Cited by 1,043PI3K/AKT/mTOR signaling in cancerTuberous Sclerosis Complex ResearchProtein Kinase Regulation and GTPase Signaling

Insulin Activation of Rheb, a Mediator of mTOR/S6K/4E-BP Signaling, Is Inhibited by TSC1 and 2

Open access
Garami, Attila, Zwartkruis, Fried J.T, Nobukuni, Takahiro, Joaquin, Manel, Roccio, Marta, Stocker, Hugo, Kozma, Sara C, Hafen, Ernst +2 more·2003·Molecular Cell

Abstract

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.

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.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s1097-2765(03)00220-x

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

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.

A few free checks a day · papers already verified open instantly · results are public

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 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

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Loewith, R., Jacinto, E., Wullschleger, S., Lorberg, A., Crespo, J.L., small GTPase Rheb is an essential regulator of S6 kinase in the Bonenfant, D., Oppliger, W., Jenoe, P., and Hall, M.N. (2002). Two control of cell growth in Drosophila. Nat. Cell Biol., in press.

Cited by

Sorted by citations

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
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
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

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