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Ragulator-Rag Complex Targets mTORC1 to the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids
Open accessAbstract
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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Cites
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“[1,2] In addition, lysosomal membrane proteins interact with cytoplasmic proteins to modulate intracellular signaling.[3] Because these lysosomal proteins are essential for various cellular functions, congenital deficiencies in these proteins OPEN ACCESS”
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“Amino acids promote the interaction of Rag GTPases (specifically Rag heterodimers containing GTP-bound RagB) with the raptor component of mTORC1 (44).”
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“Upon induction of autophagy by starvation, the mTOR kinase is released from the surface of lysosomes and becomes inactivated (33,34).”
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Capelo-Diz, A., Lachiondo‐Ortega, S., Fernández‐Ramos, D., Cañas-Martín, J., Goikoetxea‐Usandizaga, N., Serrano‐Maciá, M., Gonzalez-Rellan, M. J., Mosca, L., Vicens, J. B., Tinahones, A., et al. (2023) · Cell Metabolism · doi:10.1016/j.cmet.2023.07.002 · Cited by 46
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The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes
Takahashi, Y., Nada, S., Mori, S., Soma‐Nagae, T., Oneyama, C., & Okada, M. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.12.082 · Cited by 44
“Since the p18-p14MP1 complex is necessary for activation of mTORC1 [14], we examined the effects of inhibition of mTORC1 with rapamycin on the behavior of late endosomes/lysosomes.”
BackgroundSelf-citationLiu, R., Iadevaia, V., Avérous, J., Taylor, P. M., Zhang, Z., & Proud, C. G. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku130 · Cited by 46
“Activation of mTORC1 requires its amino acid-induced association with lysosomes (43).”
BackgroundInfluentialFrost, R. A., & Lang, C. H. (2012) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2012.04.012 · Cited by 47
Integration of signals generated by nutrients, hormones, and exercise in skeletal muscle.
Kimball, S. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.113.068387 · Cited by 46
“The Ragulator complex is anchored to late endosomal/lysosomal membranes through p18, which is myristoylated and palmitoylated (12).”
BackgroundUnraveling the role of the Target of Rapamycin signaling in sphingolipid metabolism
Teixeira, V., & Costa, V. (2015) · Progress in Lipid Research · doi:10.1016/j.plipres.2015.11.001 · Cited by 46
Recent Data on Cellular Component Turnover: Focus on Adaptations to Physical Exercise
Sanchez, A. M. J., Candau, R. B., & Bernardi, H. (2019) · Cells · doi:10.3390/cells8060542 · Cited by 46
“In accordance, studies in vitro and in animals highlighted that MTORC1 recruitment to the lysosome surface is critical to raise MTOR kinase activity [78,79].”
BackgroundHong‐Brown, L. Q., Brown, C. R., Kazi, A. A., Navaratnarajah, M., & Lang, C. H. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00407.2011 · Cited by 44
“It has been proposed that Rag GTPases bind to mTORC1 via a heterotrimeric protein complex termed the Ragulator (45).”
BackgroundPP2A-dependent TFEB activation is blocked by PIKfyve-induced mTORC1 activity
Hasegawa, J., Tokuda, E. Y., Yao, Y., Sasaki, T., Inoki, K., & Weisman, L. S. (2022) · Molecular Biology of the Cell · doi:10.1091/mbc.e21-06-0309 · Cited by 43
“The active heterodimers recruit cytoplasmic mTORC1 to the surface of the lysosomal membrane (Sekiguchi et al. , 2001; Gao and Kaiser, 2006; Sancak et al. , 2008, 2010; Bar-Peled et al. , 2012) where mTORC1 is activated by another small GTPase, Rheb (Saucedo et al. , 2003; Stocker et al. , 2003).”
