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Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids
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The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids, and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator-mediated translocation of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1.
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“None of the Rag proteins contain any lipid modification motifs that would result in their lysosomal localization, and therefore five proteins, MP1, p14, p18, HBXIP and C7orf59, which form a lysosomally-localized complex and which interact with the Rag GTPases, were found to be required to recruit them to their cognate compartment (Bar-Peled et al., 2012;Sancak et al., 2010).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sancak et al., 2010
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“None of the Rag proteins contain any lipid modification motifs that would result in their lysosomal localization, and therefore five proteins, MP1, p14, p18, HBXIP and C7orf59, which form a lysosomally-localized complex and which interact with the Rag GTPases, were found to be required to recruit them to their cognate compartment (Bar-Peled et al., 2012;Sancak et al., 2010).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Sancak et al., 2010
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InfluentialGlutaminolysis Activates Rag-mTORC1 Signaling
Durán, R. V., Oppliger, W., Robitaille, A. M., Heiserich, L., Skendaj, R., Gottlieb, E., & Hall, M. N. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.05.043 · Cited by 766
“RagA or B interacts with RagC or D to form a heterodimer (Gong et al., 2011; Sekiguchi et al., 2001) that is anchored to the surface of the lysosome (Sancak et al., 2010).”
BackgroundAutophagy in the Cellular Energetic Balance
Singh, R., & Cuervo, A. M. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.04.004 · Cited by 788
“…still unclear, but the contribution of vps34, Ras-related small GTPases (that relocatemTOR to the lysosomal compartment), and a bidirectional transporter that exchanges L-glutamine by essential amino acids have all been involved in this signaling process (Nicklin et al., 2009; Sancak et al., 2010).”
Signal integration by mTORC1 coordinates nutrient input with biosynthetic output
Dibble, C. C., & Manning, B. D. (2013) · Nature Cell Biology · doi:10.1038/ncb2763 · Cited by 743
Autophagy regulation by nutrient signaling
Russell, R. C., Yuan, H., & Guan, K. (2013) · Cell Research · doi:10.1038/cr.2013.166 · Cited by 740
Nutritional Control of Growth and Development in Yeast
Broach, J. R. (2012) · Genetics · doi:10.1534/genetics.111.135731 · Cited by 718
“The Rag complex, activated by the presence of amino acids, promotes relocalization of TORC1 from discrete cytoplasmic sites to a late endosomal or lysosomal compartment at which Rheb resides (Sancak et al. 2010).”
BackgroundAbu-Remaileh, M., Wyant, G. A., Kim, C., Laqtom, N. N., Abbasi, M., Chan, S. H., Freinkman, E., & Sabatini, D. M. (2017) · Science · doi:10.1126/science.aan6298 · Cited by 680
“Lysosomes also participate in signal transduction (3), particularly in nutrient sensing by the mechanistic target of rapamycin complex 1 (mTORC1) pathway (4, 5), and are often deregulated in common diseases, such as cancer (6).”
BackgroundSelf-citationSLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
Rebsamen, M., Pochini, L., Stasyk, T., de Araújo, M. E. G., Galluccio, M., Kandasamy, R. K., Snijder, B., Fauster, A., Rudashevskaya, E. L., Bruckner, M., et al. (2015) · Nature · doi:10.1038/nature14107 · Cited by 673
Regulation of mTORC1 and its impact on gene expression at a glance
Laplante, M., & Sabatini, D. M. (2013) · Journal of Cell Science · doi:10.1242/jcs.125773 · Cited by 697
“At the surface of the lysosome, the v-ATPase directly interacts with the Ragulator, a pentameric protein complex that is essential for amino acid regulation of mTORC1 (Bar-Peled et al., 2012; Sancak et al., 2010).”
