Leucine induced dephosphorylation of Sestrin2 promotes mTORC1 activation
Open accessAbstract
The studies described herein were designed to explore the role of Sestrin2 in mediating the selective action of leucine to activate mTORC1. The results demonstrate that Sestrin2 is a phosphoprotein and that its phosphorylation state is responsive to the availability of leucine, but not other essential amino acids. Moreover, leucine availability-induced alterations in Sestrin2 phosphorylation correlated temporally and dose dependently with the activation state of mTORC1, there being a reciprocal relationship between the degree of phosphorylation of Sestrin2 and the extent of repression of mTORC1. With leucine deprivation, Sestrin2 became more highly phosphorylated and interacted more strongly with proteins of the GATOR2 complex. Notably, in cells lacking the protein kinase ULK1, the activation state of mTORC1 was elevated in leucine-deficient medium, such that the effect of re-addition of the amino acid was blunted. In contrast, overexpression of ULK1 led to hyperphosphorylation of Sestrin2 and enhanced its interaction with GATOR2. Neither rapamycin nor Torin2 had any effect on Sestrin2 phosphorylation, suggesting that leucine deprivation-induced repression of mTORC1 was not responsible for the action of ULK1 on Sestrin2. Mass spectrometry analysis of Sestrin2 revealed three phosphorylation sites that are conserved across mammalian species. Mutation of the three sites to phospho-mimetic amino acids in exogenously expressed Sestrin2 promoted its interaction with GATOR2 and dramatically repressed mTORC1 even in the presence of leucine. Overall, the results support a model in which leucine selectively promotes dephosphorylation of Sestrin2, causing it to dissociate from and thereby activate GATOR2, leading to activation of mTORC1.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ULK1 is able to stimulate phosphorylation of SESN2 either directly or indirectly, suggesting SESNs may constitute a switch between biogenesis and autophagy.
“SESNs have also been suggested to constitute a switch between biogenesis and autophagy given the observation that ULK1, a kinase controlling the induction of autophagy, is able to stimulate phosphorylation of SESN2 either directly or indirectly (Kimball et al., 2016).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Kimball et al., 2016
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
MTOR: a pharmacologic target for autophagy regulation
Kim, Y. C., & Guan, K.-L. (2015) · Journal of Clinical Investigation · doi:10.1172/jci73939 · Cited by 2,126 · see citing works
Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy
Nicklin, P., Bergman, P., Zhang, B., Triantafellow, E., Wang, H., Nyfeler, B., Yang, H., Hild, M., Kung, C., Wilson, C., et al. (2009) · Cell · doi:10.1016/j.cell.2008.11.044 · Cited by 1,798 · see citing works
Zoncu, R., Bar-Peled, L., Efeyan, A., Wang, S., Sancak, Y., & Sabatini, D. M. (2011) · Science · doi:10.1126/science.1207056 · Cited by 1,673 · see citing works
Sestrin2 is a leucine sensor for the mTORC1 pathway
Wolfson, R. L., Chantranupong, L., Saxton, R. A., Shen, K., Scaria, S. M., Cantor, J. R., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aab2674 · Cited by 1,306 · see citing works
Nutrient-sensing mechanisms and pathways
Efeyan, A., Comb, W. C., & Sabatini, D. M. (2015) · Nature · doi:10.1038/nature14190 · Cited by 1,110 · see citing works
Bar-Peled, L., Chantranupong, L., Cherniack, A. D., Chen, W. W., Ottina, K. A., Grabiner, B. C., Spear, E. D., Carter, S. L., Meyerson, M., & Sabatini, D. M. (2013) · Science · doi:10.1126/science.1232044 · Cited by 1,080 · cited 5× · see citing works
“Epistasis studies place GATOR2 upstream of GATOR1 in the amino acid signaling pathway to mTORC1, leading to the proposal that amino acids signal to mTORC1 by promoting GATOR2-mediated repression of GATOR1 GAP activity toward RagA/B [14].”
BackgroundInfluentialRagulator Is a GEF for the Rag GTPases that Signal Amino Acid Levels to mTORC1
Bar-Peled, L., Schweitzer, L. D., Zoncu, R., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.07.032 · Cited by 918 · cited 1× · see citing works
“One is thought to involve a lysosomal membrane associated complex consisting of the Ragulator complex [10], the vacuolar ATPase (v-ATPase) [11], and the putative arginine transporter referred to as solute carrier (SLC) 38A9 [12,13].”
BackgroundEffects of insulin, glucose, and amino acids on protein turnover in rat diaphragm.