Mafi, S., Ahmadi, E., Meehan, E. V., Chiari, C. C., Mansoori, B., Sadeghi, H., Milani, S., Jafarinia, M., Taeb, S., Bashmagh, B. M., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3032 · Cited by 43
The KEAP1–NRF2 pathway regulates TFEB/TFE3-dependent lysosomal biogenesis
Ong, A. J. S., Bladen, C. E., Tigani, T. A., Karamalakis, A. P., Evason, K. J., Brown, K., & Cox, A. G. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2217425120 · Cited by 42
“More recently, lysosomes have been recognized to play a central role in nutrient sensing in part due to the lysosomal localization of the active mTORC1 complex (38).”
BackgroundMalonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor
Nicastro, R., Brohée, L., Alba, J., Nüchel, J., Figlia, G., Kipschull, S., Gollwitzer, P., Romero‐Pozuelo, J., Fernandes, S., Lamprakis, A. A., et al. (2023) · Nature Cell Biology · doi:10.1038/s41556-023-01198-6 · Cited by 48
“…the lysosomal delocalization of mTORC1 is the underlying cause of its downregulation following FASN inhibition, we exogenously expressed an ‘active’-locked RagA/C mutant dimer (RagA QL /C SN ) that partially prevents mTORC1 inactivation following amino-acid starvation 8,41 (Extended Data Fig.”
InfluentialPRKAA2, MTOR, and TFEB in the regulation of lysosomal damage response and autophagy
Shariq, M., Khan, M. F., Raj, R., Ahsan, N., & Kumar, P. (2024) · Journal of Molecular Medicine · doi:10.1007/s00109-023-02411-7 · Cited by 42
“The Ragulator-RRAG-v-ATPase complex interacts with lysosomal amino acid transporter solute carrier family 38 member 9 (SLC38A9) [91–94].”
Stay in touch with the endoplasmic reticulum
Sun, S., Gan, Z., Jia, M., Jiang, Q., Li, S., Wang, H., Li, W., Wang, Y., Bian, X., Zhao, Y. G., et al. (2024) · Science China Life Sciences · doi:10.1007/s11427-023-2443-9 · Cited by 45
“When lysosomal membrane-anchored Rag GTPases are activated in response to amino acids, they promote translocation of the mTOR complex 1 (mTORC1) kinase, a master regulator of cellular growth, to the surface of lysosomes, where it becomes activated (Sancak et al., 2010; Zoncu et al., 2011).”
BackgroundThe scaffold protein AXIN1: gene ontology, signal network, and physiological function
Qiu, L., Sun, Y., Ning, H., Chen, G., Zhao, W., & Gao, Y. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01482-4 · Cited by 43
“Subsequently, mTORC1 is activated, thereby instigating anabolic pathways [5, 118, 119].”
BackgroundMore TOR: The expanding role of mTOR in regulating immune responses
Patel, C. H., & Powell, J. D. (2025) · Immunity · doi:10.1016/j.immuni.2025.06.010 · Cited by 48
Key mediators of intracellular amino acids signaling to mTORC1 activation
Duan, Y., Li, F., Tan, K., Liu, H., Li, Y., Liu, Y., Kong, X., Tang, Y., Wu, G., & Yin, Y. (2015) · Amino Acids · doi:10.1007/s00726-015-1937-x · Cited by 43
Autophagy regulates tissue overgrowth in a context-dependent manner
Pérez, E., Das, G., Bergmann, A., & Baehrecke, E. H. (2014) · Oncogene · doi:10.1038/onc.2014.285 · Cited by 45
“In addition, autophagy influences mTOR activity under nutrient restriction by the association of this kinase with autolysosomes that control nutrient availability and the activity of mTOR (32, 33).”
BackgroundDiscovery of a Small-Molecule Probe for V-ATPase Function
Aldrich, L. N., Kuo, S.-Y., Castoreno, A. B., Goel, G., Kuballa, P., Rees, M. G., Seashore-Ludlow, B. A., Cheah, J. H., Latorre, I. J., Schreiber, S. L., et al. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b02150 · Cited by 44
PIP4kγ is a substrate for mTORC1 that maintains basal mTORC1 signaling during starvation
Mackey, A. M., Sarkes, D. A., Bettencourt, I. A., Asara, J. M., & Rameh, L. E. (2014) · Science Signaling · doi:10.1126/scisignal.2005191 · Cited by 44
Minireview: The Busy Road to Pheochromocytomas and Paragangliomas Has a New Member, TMEM127
Jiang, S., & Dahia, P. L. M. (2011) · Endocrinology · doi:10.1210/en.2011-0052 · Cited by 43
“Rag GTPases, the main mediators of mTOR stimulation in response to amino acids, function through a multiprotein complex named Ragulator to recruit mTOR from a diffuse or subvesicular cytoplasmic location, to a late endosome/lysosomal perinuclear compartment in an amino acid-dependent manner (54).”
