Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling
Open accessAbstract
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1). First, coexpression of hamartin and tuberin repressed phosphorylation of 4E-BP1, resulting in increased association of 4E-BP1 with eIF4E; importantly, a mutant of TSC2 derived from TSC patients was defective in repressing phosphorylation of 4E-BP1. Second, the activity of S6K1 was repressed by coexpression of hamartin and tuberin, but the activity of rapamycin-resistant mutants of S6K1 were not affected, implicating mTOR in the TSC-mediated inhibitory effect on S6K1. Third, hamartin and tuberin blocked the ability of amino acids to activate S6K1 within nutrient-deprived cells, a process that is dependent on mTOR. These findings strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR and suggest that the formation of tumors within TSC patients may result from aberrantly high levels of mTOR-mediated signaling to downstream targets.
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Loss of the TSC1-TSC2 protein complex leads to hyperactivation of mTOR complex 1 (mTORC1).
“Loss of the TSC1–TSC2 protein complex leads to hyperactivation of mTOR complex 1 (mTORC1)18, a key signalling node that regulates cellular anabolic and catabolic processes19.”
From mTORC1 drives cell-autonomous astrocyte reactivity in tuberous sclerosis (2026) · cites this paper as [18]
The integration of the majority of external and survival signals feeding into the (m)TORC1 pathway occurs through the TSC complex (TSCC), composed of TSC1, TSC2, and TBC1D7, which is the key signal integrator and negative regulator upstream of Rheb.
“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 Tee et al., 2002
TSC1-TSC2 were unequivocally identified as inhibitors of the mTORC1 signaling pathway, specifically by virtue of TSC2 GAP activity toward the small GTPase Rheb.
“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 Tee et al., 2002
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- Authors
- Tee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J.
- Affiliations
- Brigham and Women's Hospital (US)
- Corresponding author
- Blenis, John
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2002-09-23
- Volume
- 99
- Issue
- 21
- Pages
- 13571-13576
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC129715
- OpenAlex
- W2087812126
- Cited by
- 827
- References
- 31
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 17 · 2023: 27 · 2022: 29 · 2021: 35 · 2020: 40 · 2019: 22 · 2018: 37 · 2017: 35 · 2016: 31 · 2015: 45 · 2014: 28 · 2013: 43 · 2012: 42
- FWCI
- 17.27
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-08-09)
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM 41890, GM51405, R01GM056203, GM 56203, R01GM051405, R01GM041890, R37GM041890)
- 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
- tuberous sclerosis complex, TSC1, TSC2, hamartin, tuberin, mTOR signaling, 4E-BP1, S6K1, amino acid signaling, nutrient deprivation, rapamycin resistance, protein phosphorylation, eIF4E, tumor formation
- MeSH terms
- Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Amino Acids, Carrier Proteins, Cell Line, Humans, Insulin, Models, Biological, Phosphoproteins, Phosphorylation, Protein Kinases, Proteins, Repressor Proteins, Tuberous Sclerosis, Signal Transduction, Point Mutation, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, TOR Serine-Threonine Kinases, In Vitro Techniques
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