BackgroundSelf-citationThe Lysosome as a Regulatory Hub
Perera, R. M., & Zoncu, R. (2016) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-111315-125125 · Cited by 698
“The limiting outer membrane of the lysosome is composed of a single phospholipid bilayer of 7–10 nm that is decorated with transmembrane proteins; the most abundant such proteins are the lysosome-associated membrane protein (LAMP)1 and LAMP2, which together total 80% of lysosomal membrane proteins (Saftig & Klumperman…”
BackgroundInfluentialSelf-citationmTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide
Matsumoto, A., Pasut, A., Matsumoto, M., Yamashita, R., Fung, J., Monteleone, E., Saghatelian, A., Nakayama, K., Clohessy, J., & Pandolfi, P. (2016) · Nature · doi:10.1038/nature21034 · Cited by 594
mTORC1 signaling and the metabolic control of cell growth
Ben‐Sahra, I., & Manning, B. D. (2017) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2017.02.012 · Cited by 668
Martina, J. A., Diab, H. I., Lishu, L., Jeong-A, L., Patange, S., Raben, N., & Puertollano, R. (2014) · Science Signaling · doi:10.1126/scisignal.2004754 · Cited by 677
“To assess the regulation of TFE3 under a more physiological condition, cells were starved by incubation with amino acid–free medium for 1 hour, a treatment that inactivates mTORC1 (6, 7).”
BackgroundNguyen, T. B., Louie, S. M., Daniele, J. R., Tran, Q., Dillin, A., Zoncu, R., Nomura, D. K., & Olzmann, J. A. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.06.003 · Cited by 610
“…exploited MEFs lacking p18, a subunit of the Ragulator complex that is essential for mTORC1 lysosomal recruitment and activation (Nada et al., 2009; Sancak et al., 2010) (Figure 2A). p18 revertant (p18rev) MEFs rescued with Strep-tagged p18 (Nada et al., 2009; Sancak et al., 2010) were employed as…”
Self-citationNutrient sensing and signaling in the yeast Saccharomyces cerevisiae
Conrad, M., Schothorst, J., Kankipati, H. N., Zeebroeck, G. V., Rubio‐Texeira, M., & Thevelein, J. M. (2014) · FEMS Microbiology Reviews · doi:10.1111/1574-6976.12065 · Cited by 630
“Ego1 and 3 are functional homologs of the Ragulator complex in vertebrates (Kogan et al., 2010; Sancak et al., 2010).”
BackgroundTBC1D7 Is a Third Subunit of the TSC1-TSC2 Complex Upstream of mTORC1
Dibble, C. C., Elis, W., Menon, S., Qin, W., Klekota, J., Asara, J. M., Finan, P. M., Kwiatkowski, D. J., Murphy, L. O., & Manning, B. D. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.06.009 · Cited by 612
“These data suggest that TBC1D7 does not influence amino acid sensing by mTORC1, which involves the Rag GTPases recruiting mTORC1 to the LAMP2-containing compartment for activation by Rheb (Kim et al., 2008; Sancak et al., 2008, 2010; Zoncu et al., 2011).”
InfluentialDual Specificity Kinase DYRK3 Couples Stress Granule Condensation/Dissolution to mTORC1 Signaling
Wippich, F., Bodenmiller, B., Trajkovska, M., Wanka, S., Aebersold, R. H., & Pelkmans, L. (2013) · Cell · doi:10.1016/j.cell.2013.01.033 · Cited by 577
“Furthermore, we show that mTORC1 recruitment to SGs during stress reduces its localization to lysosomes, which is required for mTORC1 activation by amino acids (Sancak et al., 2010), and explains how stress, and inhibition of DYRK3 during stress recovery, generally reduces mTORC1 activity.”
BackgroundSpatial Coupling of mTOR and Autophagy Augments Secretory Phenotypes
Narita, M., Young, A. R. J., Arakawa, S., Samarajiwa, S. A., Nakashima, T., Yoshida, S., Hong, S., Berry, L. S., Reichelt, S., Ferreira, M., et al. (2011) · Science · doi:10.1126/science.1205407 · Cited by 594
The dynamic nature of autophagy in cancerPreprint
Kimmelman, A. C. (2011) · Genes & Development · doi:10.1101/gad.17558811 · Cited by 599
“Interestingly, there is additional spatial regulation of mTOR, as it is recruited to the lysosomal surface upon activation as well as to compartments containing autolysosomes (Sancak et al. 2010; Narita et al. 2011).”
