Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner
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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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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 Castro et al., 2003
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 Castro et al., 2003
Rheb is known to function on endomembranes in the mTORC1 pathway as a potent activator of the kinase and is the physiologic target of TSC2.
“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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- 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 › Physiology › 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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