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A complex interplay between Akt, TSC2 and the two mTOR complexes
Open accessAbstract
Akt/PKB (protein kinase B) both regulates and is regulated by the TSC (tuberous sclerosis complex) 1–TSC2 complex. Downstream of PI3K (phosphoinositide 3-kinase), Akt phosphorylates TSC2 directly on multiple sites. Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1–TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors. Through negative-feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumours lacking the TSC1–TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1–TSC2 complex has recently been uncovered. The growth-factor-stimulated kinase activity of mTORC2 [also known as the mTOR–rictor (rapamycin-insensitive companion of mTOR) complex], which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser473), was found to be defective in cells lacking the TSC1–TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1–TSC2 complex on Rheb and mTORC1. The present review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1–TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.
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“TSCC is phosphorylated by many kinases, each of which contributes either activating or inhibiting modifications under various environmental conditions, including S6K1, cyclin-dependent kinase 1 (CDK1), AMPK and Akt, which is itself activated by mTORC2 (Huang and Manning, 2009).”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Huang and Manning, 2009
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Cites
Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
Sarbassov, D. D., Guertin, D. A., Ali, S. M., & Sabatini, D. M. (2005) · Science · doi:10.1126/science.1106148 · Cited by 6,216
AKT/PKB signaling: navigating downstream
Manning, B. D., & Cantley, L. C. (2007) · Cell · doi:10.1016/j.cell.2007.06.009 · Cited by 6,115
Self-citationTOR signaling in growth and metabolism
Wullschleger, S., Loewith, R., & Hall, M. N. (2006) · Cell · doi:10.1016/j.cell.2006.01.016 · Cited by 5,787
Upstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
Engelman, J. A., Luo, J., & Cantley, L. C. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1879 · Cited by 3,330
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083
Mechanism of activation of protein kinase B by insulin and IGF‐1.
Alessi, D. R., Andjelković, M., Caudwell, B., Cron, P. D., MORRICE, N. A., Cohen, P., & Hemmings, B. A. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01045.x · Cited by 3,014
Alessi, D. R., James, S. R., Downes, C. P., Holmes, A. B., Gaffney, P. R. J., Reese, C. B., & Cohen, P. (1997) · Current Biology · doi:10.1016/s0960-9822(06)00122-9 · Cited by 2,874
Sarbassov, D. D., Ali, S. M., Kim, D.-H., Guertin, D. A., Latek, R. R., Erdjument-Bromage, H., Tempst, P., & Sabatini, D. M. (2004) · Current Biology · doi:10.1016/j.cub.2004.06.054 · Cited by 2,665
Prolonged Rapamycin Treatment Inhibits mTORC2 Assembly and Akt/PKB
Sarbassov, D. D., Ali, S. M., Sengupta, S., Sheen, J.-H., Hsu, P. P., Bagley, A. F., Markhard, A. L., & Sabatini, D. M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.029 · Cited by 2,365
The Tuberous Sclerosis Complex
Crino, P. B., Nathanson, K. L., & Henske, E. P. (2006) · New England Journal of Medicine · doi:10.1056/nejmra055323 · Cited by 1,793
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555
Self-citationGuertin, D. A., Stevens, D. M., Thoreen, C. C., Burds, A. A., Kalaany, N. Y., Moffat, J., Brown, M., Fitzgerald, K. J., & Sabatini, D. M. (2006) · Developmental Cell · doi:10.1016/j.devcel.2006.10.007 · Cited by 1,467
Fingar, D. C., & Blenis, J. (2004) · Oncogene · doi:10.1038/sj.onc.1207542 · Cited by 1,264
The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Huang, J., & Manning, B. D. (2008) · Biochemical Journal · doi:10.1042/bj20080281 · Cited by 1,237 · cited 3×
“majority of published experiments, phosphorylation of these sites does not affect the association between TSC1 and TSC2 (reviewed in [16].”
