Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling

Inoki K, Li Y, Xu T, Guan KL · 2003 · Genes & development · Atlas ID INOK2003

What this study shows

TSC2 is a GAP for Rheb; loss of TSC2 raises Rheb-GTP and constitutively activates mTOR.

Abstract

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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.

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: In vitro; Drosophila) 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	In vitro; Drosophila
Journal	Genes & development
Year	2003
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1101/gad.1110003 · PMID 12869586 · Free full text (PMC196227)

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	Biochemical/genetic (TSC2 GAP activity toward Rheb)
Target	Rheb / TSC2 / mTOR
Model	In vitro; Drosophila
Effect	TSC2 is a GAP for Rheb; Rheb-GTP activates mTOR/S6K/4EBP1 (rapamycin-sensitive)

In the Atlas

Links in the pathway map

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Cite this paper

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Inoki, K., Li, Y., Xu, T., & Guan, K. L. (2003). Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & development. https://doi.org/10.1101/gad.1110003

@article{INOK2003,
  author       = {Inoki, K. and Li, Y. and Xu, T. and Guan, K. L.},
  title        = {{Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling}},
  journal      = {Genes & development},
  year         = {2003},
  doi          = {10.1101/gad.1110003},
  note         = {PMID: 12869586},
}

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 INOK2003) [Data set]. https://mtor-atlas.org/study/INOK2003/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_INOK2003,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record INOK2003},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/INOK2003/},
  doi          = {10.5281/zenodo.22059963}
}

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