BackgroundAgarwal, S., Bell, C. M., Taylor, S. M., & Moran, R. G. (2015) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-15-0159 · Cited by 43
Kim, T., Kim, Y., Kim, H.-T., Park, S.-R., Lee, M.-Y., Park, Y.-D., Lee, C., & Jung, J. (2016) · Antioxidants and Redox Signaling · doi:10.1089/ars.2015.6386 · Cited by 43
“Moreover, the expression of Rheb, an mTORC1 co-activator, followed in a similar manner (40).”
Shaw, E., Talwadekar, M., Rashida, Z., Mohan, N., Acharya, A., Khatri, S., Laxman, S., & Kolthur‐Seetharam, U. (2019) · Molecular and Cellular Biology · doi:10.1128/mcb.00212-19 · Cited by 42
“mTOR is essential for its activation (42), and since it is a direct readout of the extent of”
BackgroundLin, C., Han, G., Ning, H., Song, J., Ran, N., Yi, X., Seow, Y., & Yin, H. (2020) · Molecular Therapy · doi:10.1016/j.ymthe.2020.03.003 · Cited by 43
“For the amino acid starvation experiments, 10% dialyzed FBS was depleted unless otherwise indicated.(46) For the v-ATPase blocking experiment, 1 mM BAF (MedChemExpress, USA) was added into the starved cells for 1 h prior to stimulation with total amino acids or glycine for 30 min.”
MethodWu, Z., Heng, J., Tian, M., Song, H., Chen, F., Guan, W., & Zhang, S. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422420000074 · Cited by 43
Coxsackievirus B3 targets TFEB to disrupt lysosomal function
Mohamud, Y., Tang, H. R., Xue, Y. C., Liu, H., Ng, C. S., Bahreyni, A., & Luo, H. (2021) · Autophagy · doi:10.1080/15548627.2021.1896925 · Cited by 43
“Phosphorylation of TFEB is mediated by MTORC1, which takes place at the lysosomal surface [29].”
BackgroundParkhitko, A. A., Favorova, O. O., Khabibullin, D., Anisimov, V. N., & Henske, E. P. (2014) · Biochemistry (Moscow) · doi:10.1134/s0006297914020023 · Cited by 44
Qin, C., Bai, L., Li, Y., & Wang, K. (2022) · Stem Cell Research & Therapy · doi:10.1186/s13287-022-02765-8 · Cited by 44
“In contrast, an appropriate activation of autophagy alleviates neuropathology as revealed by the expression levels of molecular markers such as Beclin-1, atg7, LC3, Lamp-1, Lamp-2, and mTOR [27, 31, 32].”
BackgroundStructural basis for FLCN RagC GAP activation in MiT-TFE substrate-selective mTORC1 regulation
Jansen, R. M., Peruzzo, R., Fromm, S. A., Yokom, A. L., Zoncu, R., & Hurley, J. H. (2022) · Science Advances · doi:10.1126/sciadv.add2926 · Cited by 42
“The Rag-Ragulator complex consists of two Rag GTPases (commonly referred to as Rags) that function as obligate heterodimers and are anchored to the lysosomal membrane by the pentameric scaffold Ragulator ( 13 , 14 ).”
