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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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In the citing paper
“mTORC1-TFEB signaling governs lysosomal biogenesis (Laplante and Sabatini 2012), (Inoki et al. 2003), (Tee et al. 2003), (Sardiello et al. 2009), (Settembre et al. 2012), (Settembre et al. 2013), (Sardiello et al. 2009), (Martina et al. 2014), and TFEB targets include several genes, including MCOLN1 (Nnah et al. 2019).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Inoki et al. 2003
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“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
In the citing paper
“Activation of mTORC1 by Rheb downstream of growth-factor signaling (Inoki et al. 2003), (Tee et al. 2003), controls lysosomal and autophagosome biogenesis via TFEB and the CLEAR gene network (Sardiello et al. 2009), (Settembre et al. 2012).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Inoki et al. 2003
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“…family GTPase,), and Pdia3 (protein disulfide isomerase family A member 3, also known as ERp57), an activator of the mTORC1 complex (Ram ırez et al. 2011), and Ras homolog enriched in brain (Rheb), a GTPase and key activator of mTORC1 that is inhibited by the Tsc1-Tsc2 complex (Inoki et al. 2003).”
BackgroundInfluentialAMP-activated protein kinase is physiologically regulated by inositol polyphosphate multikinase
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Metadata
- 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 › Genetics (clinical) › 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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