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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.

Tier D because it is mechanistic or in-vitro work (model: Mammalian cells), not a whole-organism health-outcome study; tier describes study design, not quality -- this is often exactly where causal biology gets established.

At a glance

Evidence tier	D Mechanistic / in vitro / review
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

Target	TSC/Rheb/mTOR/S6K -> IRS1/2
Model	Mammalian cells
Effect	Constitutive mTOR/S6K signalling depletes IRS1/2 and causes cellular insulin resistance

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Abstract

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 →

Cite this record

Barton, O. (2026). Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies — evidence-graded record SHA2004. In Oliver's mTOR Atlas. https://mtor-atlas.org/study/SHA2004/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_SHA2004,
  author       = {Barton, Oliver},
  title        = {{Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies} --- evidence-graded record SHA2004},
  howpublished = {Oliver's mTOR Atlas},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/SHA2004/},
  note         = {Dataset DOI: 10.5281/zenodo.22059963}
}

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