The DOI matches its Crossref record; 50 of the 50 references it cites were found in a registry or an index.
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Abstract
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by the formation of hamartomas in a wide range of human tissues. Mutation in either the TSC1 or TSC2 tumour suppressor gene is responsible for both the familial and sporadic forms of this disease. TSC1 and TSC2 proteins form a physical and functional complex in vivo. Here, we show that TSC1-TSC2 inhibits the p70 ribosomal protein S6 kinase 1 (an activator of translation) and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation). These functions of TSC1-TSC2 are mediated by inhibition of the mammalian target of rapamycin (mTOR). Furthermore, TSC2 is directly phosphorylated by Akt, which is involved in stimulating cell growth and is activated by growth stimulating signals, such as insulin. TSC2 is inactivated by Akt-dependent phosphorylation, which destabilizes TSC2 and disrupts its interaction with TSC1. Our data indicate a molecular mechanism for TSC2 in insulin signalling, tumour suppressor functions and in the inhibition of cell growth.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“TSC2, also known as tuberous sclerosis protein 2, functions as a GTPase-activating protein (GAP) to convert active Rheb-GTP to the inactive GDP-bound form (Rheb-GDP) resulting in the inhibition of mTOR, the mTORC1 complex [26], and the mTOR signaling pathway p70S6K [27].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [26]
In the citing paper
“tuberous sclerosis complex 2 (TSC2), that also blocks mTOR activity [26]”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [26]
In the citing paper
“Subsequently, TSC2 can be inhibited by Akt phosphorylation that serves to destabilize TSC2 and disrupt its interaction with TSC1 [26, 28].”
From Tuberous Sclerosis Protein 2 (TSC2) Modulates CCN4 Cytoprotection During Apoptotic Amyloid Toxicity in Microglia (2013) · cites this paper as [26]
In the citing paper
“The integration of the majority of external and survival signals feeding into the (m)TORC1 pathway occurs through the TSC complex (TSCC), composed of tuberous sclerosis complex protein 1 (TSC1) and TSC2, also known as hamartin and tuberin, and TBC1D7, which is the key signal integrator and negative regulator upstream of Rheb.”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Inoki et al., 2002
In the citing paper
“This identification of this regulatory mechanism, shown using the human proteins, unequivocally identified TSC1-TSC2 as inhibitors of the mTORC1 signaling pathway (Inoki et al., 2002; Tee et al., 2002), specifically by virtue of TSC2 GAP activity toward the small GTPase Rheb (Castro et al., 2003; Garami et al., 2003; Inoki et al., 2003; Saucedo et al., 2003;”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Inoki et al., 2002
Citations
Cites
Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells
Elbashir, S. M., Harborth, J., Lendeckel, W., Yalcin, A., Weber, K., & Tuschl, T. (2001) · Nature · doi:10.1038/35078107 · Cited by 9,456
Cellular survival: a play in three Akts
Datta, S. R., Brunet, A., & Greenberg, M. E. (1999) · Genes & Development · doi:10.1101/gad.13.22.2905 · Cited by 4,216
Liu, J.-P., Baker, J. C., Perkins, A. S., Robertson, E. J., & Efstratiadis, A. (1993) · Cell · doi:10.1016/s0092-8674(05)80084-4 · Cited by 2,854
Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction
Burgering, B. M. T., & Coffer, P. J. (1995) · Nature · doi:10.1038/376599a0 · Cited by 2,076
TOR, a Central Controller of Cell Growth
Schmelzle, T., & Hall, M. N. (2000) · Cell · doi:10.1016/s0092-8674(00)00117-3 · Cited by 1,914
DeChiara, T. M., Efstratiadis, A., & Robertsen, E. J. (1990) · Nature · doi:10.1038/345078a0 · Cited by 1,663
Identification and characterization of the tuberous sclerosis gene on chromosome 16
(1993) · Cell · doi:10.1016/0092-8674(93)90618-z · Cited by 1,645
Hara, K., Yonezawa, K., Weng, Q.-P., Kozlowski, M. T., BELHAM, C. M., & Avruch, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14484 · Cited by 1,370
Regulation of 4E-BP1 phosphorylation: a novel two-step mechanismPreprint
Gingras, A., Gygi, S. P., Raught, B., Polakiewicz, R. D., Abraham, R. T., Hoekstra, M. F., Aebersold, R. H., & Sonenberg, N. (1999) · Genes & Development · doi:10.1101/gad.13.11.1422 · Cited by 1,348
Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1
Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S., et al. (1994) · Nature · doi:10.1038/372182a0 · Cited by 1,081
