR in cancer cell growth and proliferation
Cargnello, M., Tcherkezian, J., & Roux, P. P. (2015) · Mutagenesis · doi:10.1093/mutage/geu045 · Cited by 172
“Amongst these, two complexes known as Ragulator and GATOR1 (GAP activity toward Rags) control the Rag GTPases by acting as guanine nucleotide exchange factor (GEF) and as GAP towards RagA/B, respectively (37,38).”
BackgroundJanus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains
Kim, H., An, S., Ro, S., Teixeira, F., Park, G. J., Kim, C., Cho, C., Kim, J.-S., Jakob, U., Lee, J. H., et al. (2015) · Nature Communications · doi:10.1038/ncomms10025 · Cited by 160
Adapt and conquer: Metabolic flexibility in cancer growth, invasion and evasion
Kreuzaler, P. A., Panina, Y., Segal, J., & Yuneva, M. O. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.08.021 · Cited by 170
Li, S., Song, Y., Quach, C., Guo, H., Jang, G.-B., Maazi, H., Zhao, S., Sands, N. A., Liu, Q., In, G. K., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09634-8 · Cited by 173
The Skp2 Pathway: A Critical Target for Cancer Therapy
Cai, Z., Moten, A., Peng, D., Hsu, C.-C., Pan, B., Manne, R., Li, H., & Lin, H. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2020.01.013 · Cited by 186
The role of lysosomes in cancer development and progression
Tang, T., Yang, Z., Wang, D., Yang, X., Wang, J., Li, L., Wen, Q., Gao, L., Bian, X., & Yu, S. (2020) · Cell & Bioscience · doi:10.1186/s13578-020-00489-x · Cited by 173
TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging
Blackwell, T. K., Sewell, A. K., Wu, Z., & Han, M. (2019) · Genetics · doi:10.1534/genetics.119.302504 · Cited by 148
The Lysosome Signaling Platform: Adapting With the Times
Inpanathan, S., & Botelho, R. J. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00113 · Cited by 160
“In the presence of amino acids, the GATOR2 complex seems to associate and impair GATOR1, eliciting GTP-loading on RagA/B and activating mTORC1 (Bar-Peled et al., 2013).”
BackgroundIntersection of mTOR and STAT signaling in immunity
Saleiro, D., & Platanias, L. C. (2015) · Trends in Immunology · doi:10.1016/j.it.2014.10.006 · Cited by 142
“Recently, it was reported that GAP activity toward Rags (GATOR) complex controls Rag A and B [68], whereas folliculin and folliculin interacting protein Saleiro and Platanias Page 2”
BackgroundDEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy
Picard, F., Makrythanasis, P., Navarro, V., Ishida, S., de Bellescize, J., Ville, D., Weckhuysen, S., Fosselle, E., Suls, A., de Jonghe, P., et al. (2014) · Neurology · doi:10.1212/wnl.0000000000000488 · Cited by 142
“It was recently shown thatDEPDC5 has a GAP (GTPase-activating protein) activity(10) and is part of a complex that negatively regulates mTORC1.(11) Here we have evaluated the importance of DEPDC5 in ADNFLE by assessing the mutation prevalence in 30 families.”
BackgroundmTOR Cross-Talk in Cancer and Potential for Combination Therapy
Conciatori, F., Ciuffreda, L., Bazzichetto, C., Falcone, I., Pilotto, S., Bria, E., Cognetti, F., & Milella, M. (2018) · Cancers · doi:10.3390/cancers10010023 · Cited by 145
“GATOR1 negatively regulates mTORC1, whereas GATOR2 acts as a positive regulator [68].”
BackgroundGermline and somatic mutations in the MTOR gene in focal cortical dysplasia and epilepsy
Møller, R. S., Weckhuysen, S., Chipaux, M., Marsan, E., Taly, V., Bebin, E. M., Hiatt, S. M., Prokop, J. W., Bowling, K. M., Mei, D., et al. (2016) · Neurology Genetics · doi:10.1212/nxg.0000000000000118 · Cited by 152
“protein activity toward Rags complex 1 (GATOR1), an amino acid–sensitive inhibitor of mTORC1.(2) Germline mutations in the GATOR1-encoding genes (DEPDC5, NPRL2, and NPRL3) have been reported in numerous familial and sporadic focal epilepsies.”
BackgroundReprogramming tumour-associated macrophages to outcompete cancer cells
Zhang, X., Li, S., Malik, I., Do, M. H., Ji, L., Chou, C., Shi, W., Capistrano, K. J., Zhang, J., Hsu, T.-W., et al. (2023) · Nature · doi:10.1038/s41586-023-06256-5 · Cited by 154
The Opposing Actions of Target of Rapamycin and AMP-Activated Protein Kinase in Cell Growth ControlPreprint
Hindupur, S. K., González, A., & Hall, M. N. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a019141 · Cited by 147
“GATOR is composed of two subcomplexes: GATOR1 and GATOR2.”
