Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins

@article{Zhang2003RhebIA,
  title={Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins},
  author={Yong Zhang and Xinsheng Gao and Leslie J. Saucedo and Bing-gen Ru and Bruce A. Edgar and Duojia Pan},
  journal={Nature Cell Biology},
  year={2003},
  volume={5},
  pages={578-581}
}
Mutations in the TSC1 or TSC2 genes cause tuberous sclerosis, a benign tumour syndrome in humans. Tsc2 possesses a domain that shares homology with the GTPase-activating protein (GAP) domain of Rap1-GAP, suggesting that a GTPase might be the physiological target of Tsc2. Here we show that the small GTPase Rheb (Ras homologue enriched in brain) is a direct target of Tsc2 GAP activity both in vivo and in vitro. Point mutations in the GAP domain of Tsc2 disrupted its ability to regulate Rheb… 
Non-canonical functions of the tuberous sclerosis complex-Rheb signalling axis
TLDR
It is proposed that there are clinically relevant functions and targets of TSC1, TSC2 and Rheb, which are independent of mTOR, and presented evidence that such non‐canonical functions of the TSC‐Rheb signalling network exist.
Rheb Binds Tuberous Sclerosis Complex 2 (TSC2) and Promotes S6 Kinase Activation in a Rapamycin- and Farnesylation-dependent Manner*
TLDR
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3 Antagonists of the TOR pathway in animal cells
TLDR
Genetic and biochemical studies in Drosophila further identified Rheb, a member of the Ras superfamily GTPases, as a direct target of the GAP activity of Tsc2 that functions between Tsc1/Tsc2 and TOR.
Biochemical and Functional Characterizations of Small GTPase Rheb and TSC2 GAP Activity
TLDR
It is demonstrated that GAP activity is essential for the cellular function of TSC2 to inhibit S6 kinase (S6K) phosphorylation.
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TLDR
Developments in Drosophila provide enhanced understanding of this signaling pathway and fundamental insights into the pathogenesis of tuberous sclerosis, and open the possibility of treatment for hamartomas by several pharmacologic approaches.
Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways.
TLDR
In the absence of either TSC1 or TSC2, high levels of Rheb-GTP lead to constitutive activation of mTOR-raptor signaling, thereby leading to enhanced and deregulated protein synthesis and cell growth.
Characterization of a Variant of Tuberous Sclerosis Complex 2 and its Interaction with Rheb
TLDR
The D74A variant of TSC2 showed to maintain protein stability (thermal and chemical), an increase in secondary (alpha helical) structure, binding and GAP activity towards Rheb, and the effects of the single point mutation on the interactions with RheB are characterized.
Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations.
TLDR
It is shown that the N-terminal half of yeast TSC1 forms a protease-resistant domain, which is evolutionarily conserved, and indicates that the disruption of the T SC1-NTD globular structure is a major cause of tuberous sclerosis.
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References

SHOWING 1-10 OF 21 REFERENCES
The Tuberous Sclerosis 2 Gene Product, Tuberin, Functions as a Rab5 GTPase Activating Protein (GAP) in Modulating Endocytosis*
TLDR
It is suggested that tuberin functions as a Rab5GAP in vivo to negatively regulate Rab5-GTP activity in endocytosis in TSC2 mutant cells.
The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis.
TLDR
The region of homology between tuberin and human rap1GAP and the murine GAP mSpa1 is more extensive than previously reported and spans approximately 160 amino acid residues encoded within exons 34-38 of the TSC2 gene.
TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth.
TLDR
It is found that the heterozygosity of TSC1 or TSC2 is sufficient to rescue the lethality of loss-of-function insulin receptor mutants and genetic analyses suggest that the TSC genes act in a parallel pathway that converges on the insulin pathway downstream from Akt.
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
TLDR
It is shown that TSC1–TSC2 inhibits the p70 ribosomal protein S6 kinase 1 and activates the eukaryotic initiation factor 4E binding protein 1 (4E-BP1, an inhibitor of translational initiation) and these functions are mediated by inhibition of the mammalian target of rapamycin (mTOR).
Identification of Tuberin, the Tuberous Sclerosis-2 Product. TUBERIN POSSESSES SPECIFIC Rap1GAP ACTIVITY (*)
TLDR
It is suggested that the loss of tuberin leads to constitutive activation of Rap1 in tumors of patients with tuberous sclerosis.
Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.
TLDR
Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation was seen in six apparently unrelated patients, which suggests that hamartin acts as a tumor suppressor.
Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling.
TLDR
It is demonstrated that reducing dS6K signaling rescues early larval lethality associated with loss of dTsc1/2 function, arguing that the S6K pathway is a promising target for the treatment of TSC.
Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling
TLDR
Hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1), which strongly implicate the tuberin-hamartin tumor suppressor complex as an inhibitor of mTOR.
Rheb is an essential regulator of S6K in controlling cell growth in Drosophila
TLDR
The genetic and biochemical analyses suggest that Rheb functions downstream of the tumour suppressors Tsc1–Tsc2 in the TOR signalling pathway to control growth, and that a major effector of RheB function is ribosomal S6 kinase (S6K).
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