Fulks, R. M., Li, J. B., & Goldberg, A. L. (1975) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)42013-9 · Cited by 914 · see citing works
Leucyl-tRNA Synthetase Is an Intracellular Leucine Sensor for the mTORC1-Signaling Pathway
Han, J. M., Jeong, S. J., Park, M. C., Kim, G., Kwon, N. H., Kim, H. K., Ha, S. H., Ryu, S. H., & Kim, S. (2012) · Cell · doi:10.1016/j.cell.2012.02.044 · Cited by 824 · see citing works
Anthony, J. C., Yoshizawa, F., Anthony, T. G., Vary, T. C., Jefferson, L. S., & Kimball, S. R. (2000) · Journal of Nutrition · doi:10.1093/jn/130.10.2413 · Cited by 804 · see citing works
Self-citationWang, S., Tsun, Z., Wolfson, R. L., Shen, K., Wyant, G., Plovanich, M. E., Yuan, E. D., Jones, T. D., Chantranupong, L., Comb, W. C., et al. (2015) · Science · doi:10.1126/science.1257132 · Cited by 772 · see citing works
Differential regulation of mTORC1 by leucine and glutamine
Jewell, J. L., Kim, Y. C., Russell, R. C., Yu, F.-X., Park, H. W., Plouffe, S. W., Tagliabracci, V. S., & Guan, K.-L. (2015) · Science · doi:10.1126/science.1259472 · Cited by 757 · see citing works
Leucine. A possible regulator of protein turnover in muscle.
Buse, M. G., & Reid, S. S. (1975) · Journal of Clinical Investigation · doi:10.1172/jci108201 · Cited by 744 · see citing works
SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1
Rebsamen, M., Pochini, L., Stasyk, T., de Araújo, M. E. G., Galluccio, M., Kandasamy, R. K., Snijder, B., Fauster, A., Rudashevskaya, E. L., Bruckner, M., et al. (2015) · Nature · doi:10.1038/nature14107 · Cited by 673 · see citing works
The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR
Egan, D., Kim, J., Shaw, R. J., & Guan, K.-L. (2011) · Autophagy · doi:10.4161/auto.7.6.15123 · Cited by 627 · see citing works
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. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.014 · Cited by 466 · see citing works
Structural basis for leucine sensing by the Sestrin2-mTORC1 pathway
Saxton, R. A., Knockenhauer, K. E., Wolfson, R. L., Chantranupong, L., Pacold, M. E., Wang, T., Schwartz, T. U., & Sabatini, D. M. (2016) · Science · doi:10.1126/science.aad2087 · Cited by 457 · see citing works
Tischler, M. E., Desautels, M., & Goldberg, A. (1982) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)68081-6 · Cited by 443 · see citing works
Regulation of Protein Synthesis in Heart Muscle
Morgan, H. E., Earl, D. C., Broadus, A. E., et al. (1971) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)77202-0 · Cited by 348 · see citing works
Leucyl-tRNA Synthetase Controls TORC1 via the EGO Complex
Bonfils, G., Jaquenoud, M., Bontron, S., Ostrowicz, C. W., Ungermann, C., & VIRGILIO, C. D. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.02.009 · Cited by 338 · see citing works
Sestrins inhibit mTORC1 kinase activation through the GATOR complex
Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y. C., Akopiants, K., Guan, K.-L., Karin, M., & Budanov, A. V. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.019 · Cited by 336 · see citing works
GCN2 sustains mTORC1 suppression upon amino acid deprivation by inducing Sestrin2Preprint
Ye, J., Palm, W., Peng, M., King, B., Lindsten, T., Li, M. O., Koumenis, C., & Thompson, C. B. (2015) · Genes & Development · doi:10.1101/gad.269324.115 · Cited by 289 · see citing works
Influence of amino acid availability on protein turnover in perfused skeletal muscle
Li, J. B., & Jefferson, L. S. (1978) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(78)90103-4 · Cited by 276 · see citing works
Self-citationAmino Acid-Dependent mTORC1 Regulation by the Lysosomal Membrane Protein SLC38A9
Jung, J., Genau, H. M., & Behrends, C. (2015) · Molecular and Cellular Biology · doi:10.1128/mcb.00125-15 · Cited by 266 · see citing works
Regulation of autophagy by coordinated action of mTORC1 and protein phosphatase 2A
Wong, P.-M., Feng, Y., Wang, J., Shi, R., & Jiang, X. (2015) · Nature Communications · doi:10.1038/ncomms9048 · Cited by 239 · see citing works
mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex
Chan, E. Y. (2009) · Science Signaling · doi:10.1126/scisignal.284pe51 · Cited by 214 · see citing works
