ArticleMolecular and cellular biology2004
Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity.
Article in Molecular and cellular biology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 126 papers.
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Who cites it
126 citing papers in PubMed, 246 citations in OpenAlex.
- Drug resistant epilepsy driven byEpilepsy & behavior reports · 2026Article
- HUWE1 stimulates mTORC1 activity by enhancing Rheb interaction with mTORC1 and supports de novo pyrimidine synthesis.Cell reports · 2025Article
- Global conformation of the Rag GTPase heterodimer governs eukaryotic amino acid sensing.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Article
- The role and mechanism of TSC in kidney diseases: a literature review.BMC nephrology · 2025Review
- Lysosomal EGFR acts as a Rheb-GEF independent of its kinase activity to activate mTORC1.Cell research · 2025Article
- Unraveling the Binding Mode of TSC2-Rheb through Protein Docking and Simulations.Biochemistry · 2025Article
- Calmodulin enhances mTORC1 signaling by preventing TSC2-Rheb binding.The Journal of biological chemistry · 2025Article
- Molecular Mechanisms Underlying Initiation and Activation of Autophagy.Biomolecules · 2024Review
- Review
- IL-37d suppresses Rheb-mTORC1 axis independently of TCS2 to alleviate alcoholic liver disease.Communications biology · 2024Article
- Regulation of TSC2 lysosome translocation and mitochondrial turnover by TSC2 acetylation status.Scientific reports · 2024Article
- The rapid proximity labeling system PhastID identifies ATP6AP1 as an unconventional GEF for Rheb.Cell research · 2024Article
- Negative Regulation of Autophagy during Macrophage Infection byInternational journal of molecular sciences · 2024Article
- Rheb1 is required for limb growth through regulating chondrogenesis in growth plate.Cell and tissue research · 2024Article
- STAT3 protects dopaminergic neurons against degeneration in animal model of Parkinson's disease.Brain research · 2024Article
- Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.International journal of molecular sciences · 2024Review
- Mechanism-Based Redesign of GAP to Activate Oncogenic Ras.Journal of the American Chemical Society · 2023Article
- Structure of the Schizosaccharomyces pombe Gtr-Lam complex reveals evolutionary divergence of mTORC1-dependent amino acid sensing.Structure (London, England : 1993) · 2023Article
- Redundant electrostatic interactions between GATOR1 and the Rag GTPase heterodimer drive efficient amino acid sensing in human cells.The Journal of biological chemistry · 2023Article
66 more citing papers are in PubMed but not listed here.
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
Tuberous sclerosis complex (TSC) is a genetic disease caused by a mutation in either the tsc1 or tsc2 tumor suppressor gene. Recent studies have demonstrated that TSC2 displays GAP (GTPase-activating protein) activity specifically towards the small G protein Rheb and inhibits its ability to stimulate the mTOR signaling pathway. Rheb and TSC2 comprise a unique pair of GTPase and GAP, because Rheb has high basal GTP levels and TSC2 does not have the catalytic arginine finger found in Ras-GAP. To investigate the function of TSC2 and Rheb in mTOR signaling, we analyzed the TSC2-stimulated Rheb GTPase activity. We found that Arg15, a residue equivalent to Gly12 in Ras, is important for Rheb to function as a substrate for TSC2 GAP. In addition, we identified asparagine residues essential for TSC2 GAP activity. We demonstrated a novel catalytic mechanism of the TSC2 GAP and Rheb that TSC2 uses a catalytic "asparagine thumb" instead of the arginine finger found in Ras-GAP. Furthermore, we discovered that farnesylation and membrane localization of Rheb is not essential for Rheb to stimulate S6 kinase (S6K) phosphorylation. Analysis of TSC1 binding defective mutants of TSC2 shows that TSC1 is not required for the TSC2 GAP activity but may function as a regulatory component in the TSC1/TSC2 complex. Our data further demonstrate that GAP activity is essential for the cellular function of TSC2 to inhibit S6K phosphorylation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.