Dabora, S. L., Jóźwiak, S., Franz, D. N., Roberts, P. S., Nieto, A., Chung, J., Choy, Y.-S., Reeve, M. P., Thiele, E. A., Egelhoff, J. C., et al. (2001) · The American Journal of Human Genetics · doi:10.1086/316951 · Cited by 998
Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR
Neshat, M. S., Mellinghoff, I. K., Tran, C., Stiles, B. L., THOMAS, G. V., Petersen, R., Frost, P., Gibbons, J. J., Wu, H., & Sawyers, C. L. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171076798 · Cited by 971
Mammalian TOR: a homeostatic ATP sensor
Dennis, P. B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S. C., & Thomas, G. (2001) · Science · doi:10.1126/science.1063518 · Cited by 962
NAVÉ, B. T., Ouwens, D. M., Withers, D. J., Alessi, D. R., & Shepherd, P. R. (1999) · Biochemical Journal · doi:10.1042/bj3440427 · Cited by 926
Sekulić, A., Hudson, C. C., Homme, J. L., Yin, P., Otterness, D. M., Karnitz, L. M., & Abraham, R. T. (2000) · PubMed · Cited by 708
Ribosomal S6 Kinase Signaling and the Control of Translation
Dufner, A., & Thomas, G. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4683 · Cited by 676 · cited 1×
“S6K activity is activated by phosphorylation on several residues, including Thr 389, Thr 421 and Ser 424 (ref”
BackgroundKwiatkowski, D. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.525 · Cited by 674
The mRNA 5′ cap-binding protein eIF4E and control of cell growth
Sonenberg, N., & Gingras, A. (1998) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(98)80150-6 · Cited by 673
The conserved phosphoinositide 3‐kinase pathway determines heart size in mice
Shioi, T., Kang, P., Douglas, P., Hampe, J., Yballe, C., Lawitts, J., Cantley, L., & Izumo, S. (2000) · EMBO Journal · doi:10.1093/emboj/19.11.2537 · Cited by 646
Disruption of the p70s6k/p85s6k gene reveals a small mouse phenotype and a new functional S6 kinase
Shima, H., Pende, M., Chen, Y., Fumagalli, S., THOMAS, G. V., & Kozma, S. C. (1998) · The EMBO Journal · doi:10.1093/emboj/17.22.6649 · Cited by 636
An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten +/− mice
Podsypanina, K., Lee, R. T., Politis, C., Hennessy, I., Crane, A., Puc, J., Neshat, M. S., Wang, H., Yang, L., Gibbons, J., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.171060098 · Cited by 568
The Drosophila Tuberous Sclerosis Complex Gene Homologs Restrict Cell Growth and Cell Proliferation
Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E., & Hariharan, I. K. (2001) · Cell · doi:10.1016/s0092-8674(01)00332-4 · Cited by 542
Jones, A. C., Shyamsundar, M. M., Thomas, M. W., Maynard, J. H., Idziaszczyk, S., Tomkins, S. E., Sampson, J. R., & Cheadle, J. P. (1999) · The American Journal of Human Genetics · doi:10.1086/302381 · Cited by 527
Potter, C. J., Huang, H., & Xu, T. (2001) · Cell · doi:10.1016/s0092-8674(01)00333-6 · Cited by 522
Regulation of pancreatic β-cell growth and survival by the serine/threonine protein kinase Akt1/PKBα
Tuttle, R. L., Gill, N. S., Pugh, W., Lee, J.-P., Koeberlein, B., Furth, E. E., Polonsky, K. S., Naji, A., & Birnbaum, M. J. (2001) · Nature Medicine · doi:10.1038/nm1001-1133 · Cited by 511
Akt/Protein Kinase B Promotes Organ Growth in Transgenic Mice
Shioi, T., McMullen, J. R., Kang, P. M., Douglas, P. S., Obata, T., Franke, T. F., Cantley, L. C., & Izumo, S. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.8.2799-2809.2002 · Cited by 503
Peterson, R., Desai, B. N., Hardwick, J. S., & Schreiber, S. (1999) · Proceedings of the National Academy of Sciences of the United States of America · doi:10.1073/pnas.96.8.4438 · Cited by 496
Identification of a Conserved Motif Required for mTOR Signaling
Schalm, S. S., & Blenis, J. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00762-5 · Cited by 490
TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth.Preprint
Gao, X., & Pan, D. (2001) · Genes & Development · doi:10.1101/gad.901101 · Cited by 484
Scott, P., Brunn, G. J., Kohn, A. D., Roth, R. A., & Lawrence, J. C. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7772 · Cited by 482
Pearson, R. B., Dennis, P. B., Han, J. W., Williamson, N. A., Kozma, S. C., Wettenhall, R. E., & Thomas, G. (1995) · The EMBO Journal · doi:10.1002/j.1460-2075.1995.tb00212.x · Cited by 443
Wienecke, R., König, A., & DeClue, J. E. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.27.16409 · Cited by 357
Onda, H., Lueck, A., Marks, P. W., Warren, H. B., & Kwiatkowski, D. J. (1999) · Journal of Clinical Investigation · doi:10.1172/jci7319 · Cited by 349
Xiao, G., Shoarinejad, F., Jin, F., Golemis, E. A., & Yeung, R. S. W. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.10.6097 · Cited by 348
A role of the kinase mTOR in cellular transformation induced by the oncoproteins P3k and Akt
