The DOI matches its Crossref record; 37 of the 38 references it cites were found in a registry or an index.
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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Citations
Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216 · cited 8×
“For example, in Ragulator null cells, Akt is slightly activated, almost certainly because the well-known inhibitory signal from mTORC1 to PI3K is absent.”
BackgroundMethodInfluentialSelf-citationDefining the role of mTOR in cancer
Guertin, D. A., & Sabatini, D. M. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.05.008 · Cited by 2,833 · cited 2×
“the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids”
BackgroundSelf-citationThe Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1
Sancak, Y., Peterson, T. R., Shaul, Y. D., Lindquist, R. A., Thoreen, C. C., Bar-Peled, L., & Sabatini, D. M. (2008) · Science · doi:10.1126/science.1157535 · Cited by 2,773 · cited 26×
“Because mTORC1 pathway activity is high in cells expressing RagB (Sancak et al., 2008), the reduced Ragulator-Rag interaction in these cells may reflect a compensatory mechanism to reduce mTORC1 activity.”
BackgroundMethodInfluentialSelf-citationLaplante, M., & Sabatini, D. M. (2009) · Journal of Cell Science · doi:10.1242/jcs.051011 · Cited by 2,284 · cited 4×
“the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids”
BackgroundMethodInfluentialSelf-citationLysosomes: fusion and function
Luzio, J. P., Pryor, P. R., & Bright, N. A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2217 · Cited by 1,807 · cited 2×
“the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids”
BackgroundGuertin, D. A., Stevens, D. M., Thoreen, C. C., Burds, A. A., Kalaany, N. Y., Moffat, J., Brown, M., Fitzgerald, K. J., & Sabatini, D. M. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.10.007 · Cited by 1,467 · cited 1×
“On the other hand, mice lacking the core mTORC1 component raptor die earlier (before embryonic day 6.5) than p14 and p18 null mice (Guertin et al., 2006).”
BackgroundInfluentialSelf-citationRegulation of TORC1 by Rag GTPases in nutrient response
Kim, E., Goraksha-Hicks, P., Li, L., Neufeld, T. P., & Guan, K.-L. (2008) · Nature Cell Biology · doi:10.1038/ncb1753 · Cited by 1,349 · cited 4×
“the Lysosomal Surface and Is Necessary for Its Activation by Amino Acids”
BackgroundInfluentialPRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase
Sancak, Y., Thoreen, C. C., Peterson, T. R., Lindquist, R. A., Kang, S. A., Spooner, E., Carr, S. A., & Sabatini, D. M. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.03.003 · Cited by 1,236 · cited 2×
“HEK293T, cells the mTORC1 pathway is strongly regulated by serum and insulin (Sancak et al., 2007).”
BackgroundSelf-citationLocalization of low molecular weight GTP binding proteins to exocytic and endocytic compartments
Chavrier, P., Parton, R. G., Hauri, H. P., Simons, K., & Zerial, M. (1990) · Cell · doi:10.1016/0092-8674(90)90369-p · Cited by 1,166
Phosphorylation and Regulation of Raf by Akt (Protein Kinase B)
Zimmermann, S., & Moelling, K. (1999) · Science · doi:10.1126/science.286.5445.1741 · Cited by 1,093 · cited 2×
“As Akt suppresses MAPK signaling by phosphorylating and inhibiting Raf (Zimmermann and Moelling, 1999), it is conceivable that the activation of Akt that occurs in Ragulator null cells could account, at least in part, for the inhibition of MAPK signaling that has been observed in these cells.”
Background
Research works printed but not linked: 3
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- Sancak, Y., Peterson, T.R., Shaul, Y.D., Lindquist, R.A., Thoreen, C.C., Bar-Peled, L., and Sabatini, D.M. (2008). The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320, 1496–1501. · DOI · Paper page
- Sancak, Y., Thoreen, C.C., Peterson, T.R., Lindquist, R.A., Kang, S.A., Spooner, E., Carr, S.A., and Sabatini, D.M. (2007). PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol. Cell 25, 903–915. · DOI · Paper page
Cited by
Sorted by citations
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509
“…evidence is needed to support this connection because the YY1 response element was not identified as a motif enriched in the promoters of mTORC1-regulated genes (Düvel et al., 2010) and little endogenous mTORC1 is found in the nucleus (Sancak et al., 2010; Sancak et al., 2008; Zoncu et al., 2011).”
InfluentialSelf-citationmTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
“The Rags are obligate heterodimers of RagA or RagB with RagC or RagD and are tethered to the lysosomal membrane through their association with the pentameric Ragulator complex comprising MP1, p14, p18, HBXIP, and C7ORF59 (Sancak et al., 2010; Bar-Peled et al., 2012).”
BackgroundSelf-citationmTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941
“The active Rag heterodimer physically interacts with RAPTOR, causing mTORC1 to cluster onto the surface of late endosomes and lysosomes, where the Rag GTPases resid”
BackgroundSelf-citationmTOR at the nexus of nutrition, growth, ageing and disease
Liu, G. Y., & Sabatini, D. M. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0199-y · Cited by 2,737
Self-citationOxidative stress and autophagy: The clash between damage and metabolic needs
Filomeni, G., De Zio, D., & Cecconi, F. (2015) · Cell Death & Differentiation · doi:10.1038/cdd.2014.150 · Cited by 2,195
“pool (mainly leucine) present within the lumen of the lysosome by the vacuolar H-ATPase (v-ATPase) and a molecular complex called Ragulator (Figure 1).(24,25) This mechanism could underlie the negative feedback acting on autophagy”
Background
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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