Self-citationLysosomes in retinal health and disease
Boya, P., Kaarniranta, K., Handa, J. T., & Sinha, D. (2023) · Trends in Neurosciences · doi:10.1016/j.tins.2023.09.006 · Cited by 44
Chemoproteomic development of SLC15A4 inhibitors with anti-inflammatory activity
Chiu, T.-Y., Lazar, D. C., Wang, W., Wozniak, J. M., Jadhav, A. M., Li, W., Gazaniga, N. R., Theofilopoulos, A. N., Teijaro, J. R., & Parker, C. G. (2024) · Nature Chemical Biology · doi:10.1038/s41589-023-01527-8 · Cited by 44
Szymańska-Rożek, P., Martin, K. R., MacKeigan, J. P., Hlavacek, W. S., & Tomasz Lipniacki, B. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116550 · Cited by 42
“Thus, the model does not include, for example, TRAF6-mediated positive feedback from AMBRA1 to ULK1 [38], indirect regulation of MTORC1 by AMPK via TSC1/TSC2/RHEB [45], MTORC1-mediated phosphorylation of components of the ULK1 complex (e.g., ATG13) other than ULK1 [14,23], the Ragulator complex or Rag GTPases [46], or…”
BackgroundThe mTOR pathway in obesity driven gastrointestinal cancers: Potential targets and clinical trials
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“insulin, insulin-like growth factor 1 (IGF-1)) and amino acid dependent (specifically leucine [7]) translocation of inactive mTORC1 from the cytoplasm to the lysosomal membrane via the Ragulator–Rag complex [8] (Fig.”
BackgroundLuo, C., Zhao, S., Zhang, M., Gao, Y., Wang, J., Hanigan, M. D., & Zheng, N. (2018) · Scientific Reports · doi:10.1038/s41598-018-22208-w · Cited by 43
The Protozoan Parasite Toxoplasma gondii Selectively Reprograms the Host Cell Translatome
Leroux, L., Lorent, J., Graber, T. E., Chaparro, V., Masvidal, L., Aguirre, M., Fonseca, B. D., van Kempen, L. C. L. T., Alain, T., Larsson, O. S., et al. (2018) · Infection and Immunity · doi:10.1128/iai.00244-18 · Cited by 42
Zhao, Y., Cholewa, J. M., Shang, H., Yang, Y., Ding, X., Wang, Q., Su, Q., Zanchi, N. E., & Xia, Z. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.646482 · Cited by 50
“Rag GTPases network directly with p14/MP1 heterodimer directly via its C-terminal domain, while Ragulator anchors the Rag GTPases to the lysosomal surface through myristoylation and palmitoylation at the N-terminus of p14 (Sancak et al., 2010; de Araujo et al., 2017).”
BackgroundTargeting fuel pocket of cancer cell metabolism: A focus on glutaminolysis
Sharma, S., Agnihotri, N., & Kumar, S. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.114943 · Cited by 42
KLF15 Is a Molecular Link between Endoplasmic Reticulum Stress and Insulin Resistance
Jung, D. Y., Chalasani, U., Pan, N., Friedline, R. H., Prosdocimo, D. A., Nam, M., Azuma, Y., Maganti, R. J., Yu, K. M., Velagapudi, A., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0077851 · Cited by 43
“Recent evidence shows that amino acids stimulate Rag GTPase-mediated translocation of mTORC1 to lysosomes, where mTORC1 is then activated by Rheb [56].”
BackgroundMaking sense of amino acid sensing
Abraham, R. T. (2015) · Science · doi:10.1126/science.aaa4570 · Cited by 42
Amino acids-Rab1A-mTORC1 signaling controls whole-body glucose homeostasis
Zhang, X., Wang, X., Yuan, Z., Radford, S. J., Liu, C., Libutti, S. K., & Zheng, X. F. S. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108830 · Cited by 41
Beyond Genetics: The Role of Metabolism in Photoreceptor Survival, Development and Repair
Hanna, J., David, L. A., Touahri, Y., Fleming, T., Screaton, R. A., & Schuurmans, C. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.887764 · Cited by 45
“Once on the lysosomal surface, mTORC1 is in the same compartment as Rheb, a GTP-binding protein that activates mTORC1 (Sancak et al., 2010).”
BackgroundSenapati, P. K., Mahapatra, K. K., Singh, A., & Bhutia, S. K. (2025) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2025.189342 · Cited by 44
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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