BackgroundEndosome maturation, transport and functions
Scott, C. C., Vacca, F., & Grüenberg, J. (2014) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2014.03.034 · Cited by 616
ASCT2/SLC1A5 controls glutamine uptake and tumour growth in triple-negative basal-like breast cancer
van Geldermalsen, M., Wang, Q., Nagarajah, R., Marshall, A. D., Thoeng, A., Gao, D., Ritchie, W., Feng, Y., Bailey, C. G., Deng, N., et al. (2015) · Oncogene · doi:10.1038/onc.2015.381 · Cited by 581
Tsun, Z.-Y., Bar-Peled, L., Chantranupong, L., Zoncu, R., Wang, T., Kim, C., Spooner, E., & Sabatini, D. M. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.09.016 · Cited by 565
“The Rag GTPases interact with mTORC1 and signal amino acid sufficiency by promoting the translocation of mTORC1 to the lysosomal surface, its site of activation.”
InfluentialSelf-citationAutophagy: The spotlight for cellular stress responses
Ravanan, P., Florance, I., & Talwar, P. (2017) · Life Sciences · doi:10.1016/j.lfs.2017.08.029 · Cited by 595
mTORC1 as the main gateway to autophagy
Rabanal‐Ruiz, Y., Otten, E. G., & Korolchuk, V. I. (2017) · Essays in Biochemistry · doi:10.1042/ebc20170027 · Cited by 591
mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy
Tian, T., Li, X., & Zhang, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030755 · Cited by 602
“Along with this process, mTORC1 is recruited to the lysosomal surface [39,40].”
BackgroundColacurcio, D. J., & Nixon, R. A. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2016.05.004 · Cited by 548
Autophagy: machinery and regulation
Yin, Z., Pascual, C., & Klionsky, D. J. (2016) · Microbial Cell · doi:10.15698/mic2016.12.546 · Cited by 582
“In mammalian cells, amino acids are sensed by the vacuolar-type H + -translocating ATPase, which is present in the lysosome membrane, in conjunction with RRAG proteins and the Ragulator complex [52], which can coordinately direct MTORC1 to the lysosome membrane where it becomes activated by the GTPase RHEB [53].”
SAMTOR is an S -adenosylmethionine sensor for the mTORC1 pathway
Gu, X., Orozco, J. M., Saxton, R. A., Condon, K. J., Liu, G. Y., Krawczyk, P. A., Scaria, S. M., Harper, J. W., Gygi, S. P., & Sabatini, D. M. (2017) · Science · doi:10.1126/science.aao3265 · Cited by 598
Self-citationProtein Phosphorylation: A Major Switch Mechanism for Metabolic Regulation
Humphrey, S. J., James, D. E., & Mann, M. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.09.013 · Cited by 574
“Protein metabolism in turn also regulates signaling because mTORC1 senses amino acids via the Ragulator–Rag complex at the lysosomal surface [65–67].”
BackgroundLysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex
Castellano, B. M., Thelen, A. M., Moldavski, O., Feltes, M., van der Welle, R. E. N., Mydock-McGrane, L., Jiang, X., van Eijkeren, R. J., Davis, O. B., Louie, S. M., et al. (2017) · Science · doi:10.1126/science.aag1417 · Cited by 562
Self-citationZhang, C., Jiang, B., Li, M., Zhu, M., Peng, Y., Zhang, Y., Wu, Y., Li, T. Y., Yu, L., Lu, Z., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.06.014 · Cited by 565
“…of LAMTOR1 through LAMTOR5 (late endosomal/lysosomal adaptor, MAPK and mTOR activator 1–5), is a critical pentamer complex that not only anchors RAG proteins to the endosome but also functions as their GEF (guanine nucleotide exchange factor) (Bar-Peled et al., 2012; Sancak et al., 2010).”
InfluentialRapalogs and mTOR inhibitors as anti-aging therapeutics
Lamming, D. W., Ye, L., Sabatini, D. M., & Baur, J. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64099 · Cited by 531
“The Rag proteins activate mTORC1 by localizing mTORC1 to the lysosome via interaction with the ragulator complex (110).”
BackgroundSelf-citationThe Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway
Wolfson, R. L., & Sabatini, D. M. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.07.001 · Cited by 563
“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript its activity, including growth factors, cellular stresses, and energy and amino acid levels (Saxton and Sabatini, 2017).”
Self-citationDual role of autophagy in hallmarks of cancer
Singh, S. S., Vats, S., Chia, A. Y.-Q., Tan, T. Z., Deng, S., Ong, M. S., Arfuso, F., Yap, C. T., Goh, B. C., Sethi, G., et al. (2018) · Oncogene · doi:10.1038/s41388-017-0046-6 · Cited by 542
Puertollano, R., Ferguson, S. M., Brugarolas, J., & Ballabio, A. (2018) · The EMBO Journal · doi:10.15252/embj.201798804 · Cited by 530
“This study led to the identification of a transcriptional network of genes involved in lysosomal biogenesis, named coordinated lysosomal expression and regulation (CLEAR) network, and of TFEB as its master regulator (Sardiello et al , 2009).”