BackgroundInfluentialSelf-citationThe TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins
Harrington, L. S., Findlay, G. M., Gray, A., Толкачева, Т. А., Wigfield, S., Rebholz, H., Barnett, J., Leslie, N. R., Cheng, S., Shepherd, P. R., et al. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200403069 · Cited by 1,123
Akt regulates growth by directly phosphorylating Tsc2
Potter, C. J., Pedraza, L. G., & Xu, T. (2002) · Nature Cell Biology · doi:10.1038/ncb840 · Cited by 959
Shah, O. J., Wang, Z., & Hunter, T. R. (2004) · Current Biology · doi:10.1016/j.cub.2004.08.026 · Cited by 800
DeYoung, M. P., Horak, P., Sofer, A., Sgroi, D., & Ellisen, L. W. (2008) · Genes & Development · doi:10.1101/gad.1617608 · Cited by 710
mSin1 Is Necessary for Akt/PKB Phosphorylation, and Its Isoforms Define Three Distinct mTORC2s
Frías, M. A., Thoreen, C. C., Jaffe, J. D., Schroder, W. A., Sculley, T. B., Carr, S. A., & Sabatini, D. M. (2006) · Current Biology · doi:10.1016/j.cub.2006.08.001 · Cited by 690
Kwiatkowski, D. J. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.525 · Cited by 674
Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling
Ikenoue, T., Inoki, K., Yang, Q., Zhou, X., & Guan, K. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.119 · Cited by 605
Facchinetti, V., Ouyang, W., Wei, H., Soto, N., Lazorchak, A. S., Gould, C. M., Lowry, C. J., Newton, A. C., Mao, Y., Miao, Q., et al. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.120 · Cited by 527
Akt/Protein Kinase B Is Regulated by Autophosphorylation at the Hypothetical PDK-2 Site
Toker, A., & Newton, A. C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8271 · Cited by 522
The TSC1-TSC2 Complex Is Required for Proper Activation of mTOR Complex 2
Huang, J., Dibble, C. C., Matsuzaki, M., & Manning, B. D. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.00289-08 · Cited by 520
Self-citationManning, B. D. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200408161 · Cited by 485
Self-citationRheb fills a GAP between TSC and TOR
Manning, B. (2003) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2003.09.003 · Cited by 483
Self-citationTran, H. G., Brunet, A., Griffith, E. C., & Greenberg, M. E. (2003) · Science Signaling · doi:10.1126/stke.2003.172.re5 · Cited by 466
PKBα/Akt1 Acts Downstream of DNA-PK in the DNA Double-Strand Break Response and Promotes Survival
Bozulic, L., Sürücü, B., Hynx, D., & Hemmings, B. A. (2008) · Molecular Cell · doi:10.1016/j.molcel.2008.02.024 · Cited by 397
Restraining PI3K: mTOR signalling goes back to the membrane
Harrington, L. S., Findlay, G. M., & Lamb, R. F. (2004) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2004.11.003 · Cited by 369
Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning
Cai, S.-L., Tee, A. R., Short, J. D., Bergeron, J. M., Kim, J., Shen, J., Guo, R., Johnson, C. L., Kiguchi, K., & Walker, C. L. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507119 · Cited by 359
S6K1 Regulates GSK3 under Conditions of mTOR-Dependent Feedback Inhibition of Akt
Zhang, H. H., Lipovsky, A. I., Dibble, C. C., Şahin, M., & Manning, B. D. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.09.019 · Cited by 309
Self-citationFeedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2Preprint
Manning, B. D., Logsdon, M. N., Lipovsky, A. I., Abbott, D. W., Kwiatkowski, D. J., & Cantley, L. C. (2005) · Genes & Development · doi:10.1101/gad.1314605 · Cited by 236
Self-citationFOXO-regulated transcription restricts overgrowth of Tsc mutant organs
Harvey, K. F., Mattila, J., Sofer, A., Bennett, F. C., Ramsey, M. R., Ellisen, L. W., Puig, Ó., & Hariharan, I. K. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200710100 · Cited by 45
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Watterson, K. R., Bestow, D., Gallagher, J. R., Hamilton, D. L., Ashford, F. B., Meakin, P. J., & Ashford, M. L. J. (2012) · Neurosignals · doi:10.1159/000334144 · Cited by 3,395
Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks
Alers, S., Löffler, A. S., Wesselborg, S., & Stork, B. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.06159-11 · Cited by 1,483
mTOR signaling: At the crossroads of plasticity, memory and disease
Hoeffer, C. A., & Klann, E. (2010) · Trends in Neurosciences · doi:10.1016/j.tins.2009.11.003 · Cited by 1,128
Heras-Sandoval, D., Pérez-Rojas, J. M., Hernández-Damián, J., & Pedraza-Chaverri, J. (2014) · Cellular Signalling · doi:10.1016/j.cellsig.2014.08.019 · Cited by 1,091
The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review
Sun, K., Luo, J., Guo, J., Yao, X., Jing, X., & Guo, F. (2020) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2020.02.027 · Cited by 685
Metadata
- Authors
- Huang, J., & Manning, B. D.
- Affiliations
- Harvard University (US)
- Corresponding author
- Manning, Brendan D.
- Venue
- Biochemical Society Transactions
- Publisher
- Portland Press Ltd.
- Published
- 2009-01-20
- Volume
- 37
- Issue
- 1
- Pages
- 217-222
- ISSN
- 0300-5127 (ISSN-L)
- 1470-8752
- PMC
- PMC2778026
- OpenAlex
- W2065322400
- Cited by
- 724
- References
- 35
- Citations by year
- 2026: 17 · 2025: 18 · 2024: 21 · 2023: 22 · 2022: 31 · 2021: 31 · 2020: 37 · 2019: 40 · 2018: 49 · 2017: 40 · 2016: 38 · 2015: 53 · 2014: 60 · 2013: 51 · 2012: 67
- FWCI
- 5.25
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Society Transactions (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA122617, P01CA120964)
- 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
- Akt, TSC1/TSC2 complex, tuberous sclerosis complex, mTORC1, mTORC2, PI3K signaling, Rheb, Akt phosphorylation, negative feedback regulation, growth factor signaling, tumor growth
- MeSH terms
- Tuberous Sclerosis Complex 2 Protein, Animals, Humans, Protein Kinases, Transcription Factors, Phosphatidylinositol 3-Kinases, Feedback, Physiological, Tumor Suppressor Proteins, Proto-Oncogene Proteins c-akt, TOR Serine-Threonine Kinases
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