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Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner
Open accessAbstract
Recently the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product has been identified as a negative regulator of protein synthesis upstream of the mTOR and ribosomal S6 kinases. Because of the homology of TSC2 with GTPase-activating proteins for Rap1, we examined whether a Ras/Rap-related GTPase might be involved in this process. TSC2 was found to bind to Rheb-GTP in vitro and to reduce Rheb GTP levels in vivo. Over-expression of Rheb but not Rap1 promoted the activation of S6 kinase in a rapamycin-dependent manner, suggesting that Rheb acts upstream of mTOR. The ability of Rheb to induce S6 phosphorylation was also inhibited by a farnesyl transferase inhibitor, suggesting that Rheb may be responsible for the Ras-independent anti-neoplastic properties of this drug.
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In the citing paper
“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 Castro et al., 2003
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 Castro et al., 2003
In the citing paper
“Despite a lack of clear experimental evidence pointing to a defined localization pattern, Rheb is known to function on endomembranes in the mTORC1 pathway as a potent activator of the kinase (Long et al., 2005; Sato et al., 2009) and is the physiologic target of TSC2 (Castro et al., 2003; Garami et al., 2003; Inoki et al., 2003; Saucedo et al., 2003; Stocker et al., 2003; Tee et al., 2003; Zhang e”
From Signal integration in the (m)TORC1 growth pathway (2018) · cites this paper as Castro et al., 2003
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RetractedTSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
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Metadata
- Authors
- Castro, A. F., Rebhun, J. F., Clark, G. J., & Quilliam, L. A.
- Affiliations
- Indiana University School of Medicine (US)
- National Institutes of Health (US)
- Corresponding author
- Castro, Ariel F.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-08
- Volume
- 278
- Issue
- 35
- Pages
- 32493-32496
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1977747566
- Cited by
- 381
- References
- 46
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 10 · 2023: 15 · 2022: 10 · 2021: 14 · 2020: 15 · 2019: 4 · 2018: 9 · 2017: 3 · 2016: 9 · 2015: 13 · 2014: 17 · 2013: 17 · 2012: 20
- FWCI
- 11.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- 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 › Protein Kinase Regulation and GTPase Signaling
- Keywords
- Rheb, tuberous sclerosis complex 2, TSC2, mTOR, rapamycin, farnesylation, farnesyltransferase inhibitors, GTPase-activating protein, protein synthesis regulation, tumor suppressor
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 2 Protein, Antineoplastic Agents, Cell Line, Enzyme Activation, Humans, Neuropeptides, Phosphorylation, Plasmids, Protein Binding, Protein Kinases, Repressor Proteins, Immunoblotting, Gene Expression Regulation, Enzymologic, Protein Prenylation, Ribosomal Protein S6 Kinases, Sirolimus, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, TOR Serine-Threonine Kinases
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