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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.
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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
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Regulation of 4E-BP1 phosphorylation: a novel two-step mechanismPreprint
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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
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