Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Open accessAbstract
Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2 . The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.
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The TSC complex acts as a GTPase activating protein for Rheb, employing a GAP domain within the TSC2 subunit.
“The TSC complex (TSCC) acts as a GTPase activating protein (GAP) for Rheb, employing a GAP domain within the TSC2 subunit”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Inoki et al., 2003
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- Authors
- Inoki, K., Li, Y., Xu, T., & Guan, K.-L.
- Affiliations
- University of Michigan (US)
- Howard Hughes Medical Institute (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-07-17
- Volume
- 17
- Issue
- 15
- Pages
- 1829-1834
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC196227
- OpenAlex
- W2056137479
- Cited by
- 1,911
- References
- 34
- Citations by year
- 2026: 44 · 2025: 68 · 2024: 75 · 2023: 78 · 2022: 72 · 2021: 107 · 2020: 103 · 2019: 73 · 2018: 97 · 2017: 112 · 2016: 111 · 2015: 127 · 2014: 92 · 2013: 101 · 2012: 94
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (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 › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Keywords
- TSC2, GTPase-activating protein, mTOR signaling, tuberous sclerosis complex, S6K phosphorylation, 4E-BP1 phosphorylation, rapamycin, nutrient signaling, cellular energy status, cell growth regulation, Ras family GTPases
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Antibiotics, Antineoplastic, Cell Division, Cell Line, Dose-Response Relationship, Drug, Genes, Dominant, Guanosine Triphosphate, Humans, Hydrolysis, Models, Biological, Mutation, Neuropeptides, Phosphorylation, Plasmids, Protein Binding, Protein Kinases, Proteins, Repressor Proteins, Time Factors, Protein Biosynthesis, Signal Transduction, Protein Structure, Tertiary, Sirolimus, GTP Phosphohydrolases, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, TOR Serine-Threonine Kinases
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