BackgroundInfluentialRagulator and SLC38A9 activate the Rag GTPases through noncanonical GEF mechanisms
Shen, K., & Sabatini, D. M. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1811727115 · Cited by 165
Self-citationFamilial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3
Sim, J. C. H., Scerri, T., Fanjul-Fernández, M., Riseley, J. R., Gillies, G., Pope, K., van Roozendaal, H., Heng, J., Mandelstam, S., McGillivray, G., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24502 · Cited by 135
“DEPDC5, NPRL3, and NPRL2 are subunits of the GAP Activity Towards Rags 1 (GATOR1) complex, a negative regulator of mTOR activity.(6) Germline mutations in DEPDC5 and somatic mutations in MTOR account for 15% to 40% of FCDIIa and IIb,(3,7,8) suggesting that other causes of FCD remain to be discovered.”
BackgroundRice, G., Park, S., Gavazzi, F., Adang, L., Ayuk, L. A., Eyck, L. V., Seabra, L., Barrea, C., Battini, R., Bélot, A., et al. (2020) · Human Mutation · doi:10.1002/(issn)1098-1004 · Cited by 134
“NPRL3 isoform 1 dimerizes with its partner NPRL2 and, together with DEPCDC5, they form a protein complex called GATOR1 in mammals, which in turns is involved in many cellular processes such as stimulation of protein synthesis, growth, metabolism, and the inhibition of autophagy (Bar‐Peled et al., 2013).”
Advances in Autophagy Regulatory Mechanisms
Gallagher, L. E., Williamson, L. E., & Chan, E. Y. W. (2016) · Cells · doi:10.3390/cells5020024 · Cited by 140
Dynamic Visualization of mTORC1 Activity in Living Cells
Zhou, X., Clister, T., Lowry, P. R., Seldin, M. M., Wong, G. W., & Zhang, J. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.02.031 · Cited by 150
“When amino acids are absent, the Rag GAP complex (GATOR1) inactivates the Rag GTPases and leads to the dissociation of mTORC1 from the lysosomal surface (Bar-Peled et al., 2013).”
BackgroundRegulation of Body Size and Growth Control
Texada, M. J., Koyama, T., & Rewitz, K. (2020) · Genetics · doi:10.1534/genetics.120.303095 · Cited by 177
Sensing and Signaling of Methionine Metabolism
Lauinger, L., & Kaiser, P. (2021) · Metabolites · doi:10.3390/metabo11020083 · Cited by 142
“A negative regulator in this pathway is the GTPase activation protein complex GATOR1 (SEACIT in yeast) [39].”
BackgroundA recollection of mTOR signaling in learning and memoryPreprint
Graber, T. E., McCamphill, P. K., & Sossin, W. S. (2013) · Learning & Memory · doi:10.1101/lm.027664.112 · Cited by 143
“In contrast, the novel trimeric GATOR1 complex acts as a GAP for the Rag proteins and thus down-regulates mTORC1 activation during amino acid deprivation (Bar-Peled et al. 2013).”
BackgroundSadria, M., & Layton, A. T. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00706-1 · Cited by 150
“In some lung, breast, ovarian cancers and in glioblas-tomas [59], mTORC1 is hyperactived and these cancer cells have been shown to be hypersensitive to rapamycin.”
BackgroundThe potential role of necroptosis in inflammaging and aging
Royce, G. H., Brown‐Borg, H. M., & Deepa, S. S. (2019) · GeroScience · doi:10.1007/s11357-019-00131-w · Cited by 137
Lysosomal GPCR-like protein LYCHOS signals cholesterol sufficiency to mTORC1
Shin, H. R., Citron, Y. R., Wang, L., Tribouillard, L., Goul, C. S., Stipp, R., Sugasawa, Y., Jain, A., Samson, N., Lim, C.-Y., et al. (2022) · Science · doi:10.1126/science.abg6621 · Cited by 149
Non-canonical mTORC1 signaling at the lysosome
Napolitano, G., Malta, C. D., & Ballabio, A. (2022) · Trends in Cell Biology · doi:10.1016/j.tcb.2022.04.012 · Cited by 139
Toward rapamycin analog (rapalog)-based precision cancer therapy
Meng, L.-H., & Zheng, X. F. S. (2015) · Acta Pharmacologica Sinica · doi:10.1038/aps.2015.68 · Cited by 125
Architecture of human Rag GTPase heterodimers and their complex with mTORC1
Anandapadamanaban, M., Masson, G. R., Perisic, O., Berndt, A., Kaufman, J., Johnson, C. M., Santhanam, B., Rogala, K. B., Sabatini, D. M., & Williams, R. L. (2019) · Science · doi:10.1126/science.aax3939 · Cited by 147
Self-citationmTOR: A Cellular Regulator Interface in Health and Disease
Boutouja, F., Stiehm, C. M., & Platta, H. W. (2019) · Cells · doi:10.3390/cells8010018 · Cited by 139
“Cytosolic amino acids, as demonstrated for arginine and leucine, are sensed by TORC1 through the dynamic interplay of the GATOR1 and GATOR2 complexes [75].”
