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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Five proteins, MP1, p14, p18, HBXIP and C7orf59, form a lysosomally-localized complex, interact with the Rag GTPases, and are required to recruit the Rag GTPases to their cognate compartment.
“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
None of the Rag proteins contain lipid modification motifs that would result in their lysosomal localization.
“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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- 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
- Health Sciences › Medicine › Epidemiology › 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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