Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies

Shah OJ, Wang Zhiyong, Hunter T · 2004 · Current Biology · Atlas ID SHA2004

What this study shows

The companion paper to Harrington 2004, published two months later. In cultured mammalian cells, constitutive Rheb/mTOR/S6K activity depletes IRS1 and IRS2, producing cellular insulin resistance and impaired survival signalling. Together the two papers establish the S6K1 -> IRS negative feedback arm.

Abstract

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Tuberous sclerosis is a largely benign tumor syndrome derived from the acquisition of somatic lesions in genes encoding the tumor suppressor products, TSC1 or TSC2. Loss of function of the TSC1-TSC2 complex, which acts as a Rheb GAP, yields constitutive, unrestrained signaling from the cell growth machinery comprised of Rheb, mTOR, and S6K. We demonstrate herein that constitutive activation of the Rheb/mTOR/S6K cassette, whether by genetic deletion of TSC1 or TSC2 or by ectopic expression of Rheb, is sufficient to induce insulin resistance.

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: 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	Mammalian cells
Journal	Current Biology
Year	2004
Peer reviewed	Yes
Record last updated	2026-07-29
Source	DOI 10.1016/j.cub.2004.08.026 · PMID 15380067

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	TSC1 or TSC2 deletion; ectopic Rheb expression
Target	Rheb/mTOR/S6K -> IRS1/IRS2
Model	Mammalian cells
Effect	Constitutive Rheb/mTOR/S6K signalling depletes IRS1/2, causing cellular insulin resistance and weaker survival signalling

In the Atlas

Links in the pathway map

Supports S6K1 inhibits IRS-1 / IRS-2
Supports Insulin activates PI3K

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Cite this paper

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Shah, O. J., Wang Zhiyong, & Hunter, T. (2004). Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies. Current Biology. https://doi.org/10.1016/j.cub.2004.08.026

@article{SHA2004,
  author       = {Shah, O. J. and Wang Zhiyong and Hunter, T.},
  title        = {{Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies}},
  journal      = {Current Biology},
  year         = {2004},
  doi          = {10.1016/j.cub.2004.08.026},
  note         = {PMID: 15380067},
}

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 SHA2004) [Data set]. https://mtor-atlas.org/study/SHA2004/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_SHA2004,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record SHA2004},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/SHA2004/},
  doi          = {10.5281/zenodo.22059963}
}

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