The Folliculin Tumor Suppressor Is a GAP for the RagC/D GTPases That Signal Amino Acid Levels to mTORC1
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The mTORC1 kinase is a master growth regulator that senses numerous environmental cues, including amino acids. 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. The Rags are unusual GTPases in that they function as obligate heterodimers, which consist of RagA or B bound to RagC or D. While the loading of RagA/B with GTP initiates amino acid signaling to mTORC1, the role of RagC/D is unknown. Here, we show that RagC/D is a key regulator of the interaction of mTORC1 with the Rag heterodimer and that, unexpectedly, RagC/D must be GDP bound for the interaction to occur. We identify FLCN and its binding partners, FNIP1/2, as Rag-interacting proteins with GAP activity for RagC/D, but not RagA/B. Thus, we reveal a role for RagC/D in mTORC1 activation and a molecular function for the FLCN tumor suppressor.
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Endogenous FLCN-FNIP1/2 and Lst4-Lst7 complexes exhibit lysosomal or vacuolar localization during nutrient deficiency, and once there FLCN-FNIP2 acts as the GAP for RagC/D.
“Endogenous FLCN-FNIP1/2 and Lst4-Lst7 complexes exhibit lysosomal or vacuolar localization during nutrient deficiency, respectively (Petit et al., 2013; Tsun et al., 2013; Péli-Gulli et al., 2015), and once there FLCN-FNIP2 acts as the GAP for RagC/D.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Tsun et al., 2013
An obligate FLCN-FNIP complex is necessary for the Rag interaction, since RagA and RagC coimmunoprecipitate with FLCN only when FNIP2 is coexpressed, and this interaction is strengthened during nutrient starvation and resulted in inhibition of (m)TORC1 activity.
“An obligate FLCN-FNIP complex is necessary for the Rag interaction, since RagA and RagC coimmunoprecipitate with FLCN only when FNIP2 is coexpressed, and this interaction is strengthened during nutrient starvation and resulted in inhibition of (m)TORC1 activity (Tsun et al., 2013; Péli-Gulli et al., 2015).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Tsun et al., 2013
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- Authors
- Tsun, Z.-Y., Bar-Peled, L., Chantranupong, L., Zoncu, R., Wang, T., Kim, C., Spooner, E., & Sabatini, D. M.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Sabatini, David M.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 52
- Issue
- 4
- Pages
- 495-505
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC3867817
- OpenAlex
- W1995455069
- Cited by
- 565
- References
- 72
- Citations by year
- 2026: 35 · 2025: 32 · 2024: 36 · 2023: 42 · 2022: 40 · 2021: 61 · 2020: 50 · 2019: 41 · 2018: 46 · 2017: 46 · 2016: 55 · 2015: 42 · 2014: 34 · 2013: 3 · 2012: 1
- FWCI
- 20.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- National Science Foundation
- Howard Hughes Medical Institute
- Jane Coffin Childs Memorial Fund for Medical Research
- National Institutes of Health
- National Cancer Institute (CA103866, R01CA103866, F30CA180754, R01CA129105, F31CA180271, 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- folliculin, mTORC1, amino acid signaling, GTPase-activating protein, lysosomal translocation, tumor suppressor, growth regulation
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Amino Acids, Carrier Proteins, Humans, Intracellular Membranes, Lysosomes, Protein Binding, Proto-Oncogene Proteins, Signal Transduction, Monomeric GTP-Binding Proteins, GTPase-Activating Proteins, Protein Transport, Tumor Suppressor Proteins, Multiprotein Complexes, HEK293 Cells, TOR Serine-Threonine Kinases
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