The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1
Open accessAbstract
The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find that the Sestrins, a family of poorly understood growth regulators (Sestrin1-Sestrin3), interact with GATOR2 in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 signaling requires GATOR1 and the Rag GTPases, and the Sestrins regulate the localization of mTORC1 in response to amino acids. Thus, we identify the Sestrins as GATOR2-interacting proteins that regulate the amino-acid-sensing branch of the mTORC1 pathway.
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The mechanisms exposed above are distinct from another sestrin-inhibitory complex, containing GATOR and RAG A/B GTPase, that involves the mTOR pathway.
“The mechanisms exposed above are distinct from another sestrin-inhibitory complex, containing GATOR and RAG A/B GTPase that involves the mTOR pathway (197–199).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [199]
Several human proteins are now recognized as key metabolite sensors for the mTORC1 pathway: SESN1 and SESN2, CASTOR1, and SAMTOR, and may also include SLC38A9 and the vacuolar (v)-ATPase.
“However, several human proteins are now recognized as key metabolite sensors for the mTORC1 pathway. These include SESN1 and SESN2 (Chantranupong et al., 2014; Parmigiani et al., 2014; Peng et al., 2014), CASTOR1 (Chantranupong et al., 2016), and SAMTOR (Gu et al., 2017), and may also include SLC38A9 (Jung et al., 2015; Rebsamen et al., 2015; Wang et al., 2015) and the vacuolar (v)-ATPase (Zoncu”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Chantranupong et al., 2014
SESN2 interacts with GATOR2, with the interaction conditionally strengthened by both amino acid deprivation and DNA damage-induced stress.
“SESN2 interacts with GATOR2 (Chantranupong et al., 2014; Parmigiani et al., 2014; Kim J S et al., 2015), with the interaction conditionally strengthened by both amino acid deprivation (Chantranupong et al., 2014) and DNA damage-induced stress (Parmigiani et al., 2014).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Chantranupong et al., 2014
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- Authors
- Chantranupong, L., Wolfson, R. L., Orozco, J. M., Saxton, R. A., Scaria, S. M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S. P., & Sabatini, D. M.
- Affiliations
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- Whitehead Institute for Biomedical Research (US)
- Harvard University (US)
- Corresponding author
- Sabatini, David M.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 9
- Issue
- 1
- Pages
- 1-8
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4223866
- OpenAlex
- W2079172266
- Cited by
- 466
- References
- 44
- Citations by year
- 2026: 16 · 2025: 20 · 2024: 28 · 2023: 34 · 2022: 52 · 2021: 55 · 2020: 49 · 2019: 40 · 2018: 37 · 2017: 43 · 2016: 46 · 2015: 43 · 2014: 3
- FWCI
- 18.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Cancer Institute (R01CA103866, R01CA129105, F31CA180271)
- National Institute of General Medical Sciences (GM 67945, R01GM067945, T32GM007753, T32GM007287)
- 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
- sestrins, Sestrin2, GATOR2, GATOR1, mTORC1, amino acid sensing, Rag GTPases, raga, GTPase-activating protein, lysosomal translocation, cell growth regulation, protein-protein interaction
- MeSH terms
- Mechanistic Target of Rapamycin Complex 1, Sestrins, Amino Acids, Heat-Shock Proteins, Humans, Nuclear Proteins, Signal Transduction, Multiprotein Complexes, HEK293 Cells, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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