Aoki, M., Blazek, E., & Vogt, P. K. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.1.136 · Cited by 311
Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K
Kozma, S. C., & Thomas, G. (2002) · BioEssays · doi:10.1002/bies.10031 · Cited by 289
4E-BP1 and S6K1: translational integration sites for nutritional and hormonal information in muscle
Shah, O. J., Anthony, J. C., Kimball, S. R., & Jefferson, L. S. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.279.4.e715 · Cited by 286
Reynolds, T., Bodine, S. C., & Lawrence, J. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m201142200 · Cited by 268
gigas, a Drosophila Homolog of Tuberous Sclerosis Gene Product-2, Regulates the Cell Cycle
Ito, N., & Rubin, G. M. (1999) · Cell · doi:10.1016/s0092-8674(00)80657-1 · Cited by 258
Stocker, H., & Hafen, E. (2000) · Current Opinion in Genetics and Development · doi:10.1016/s0959-437x(00)00123-4 · Cited by 257
Benvenuto, G., Li, S., Brown, S. J., Braverman, R., Vass, W. C., Cheadle, J. P., Halley, D. J. J., Sampson, J. R., Wienecke, R., & DeClue, J. E. (2000) · Oncogene · doi:10.1038/sj.onc.1204009 · Cited by 253
Kobayashi, T., Minowa, O., Sugitani, Y., Takai, S., Mitani, H., Kobayashi, E., Noda, T., & Hino, O. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151033798 · Cited by 251
Multiple Independent Inputs Are Required for Activation of the p70 S6 Kinase
Weng, Q.-P., Andrabi, K. I., Kozlowski, M. T., Grove, J. R., & Avruch, J. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.5.2333 · Cited by 225
Miron, M., Verdú, J., Lachance, P. E. D., Birnbaum, M. J., Lasko, P. F., & Sonenberg, N. (2001) · Nature Cell Biology · doi:10.1038/35078571 · Cited by 221
Phenotypes of the Tuberous Sclerosis Complex with a Revision of Diagnostic Criteria
Gómez, M. R. (1991) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1991.tb37742.x · Cited by 204
dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1
Radimerski, T., Montagne, J., Rintelen, F., Stocker, H., KAAY, J. V. D., Downes, C. P., Hafen, E., & Thomas, G. (2002) · Nature Cell Biology · doi:10.1038/ncb763 · Cited by 190
PI 3-kinase, mTOR, protein synthesis and cancer
Vogt, P. K. (2001) · Trends in Molecular Medicine · doi:10.1016/s1471-4914(01)02161-x · Cited by 120
Germ-Line Mutational Analysis of the TSC2 Gene in 90 Tuberous-Sclerosis Patients
Au, K. S., Rodriguez, J. A., Finch, J. L., Volcik, K. A., Roach, E. S., Delgado, M. R., Rodriguez, E., & Northrup, H. (1998) · The American Journal of Human Genetics · doi:10.1086/301705 · Cited by 119
The genetic basis of tuberous sclerosis
Young, J., & Povey, S. (1998) · Molecular Medicine Today · doi:10.1016/s1357-4310(98)01245-3 · Cited by 109
The genetic control of organ growth: insights from Drosophila
Weinkove, D., & Leevers, S. J. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)00042-8 · Cited by 103
Cited by
Sorted by citations
mTOR 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
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227
Self-citationAKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
TSC2 Mediates Cellular Energy Response to Control Cell Growth and Survival
Inoki, K., Zhu, T., & Guan, K.-L. (2003) · Cell · doi:10.1016/s0092-8674(03)00929-2 · Cited by 3,914
Self-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
Metadata
- Authors
- Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Guan, Kun-Liang
- Venue
- Nature Cell Biology
- Published
- 2002-08-12
- Volume
- 4
- Issue
- 9
- Pages
- 648-657
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2011282245
- Cited by
- 3,083
- References
- 50
- Citations by year
- 2026: 64 · 2025: 77 · 2024: 101 · 2023: 115 · 2022: 121 · 2021: 139 · 2020: 136 · 2019: 111 · 2018: 131 · 2017: 148 · 2016: 143 · 2015: 180 · 2014: 161 · 2013: 159 · 2012: 168
- FWCI
- 34.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Genetics (clinical) › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TSC2, tuberous sclerosis complex, TSC1/TSC2 complex, Akt phosphorylation, mTOR signaling, 4E-BP1, translational regulation, insulin signaling, tumor suppression, protein stability, cell growth inhibition
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Binding Sites, Carrier Proteins, Cell Line, Humans, Insulin, Models, Biological, Mutation, Phosphoproteins, Phosphorylation, Protein Kinases, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Tuberous Sclerosis, Signal Transduction, Genes, Tumor Suppressor, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Ribosomal Protein S6 Kinases, Tumor Suppressor Proteins, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, 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