BackgroundDysregulation of skeletal muscle protein metabolism by alcohol
Steiner, J. L., & Lang, C. H. (2015) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00006.2015 · Cited by 144
“Stimulation of mTORC1 signaling by feeding is dependent not only on hormonal activation of the canonical Akt pathway (26) but also amino acid-specific stimulation of a separate pathway composed of the Rag GTPases v-ATPase, Ragulator, GATOR1, and GATOR2 protein complexes (4).”
BackgroundAmino Acid Sensing in Metabolic Homeostasis and Health
Hu, X., & Guo, F. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa026 · Cited by 143
TOR‐mediated regulation of metabolism in aging
Antikainen, H., Driscoll, M., Haspel, G., & Dobrowolski, R. (2017) · Aging Cell · doi:10.1111/acel.12689 · Cited by 122
“GATOR1 to render mTORC1 unresponsive to amino acids (Bar-Peled et al., 2013).”
BackgroundBond, P. (2016) · Journal of the International Society of Sports Nutrition · doi:10.1186/s12970-016-0118-y · Cited by 121
Lysosomal signaling in control of degradation pathways.
Huber, L., & Teis, D. (2016) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2016.01.006 · Cited by 121
Evolutionary Conservation of the Components in the TOR Signaling Pathways
Tatebe, H., & Shiozaki, K. (2017) · Biomolecules · doi:10.3390/biom7040077 · Cited by 130
“DEPDC5: DEP domain containing 5; NPRL2: nitrogen permease regulator 2-like protein; NPRL3: nitrogen permease regulator 3-like protein; RAPTOR: regulatory associated protein of mTOR; RHEB: Ras homolog enriched in brain; RICTOR: rapamycin-insensitive companion of mTOR; SIN1: stress-activated protein kinase interacting p…”
BackgroundAmino Acid Activation of mTORC1 by a PB1-Domain-Driven Kinase Complex Cascade
Linares, J. F., Durán, Á., Reina‐Campos, M., Aza‐Blanc, P., Campos, A. R., Moscat, J., & Díaz-Meco, M. T. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.07.045 · Cited by 123
“Additionally, the Rags have been shown to be regulated by other proteins including the GATOR1 complex (Bar-Peled et al., 2013), FLCN (Petit et al., 2013; Tsun et al., 2013), and sestrins (Budanov and Karin, 2008; Chantranupong et al., 2014).”
BackgroundDEPDC5 mutations in genetic focal epilepsies of childhood
Lal, D., Reinthaler, E. M., Schubert, J., Muhle, H., Riesch, E., Kluger, G. J., Jabbari, K., Kawalia, A., Bäumel, C., Holthausen, H., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24127 · Cited by 122
“DEPDC5 is a member of the GATOR1 complex that interacts with the mammalian target of rapamycin (mTOR) complex1, which is potentially accessible by mTOR inhibitors.(4) Rolandic epilepsy (RE), or benign epilepsy with centrotemporal spikes (BECTS), is a common focal epilepsy syndrome of childhood.”
BackgroundHow Lysosomes Sense, Integrate, and Cope with Stress
Säftig, P., & Puertollano, R. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.09.004 · Cited by 139
Zhang, W., Du, G., Zhou, J., & Chen, J. (2018) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00040-17 · Cited by 150
“Both SEACIT and SEACAT have corresponding mammalian homologs, which are termed GATOR1 and GATOR2, respectively (89).”
BackgroundInfluentialUsing Molecular Biology to Maximize Concurrent Training
Baar, K. (2014) · Sports Medicine · doi:10.1007/s40279-014-0252-0 · Cited by 135
“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].”
BackgroundKLHL22 activates amino-acid-dependent mTORC1 signalling to promote tumorigenesis and ageing
Chen, J., Ou, Y., Yang, Y., Li, W., Xu, Y., Xie, Y., & Liu, Y. (2018) · Nature · doi:10.1038/s41586-018-0128-9 · Cited by 131
Emerging Role of mTOR in the Response to Cancer Therapeutics
Ilagan, E., & Manning, B. D. (2016) · Trends in cancer · doi:10.1016/j.trecan.2016.03.008 · Cited by 118
“While mutations leading to increased signaling of the Rag GTPases to mTORC1, or activating mutations on mTOR itself, have been identified [26, 27, 75, 76], the vast majority of oncogenes and tumor suppressors influencing the activation state of mTORC1 signal through the TSC complex (Figure 2).”
