The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Open accessAbstract
Tuberous sclerosis complex (TSC) is a genetic disease caused by mutation in either TSC1 or TSC2 . The TSC1 and TSC2 gene products form a functional complex and inhibit phosphorylation of S6K and 4EBP1. These functions of TSC1/TSC2 are likely mediated by mTOR. Here we report that TSC2 is a GTPase-activating protein (GAP) toward Rheb, a Ras family GTPase. Rheb stimulates phosphorylation of S6K and 4EBP1. This function of Rheb is blocked by rapamycin and dominant-negative mTOR. Rheb stimulates the phosphorylation of mTOR and plays an essential role in regulation of S6K and 4EBP1 in response to nutrients and cellular energy status. Our data demonstrate that Rheb acts downstream of TSC1/TSC2 and upstream of mTOR to regulate cell growth.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“mTORC1-TFEB signaling governs lysosomal biogenesis (Laplante and Sabatini 2012), (Inoki et al. 2003), (Tee et al. 2003), (Sardiello et al. 2009), (Settembre et al. 2012), (Settembre et al. 2013), (Sardiello et al. 2009), (Martina et al. 2014), and TFEB targets include several genes, including MCOLN1 (Nnah et al. 2019).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Inoki et al. 2003
Experimental — accuracy not yet measuredIn 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 Inoki et al., 2003
In the citing paper
“Activation of mTORC1 by Rheb downstream of growth-factor signaling (Inoki et al. 2003), (Tee et al. 2003), controls lysosomal and autophagosome biogenesis via TFEB and the CLEAR gene network (Sardiello et al. 2009), (Settembre et al. 2012).”
From TMEM55B downregulation promotes neurodegeneration in Alzheimer’s disease models (2026) · cites this paper as Inoki et al. 2003
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083
Self-citationeIF4 Initiation Factors: Effectors of mRNA Recruitment to Ribosomes and Regulators of Translation
Gingras, A., Raught, B., & Sonenberg, N. (1999) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.68.1.913 · Cited by 2,103
Identification and characterization of the tuberous sclerosis gene on chromosome 16
(1993) · Cell · doi:10.1016/0092-8674(93)90618-z · Cited by 1,645
Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002) · Molecular Cell · doi:10.1016/s1097-2765(02)00568-3 · Cited by 1,555
Hara, K., Yonezawa, K., Weng, Q.-P., Kozlowski, M. T., BELHAM, C. M., & Avruch, J. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.23.14484 · Cited by 1,370
A Cytoplasmic Protein Stimulates Normal N- ras p21 GTPase, But Does Not Affect Oncogenic Mutants
Trahey, M., & McCormick, F. (1987) · Science · doi:10.1126/science.2821624 · Cited by 1,211
FUNCTION AND REGULATION OF RAS
Lowy, D. R., & Willumsen, B. M. (1993) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.62.070193.004223 · Cited by 1,164
Phosphatidic Acid-Mediated Mitogenic Activation of mTOR Signaling
Fang, Y., Vilella-Bach, M., Bachmann, R., Flanigan, A., & Chen, J. (2001) · Science · doi:10.1126/science.1066015 · Cited by 1,055
Mammalian TOR: a homeostatic ATP sensor
Dennis, P. B., Jaeschke, A., Saitoh, M., Fowler, B., Kozma, S. C., & Thomas, G. (2001) · Science · doi:10.1126/science.1063518 · Cited by 962
Tee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.202476899 · Cited by 827
Research works printed but not linked: 1
- 2002, Cancer Res., 62, 5645
Cited by
Sorted by citations
mTOR Signaling in Growth Control and Disease
Laplante, M., & Sabatini, D. M. (2012) · Cell · doi:10.1016/j.cell.2012.03.017 · Cited by 8,509
mTOR Signaling in Growth, Metabolism, and Disease
Saxton, R. A., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.02.004 · Cited by 7,555
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1
Kim, J., Kundu, M., Viollet, B., & Guan, K.-L. (2011) · Nature Cell Biology · doi:10.1038/ncb2152 · Cited by 7,227
Self-citationUpstream and downstream of mTOR
Hay, N., & Sonenberg, N. (2004) · Genes & Development · doi:10.1101/gad.1212704 · Cited by 4,181
mTOR: from growth signal integration to cancer, diabetes and ageing
Zoncu, R., Efeyan, A., & Sabatini, D. M. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3025 · Cited by 3,941
Metadata
- Authors
- Inoki, K., Li, Y., Xu, T., & Guan, K.-L.
- Affiliations
- University of Michigan (US)
- Howard Hughes Medical Institute (US)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2003-07-17
- Volume
- 17
- Issue
- 15
- Pages
- 1829-1834
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC196227
- OpenAlex
- W2056137479
- Cited by
- 1,911
- References
- 34
- Citations by year
- 2026: 44 · 2025: 68 · 2024: 75 · 2023: 78 · 2022: 72 · 2021: 107 · 2020: 103 · 2019: 73 · 2018: 97 · 2017: 112 · 2016: 111 · 2015: 127 · 2014: 92 · 2013: 101 · 2012: 94
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK124709)
- 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 › Metabolism, Diabetes, and Cancer
- Keywords
- TSC2, GTPase-activating protein, mTOR signaling, tuberous sclerosis complex, S6K phosphorylation, 4E-BP1 phosphorylation, rapamycin, nutrient signaling, cellular energy status, cell growth regulation, Ras family GTPases
- MeSH terms
- Ras Homolog Enriched in Brain Protein, Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Antibiotics, Antineoplastic, Cell Division, Cell Line, Dose-Response Relationship, Drug, Genes, Dominant, Guanosine Triphosphate, Humans, Hydrolysis, Models, Biological, Mutation, Neuropeptides, Phosphorylation, Plasmids, Protein Binding, Protein Kinases, Proteins, Repressor Proteins, Time Factors, Protein Biosynthesis, Signal Transduction, Protein Structure, Tertiary, Sirolimus, GTP Phosphohydrolases, Monomeric GTP-Binding Proteins, Tumor Suppressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, TOR Serine-Threonine Kinases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
