Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2

Garami A, Zwartkruis FJ, Nobukuni T, Joaquin M, Roccio M, Stocker H, Kozma SC, Hafen E, Bos JL, Thomas G · 2003 · Molecular cell · Atlas ID GAR2003

What this study shows

Insulin activates Rheb-GTP, inhibited by TSC1/2, positioning Rheb as the direct upstream activator of TOR.

Abstract

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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.

Read the full abstract on PubMed →

At a glance

Evidence type	M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Drosophila & mammalian cells) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is.
Study type	5 - Mechanistic / In Vitro
Model system	Drosophila & mammalian cells
Journal	Molecular cell
Year	2003
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1016/s1097-2765(03)00220-x · PMID 12820960

Extracted findings

These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.

Intervention	Genetic/biochemical (Rheb, TSC1/2)
Target	Rheb / TSC1-TSC2 / mTOR-S6K-4EBP
Model	Drosophila & mammalian cells
Effect	Insulin activates Rheb, a mediator of mTOR/S6K/4E-BP signaling, and this is inhibited by TSC1/2

In the Atlas

Links in the pathway map

Supports TSC1/TSC2 inhibits Rheb
Supports Insulin activates PI3K

Learn the biology

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Cite this paper

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Garami, A., Zwartkruis, F. J., Nobukuni, T., Joaquin, M., Roccio, M., Stocker, H., Kozma, S. C., Hafen, E., Bos, J. L., & Thomas, G. (2003). Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2. Molecular cell. https://doi.org/10.1016/s1097-2765(03)00220-x

@article{GAR2003,
  author       = {Garami, A. and Zwartkruis, F. J. and Nobukuni, T. and Joaquin, M. and Roccio, M. and Stocker, H. and Kozma, S. C. and Hafen, E. and Bos, J. L. and Thomas, G.},
  title        = {{Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2}},
  journal      = {Molecular cell},
  year         = {2003},
  doi          = {10.1016/s1097-2765(03)00220-x},
  note         = {PMID: 12820960},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record GAR2003) [Data set]. https://mtor-atlas.org/study/GAR2003/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_GAR2003,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record GAR2003},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/GAR2003/},
  doi          = {10.5281/zenodo.22059963}
}

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