BackgroundCrino, P. (2014) · Seminars in neurology · doi:10.1017/9781108355209.068 · Cited by 117
Macropinocytosis, mTORC1 and cellular growth control
Yoshida, S., Pacitto, R., Inoki, K., & Swanson, J. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2710-y · Cited by 114
“Thus, GATOR2 activates the Rag heterodimer by inactivating GATOR1.”
BackgroundInfluentialA lysosome-centered view of nutrient homeostasis
Mony, V. K., Benjamin-Davalos, S., & O’Rourke, E. J. (2016) · Autophagy · doi:10.1080/15548627.2016.1147671 · Cited by 122
“17 In addition, the GATOR complex ( G TPase a ctivating protein to ward R ag GTPases), a multiprotein complex consisting of 2 subcomplexes, GATOR1 (DEPDC5-NPRL2-NPRL3) and GATOR2 (MIOS-SEH1L-WDR24-WDR59-SEC13), regulates the RAG GTPases.”
BackgroundInfluentialThe Ubiquitination of RagA GTPase by RNF152 Negatively Regulates mTORC1 Activation
Deng, L., Jiang, C., Chen, L., Jin, J., Wei, J., Zhao, L., Chen, M., Pan, W., Yan, X., Chu, H., et al. (2015) · Molecular Cell · doi:10.1016/j.molcel.2015.03.033 · Cited by 126
“GATOR1 is a complex that consists of DEPC5, Nprl3, and Nprl2 that acts as a GAP protein for Rag proteins (Bar-Peled et al., 2013).”
BackgroundInfluentialCondon, K. J., Orozco, J. M., Adelmann, C. H., Spinelli, J., van der Helm, P. W., Roberts, J. M., Kunchok, T., & Sabatini, D. (2020) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1101/2020.10.22.351361 · Cited by 112
“The first consists of components of GATOR2, a known positive regulator of the pathway that likely acts upstream of GATOR1 to inhibit its function (25).”
BackgroundSelf-citationSEACing the GAP that nEGOCiates TORC1 activation
Panchaud, N., Gulli, M., & VIRGILIO, C. D. (2013) · Cell Cycle · doi:10.4161/cc.26000 · Cited by 115
“, DEPDC5-Nprl2Nprl3), coined GATOR1, also acts as a GAP toward RagA and RagB.(25) Intriguingly, various glioblastomas and ovarian cancers contain nonsense or frameshift mutations or truncating deletions in GATOR1-encoding genes, and a number of cancer cell lines with homozygous deletions in DEPDC5, NPRL2, or NPRL3 exh…”
BackgroundInfluentialThe Multifaceted Role of Nutrient Sensing and mTORC1 Signaling in Physiology and Aging
Fernandes, S., & Demetriades, C. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.707372 · Cited by 131
Cryo-EM Structure of the Human FLCN-FNIP2-Rag-Ragulator Complex
Shen, K., Rogala, K. B., Chou, H., Huang, R. K., Yu, Z., & Sabatini, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.10.036 · Cited by 135
“To determine the specificity of our assay, we carried out similar assays using RagA(Q66L) or RagC(Q120L) mutants, which have been shown to suppress the stimulatory effect of GATOR1 or FLCN-FNIP2, respectively (Bar-Peled et al., 2013; Tsun et al., 2013).”
BackgroundMethodSelf-citationLysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3
Villegas, F., Lehalle, D., Mayer, D., Rittirsch, M., Stadler, M. B., Zinner, M., Olivieri, D., Vabres, P., Duplomb-Jego, L., De Bont, E. S. J. M., et al. (2019) · Cell Stem Cell · doi:10.1016/j.stem.2018.11.021 · Cited by 110
Systemic tryptophan homeostasis
Klaessens, S., Stroobant, V., Plaen, E. D., & den Eynde, B. J. V. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.897929 · Cited by 127
“fully described but regulate the nucleotide-bound state of Rags (Figure 3) (Bar-Peled et al., 2013).”
BackgroundBiochemical Basis of Sestrin Physiological Activities
Ho, A., Cho, C., Namkoong, S., Cho, U., & Lee, J. H. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.04.005 · Cited by 115
“GATOR2 is known to suppress GATOR1, a heterotrimeric complex that functions as a GAP for RagA/B [60].”
The Molecular Basis for Load-Induced Skeletal Muscle Hypertrophy
Marcotte, G. R., West, D. W. D., & Baar, K. (2014) · Calcified Tissue International · doi:10.1007/s00223-014-9925-9 · Cited by 123
“In the absence of amino acids, RagA/B is held in the inactive GDP bound state by the heterotrimeric GAP protein complex GATOR1 [108].”
BackgroundInfluential
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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