Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling

Tee AR, Fingar DC, Manning BD, Kwiatkowski DJ, Cantley LC, Blenis J · 2002 · PNAS · Atlas ID TEE2002

What this study shows

The authors coexpressed hamartin (TSC1) and tuberin (TSC2) in cultured cells and followed two main outputs of mTOR. Together, the two proteins reduced phosphorylation of 4E-BP1, so more 4E-BP1 stayed bound to the translation factor eIF4E; a TSC2 mutant found in TSC patients was defective at this. Hamartin plus tuberin also lowered S6K1 activity, but did not affect S6K1 mutants that resist rapamycin, which points to mTOR as the step being blocked. In nutrient-deprived cells, hamartin and tuberin prevented amino acids from switching S6K1 back on. The authors concluded that the TSC1-TSC2 complex acts as an inhibitor of mTOR signalling and suggested that TSC tumours may come from too much mTOR activity. Boundary: overexpression in cultured mammalian cells; the link to tumours in TSC patients is a proposal, not tested in patient tissue here.

Abstract

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Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that occurs upon mutation of either the TSC1 or TSC2 genes, which encode the protein products hamartin and tuberin, respectively. Here, we show that hamartin and tuberin function together to inhibit mammalian target of rapamycin (mTOR)-mediated signaling to eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1).

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: Cultured mammalian cells (HEK293-type transfection system per MeSH 'Cell Line'); coexpression of TSC1/TSC2, patient-derived TSC2 mutant, rapamycin-resistant S6K1 mutants) 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	Cultured mammalian cells (HEK293-type transfection system per MeSH 'Cell Line'); coexpression of TSC1/TSC2, patient-derived TSC2 mutant, rapamycin-resistant S6K1 mutants
Journal	PNAS
Year	2002
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1073/pnas.202476899 · PMID 12271141 · Free full text (PMC129715)

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	Coexpression of TSC1 + TSC2 (and patient-derived TSC2 mutant)
Target	4E-BP1 phosphorylation, 4E-BP1-eIF4E binding, S6K1 activity
Model	Mammalian cell lines
Effect	TSC1/TSC2 coexpression decreases mTOR signalling to 4E-BP1 and S6K1

In the Atlas

Links in the pathway map

Supports TSC1/TSC2 inhibits mTORC1

Cite this paper

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Tee, A. R., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C., & Blenis, J. (2002). Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. PNAS. https://doi.org/10.1073/pnas.202476899

@article{TEE2002,
  author       = {Tee, A. R. and Fingar, D. C. and Manning, B. D. and Kwiatkowski, D. J. and Cantley, L. C. and Blenis, J.},
  title        = {{Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling}},
  journal      = {PNAS},
  year         = {2002},
  doi          = {10.1073/pnas.202476899},
  note         = {PMID: 12271141},
}

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 TEE2002) [Data set]. https://mtor-atlas.org/study/TEE2002/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_TEE2002,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record TEE2002},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/TEE2002/},
  doi          = {10.5281/zenodo.22059963}
}

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