The DOI matches its Crossref record; 34 of the 35 references it cites were found in a registry or an index.
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.
Overview
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
Verification
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?
In the citing paper
“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
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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
Flagged first, then by citations
1 of the 35 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Items 701–723 of 723
Navas-Pérez, E., Vicente-García, C., Mirra, S., Burguera, D., Fernàndez‐Castillo, N., Ferrán, J. L., López-Mayorga, M., Alaiz-Noya, M., Suárez‐Pereira, I., Antón-Galindo, E., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13142471
Hesari, M., Shackebaei, D., Mohammadi, P., Miraghaee, S., Yari, K., Haghighi, Z. M. S., Majnooni, M. B., & Yarmohammadi, F. (2026) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-026-02000-8
Alam, T., & Akther, S. (2026) · PLoS ONE · doi:10.1371/journal.pone.0343189
Jin, Z., Zhu, S., Wang, C., Wang, T., Liu, J., & Wu, Y. (2026) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2026.106909
Ferroptosis mechanisms in early brain injury after subarachnoid hemorrhage
Du, W., Chen, J., Cheng, G., Yang, Y., Shi, Y., & Wang, Y.-H. (2026) · Brain Research · doi:10.1016/j.brainres.2026.150257
Papazoglou, I. (2013) · theses.fr (ABES) · doi:10.70675/06d278b5zf0a0z456dz9c4cz9dc680b45fd3 · Cited by 1
Amine, H. (2016) · theses.fr (ABES) · doi:10.70675/8fc153dfzc95cz4209zabf7z1567442c940d
Rôle de la calréticuline dans les néoplasmes myéloprolifératifs
El-Khoury, M. (2016) · theses.fr (ABES) · doi:10.70675/e4cbd01dz8d78z44f3zad7dzfa7300e6a7c6
Cousin, C. (2014) · theses.fr (ABES) · doi:10.70675/41ccd5b2za7faz4a5fzb045z8c5ebadb4250
Sex differences in response to longevity interventions
Hajdarovic, K. H., Riddle, N. C., & Webb, A. E. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103123 · Cited by 1
Tuberous sclerosis complex : molecular target of mTORC1 and the role of S6Ks
Bonucci, M. (2019) · theses.fr (ABES) · doi:10.70675/fd5e0059z9c7bz468ezb8bdz4c2214da80c2
Modulation de l'autophagie neuronale par la sérine protéase tPA en conditions ischémiques
Thiebaut, A. M. (2019) · theses.fr (ABES) · doi:10.70675/6586c0abz9e4cz455fz95ffzc52ec76397f8
Low protein diet induced anti-cancer immune response
Bossowski, J. P. (2018) · theses.fr (ABES) · doi:10.70675/df1b8a94z84ccz47d6z9b67zcd24191657d6
Exploration of the mechanism of lipid droplets regulating animal adipose tissue thermogenesis
Feng, F., Gao, X., Gun, S., & Yang, Q. (2026) · Journal of Thermal Biology · doi:10.1016/j.jtherbio.2026.104487
An aging hallmark, Alzheimer's disease, and APOE nexus
Gabrielli, A. P., Weidling, I. W., Lysaker, C. R., Novikova, L., Ranjan, A., Wang, X., Wilkins, H., & Swerdlow, R. H. (2026) · Journal of Alzheimer s Disease · doi:10.1177/13872877261452598
Orchestration of Autophagy and Senescence: Kinases Take the Center Stage
Basu, A. (2026) · Cells · doi:10.3390/cells15131176
Arora, I., Rath, S., Jamal, Q. M. S., Aljohani, A., Hamid, A., Abu-Zaid, A., Khan, M. I., & Yaqinuddin, A. (2026) · Cells · doi:10.3390/cells15211997
Cooperating Events in Core Binding Factor Leukemia Development: A Dissertation
Madera, D. (2011) · The Journal of the American Medical Association (JAMA) Network (American Medical Association) · doi:10.13028/k9gj-gr76
Novel Regulation of mTOR Complex 1 Signaling by Site-Specific mTOR Phosphorylation.
Üstünel, B. E. (2012) · Deep Blue (University of Michigan)
The Senescent Cell Induced Bystander Effect
Wordsworth, J. (2014)
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
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