Bennet, W. M., Connacher, A. A., Scrimgeour, C. M., Smith, K., & Rennie, M. J. (1989) · Clinical Science · doi:10.1042/cs0760447 · Cited by 213 · see citing works
Anthony, J. C., Reiter, A. K., Anthony, T. G., Crozier, S. J., Lang, C. H., MacLean, D. A., Kimball, S. R., & Jefferson, L. S. (2002) · Diabetes · doi:10.2337/diabetes.51.4.928 · Cited by 177 · see citing works
Self-citationJanus-faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains
Kim, H., An, S., Ro, S.-H., Teixeira, F., Park, G. J., Kim, C., Cho, C., Kim, J.-S., Jakob, U., Lee, J.-H., et al. (2015) · Nature Communications · doi:10.1038/ncomms10025 · Cited by 152 · see citing works
ERK and Akt signaling pathways function through parallel mechanisms to promote mTORC1 signaling
Winter, J. N., Jefferson, L. S., & Kimball, S. R. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00504.2010 · Cited by 130 · see citing works
Self-citationSestrin2 promotes Unc‐51‐like kinase 1 mediated phosphorylation of p62/sequestosome‐1
Ro, S., Semple, I. A., Park, H., Park, H., Park, H., Kim, M., Kim, J. S., & Lee, J. H. (2014) · FEBS Journal · doi:10.1111/febs.12905 · Cited by 123 · see citing works
Mechanisms Involved in the Coordinate Regulation of mTORC1 by Insulin and Amino Acids
Dennis, M. D., Baum, J., Kimball, S. R., & Jefferson, L. S. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.209171 · Cited by 93 · see citing works
Self-citationGordon, B. S., Kazi, A. A., Coleman, C., Dennis, M. D., Chau, V., Jefferson, L., & Kimball, S. (2013) · Cellular Signalling · doi:10.1016/j.cellsig.2013.11.035 · Cited by 61 · see citing works
Self-citationAmino acid levels in plasma, liver, and skeletal muscle during protein deprivation
Adibi, S. A., Modesto, T., El, M., & Pm, A. (1973) · American Journal of Physiology-Legacy Content · doi:10.1152/ajplegacy.1973.225.2.408 · Cited by 58 · see citing works
Sphingolipid storage impairs autophagic clearance of Alzheimer-associated proteins
Tamboli, I. Y., Tien, N. T., & Walter, J. (2011) · Autophagy · doi:10.4161/auto.7.6.15122 · Cited by 29 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Current Concepts and Unresolved Questions in Dietary Protein Requirements and Supplements in Adults
Phillips, S. M. (2017) · Frontiers in Nutrition · doi:10.3389/fnut.2017.00013 · Cited by 145 · see citing works
Resistance exercise enhances long-term mTORC1 sensitivity to leucine
D'Hulst, G., Masschelein, E., & De Bock, K. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101615 · Cited by 42 · see citing works
Signal integration in the (m)TORC1 growth pathway
Ramlaul, K., & Aylett, C. H. S. (2018) · Frontiers in Biology · doi:10.1007/s11515-018-1501-7 · Cited by 12 · see citing works
- Authors
- Kimball, S. R., Gordon, B. S., Moyer, J. E., Dennis, M. D., & Jefferson, L. S.
- Affiliations
- Pennsylvania State University (US)
- Corresponding author
- Kimball, Scot R.
- Venue
- Cellular Signalling
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 28
- Issue
- 8
- Pages
- 896-906
- ISSN
- 0898-6568 (ISSN-L)
- PMC
- PMC4899281
- OpenAlex
- W2309391948
- Cited by
- 97
- References
- 35
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 5 · 2023: 16 · 2022: 10 · 2021: 11 · 2020: 22 · 2019: 8 · 2018: 5 · 2017: 9 · 2016: 1
- FWCI
- 3.98
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cellular Signalling (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Journal of International Crisis and Risk Communication Research (submittedVersion)
- Funders
- NIH (DK-13499, DK-15658, EY023612)
- American Diabetes Association Pathway to Stop Diabetes Grant (1-14-INI-04)
- 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
- Sestrin2, mTORC1 activation, leucine, leucine deprivation, protein dephosphorylation, ULK1, amino acid signaling, phosphorylation sites, phosphomimetic mutant, rapamycin, Torin2
- MeSH terms
- Autophagy-Related Protein-1 Homolog, Mechanistic Target of Rapamycin Complex 1, Sestrins, Amino Acid Sequence, Animals, Electrophoresis, HeLa Cells, Humans, Leucine, Models, Biological, Nuclear Proteins, Phosphorylation, Protein Binding, Mass Spectrometry, Time Factors, Signal Transduction, Mutagenesis, Site-Directed, Multiprotein Complexes, Mice, 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 ›
Are you an author, or do you see a problem with this page? Request a review