Where is mTOR and what is it doing there?
Betz, C., & Hall, M. N. (2013) · The Journal of Cell Biology · doi:10.1083/jcb.201306041 · Cited by 533
Fighting neurodegeneration with rapamycin: mechanistic insights
Bové, J., Martínez‐Vicente, M., & Vila, M. (2011) · Nature reviews. Neuroscience · doi:10.1038/nrn3068 · Cited by 533
“Signal integration also occurs at the level of lysosomes: in response to amino acids, mTORC1 is recruited to the surface of lysosomes located in the periphery of the cell, where mTORC1 can become activate”
BackgroundDietary protein for athletes: From requirements to optimum adaptation
Phillips, S. M., & Van Loon, L. J. C. (2011) · Journal of Sports Sciences · doi:10.1080/02640414.2011.619204 · Cited by 530
“Collectively, these findings indicate that so long as protein intake is sufficient, carbohydrate does little to augment post-exercise protein turnover (Glynn et al, 2010 ; Koopman et al, 2007 ; Sancak et al, 2010 ).”
BackgroundmTOR as a key regulator in maintaining skeletal muscle mass
Yoon, M.-S. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00788 · Cited by 495
“Lysosomal localization of mTOR does not activate mTOR directly, but rather provides close proximity to Rheb, an essential activator of mTOR (Saxton and Sabatini, 2017). mTORC1 is activated by direct interaction with the GTP-bound form of Rheb (Sancak et al., 2008, 2010), which is regulated by the TSC complex [TSC1, TS…”
BackgroundMethodInfluentialRoberts, D. J., & Miyamoto, S. (2014) · Cell Death and Differentiation · doi:10.1038/cdd.2014.173 · Cited by 523
Twenty-five years of mTOR: Uncovering the link from nutrients to growth
Sabatini, D. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1716173114 · Cited by 525
“Through the efforts of Yasemin Sancak, Tim Peterson, and Roberto Zoncu, who has been the only card-carrying cell biologist in my laboratory, we showed that lysosomes are a scaffolding platform on which mTORC1 becomes activated and also an active participant in the amino acid sensing process, as mTORC1 can sense amino…”
BackgroundSelf-citationAmino acid homeostasis and signalling in mammalian cells and organisms
Bröer, S., & Bröer, A. (2017) · Biochemical Journal · doi:10.1042/bcj20160822 · Cited by 518
Metadata
- Authors
- Sancak, Y., Bar-Peled, L., Zoncu, R., Markhard, A. L., Nada, S., & Sabatini, D. M.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sabatini, David M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-04
- Volume
- 141
- Issue
- 2
- Pages
- 290-303
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3024592
- OpenAlex
- W2027785297
- Cited by
- 2,464
- References
- 38
- Citations by year
- 2026: 112 · 2025: 132 · 2024: 136 · 2023: 148 · 2022: 169 · 2021: 188 · 2020: 164 · 2019: 138 · 2018: 162 · 2017: 166 · 2016: 166 · 2015: 198 · 2014: 166 · 2013: 146 · 2012: 136
- FWCI
- 54.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1239 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- PMC
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (CA103866, R01CA103866, R01CA129105)
- National Institute of Allergy and Infectious Diseases (R37AI047389, AI47389), R01AI047389)
- National Institute of Environmental Health Sciences (DP2ES032761)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- mTORC1, Ragulator complex, Rag GTPases, amino acid signaling, Rheb, TOR signaling
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Mechanistic Target of Rapamycin Complex 1, Regulatory-Associated Protein of mTOR, Amino Acids, Animals, Cell Line, Drosophila, Humans, Intracellular Membranes, Lysosomes, Models, Biological, Mutation, Neuropeptides, Protein Binding, Proteins, Recombinant Proteins, Transcription Factors, Signal Transduction, Protein Serine-Threonine Kinases, Monomeric GTP-Binding Proteins, MAP Kinase Signaling System, Protein Transport, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 2, TOR Serine-Threonine Kinases
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