Insulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2
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Tumor suppressor genes evolved as negative effectors of mitogen and nutrient signaling pathways, such that mutations in these genes can lead to pathological states of growth. Tuberous sclerosis (TSC) is a potentially devastating disease associated with mutations in two tumor suppressor genes, TSC1 and 2, that function as a complex to suppress signaling in the mTOR/S6K/4E-BP pathway. However, the inhibitory target of TSC1/2 and the mechanism by which it acts are unknown. Here we provide evidence that TSC1/2 is a GAP for the small GTPase Rheb and that insulin-mediated Rheb activation is PI3K dependent. Moreover, Rheb overexpression induces S6K1 phosphorylation and inhibits PKB phosphorylation, as do loss-of-function mutations in TSC1/2, but contrary to earlier reports Rheb has no effect on MAPK phosphorylation. Finally, coexpression of a human TSC2 cDNA harboring a disease-associated point mutation in the GAP domain, failed to stimulate Rheb GTPase activity or block Rheb activation of S6K1.
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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 Garami et al., 2003
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- Authors
- Garami, A., Zwartkruis, F. J. T., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S. C., Hafen, E., Bos, J. L., & Thomas, G.
- Affiliations
- Friedrich Miescher Institute (CH)
- Utrecht University (NL)
- University of Zurich (CH)
- Corresponding author
- Thomas, George
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 11
- Issue
- 6
- Pages
- 1457-1466
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2082853003
- Cited by
- 1,043
- References
- 60
- Citations by year
- 2026: 9 · 2025: 28 · 2024: 24 · 2023: 31 · 2022: 28 · 2021: 55 · 2020: 45 · 2019: 28 · 2018: 41 · 2017: 34 · 2016: 37 · 2015: 47 · 2014: 31 · 2013: 64 · 2012: 60
- FWCI
- 23.37
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- 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, TSC1, TSC2, tuberous sclerosis complex, insulin signaling, GTPase-activating protein, phosphatidylinositol 3-kinase, S6K1 phosphorylation, Akt phosphorylation, MAPK signaling, tumor suppressor
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Animals, Carrier Proteins, Cell Line, Chlorocebus aethiops, HeLa Cells, Humans, Insulin, Neuropeptides, Phosphoproteins, Protein Kinases, Proteins, Repressor Proteins, Tumor Cells, Cultured, Signal Transduction, Genes, Tumor Suppressor, Point Mutation, Protein Structure, Tertiary, Cell Cycle Proteins, COS Cells, Phosphatidylinositol 3-Kinases, Ribosomal Protein S6 Kinases, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, TOR Serine-Threonine Kinases
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