Cited by 828PI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex ResearchMetabolism, Diabetes, and Cancer

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Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling

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Tee, Andrew R., Fingar, Diane C., Manning, Brendan D., Kwiatkowski, David J., Cantley, Lewis C., Blenis, John·2002·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.202476899PMC PMC129715

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Abstract

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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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: Tee, Andrew R.
Fingar, Diane C.
Manning, Brendan D.
Kwiatkowski, David J.
Cantley, Lewis C.
Blenis, John
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
DOI: 10.1073/pnas.202476899
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 › Genetics (clinical) › 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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Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling

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