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, CDK1, AMPK and Akt, which is itself activated by mTORC2.
“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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- 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 › Physiology › 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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