Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway

Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC · 2002 · Molecular Cell · Atlas ID MAN2002

What this study shows

The authors combined biochemistry with a search for Akt consensus motifs and picked out tuberin, the TSC2 tumour suppressor protein, as a likely Akt substrate. They showed that activating PI3K leads to phosphorylation of tuberin at sites matching the Akt motif, and that Akt can phosphorylate tuberin both in vitro and in cells. Two of these sites, S939 and T1462, were regulated by PI3K, and T1462 stayed phosphorylated in tumour cell lines lacking PTEN. A tuberin mutant without the main PI3K-dependent sites blocked activation of S6K1. Together with papers from other labs in the same months, this was one of the early papers to link growth-factor signalling through Akt to the TSC complex and mTORC1 output. Boundary: cultured mammalian cells and in vitro kinase assays, with overexpressed tuberin mutants; no whole-animal or human tissue data.

Abstract

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The S/T-protein kinases activated by phosphoinositide 3-kinase (PI3K) regulate a myriad of cellular processes. Here, we show that an approach using a combination of biochemistry and bioinformatics can identify substrates of these kinases. This approach identifies the tuberous sclerosis complex-2 gene product, tuberin, as a potential target of Akt/PKB. We demonstrate that, upon activation of PI3K, tuberin is phosphorylated on consensus recognition sites for PI3K-dependent S/T kinases. Moreover, Akt/PKB can phosphorylate tuberin in vitro and in vivo.

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 cell lines (mouse 3T3 cells, human cells) and PTEN-null tumour-derived cell lines; in vitro kinase assays) 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 cell lines (mouse 3T3 cells, human cells) and PTEN-null tumour-derived cell lines; in vitro kinase assays
Journal	Molecular Cell
Year	2002
Peer reviewed	Yes
Record last updated	2026-10-01
Source	DOI 10.1016/s1097-2765(02)00568-3 · PMID 12150915

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	PI3K activation; Akt/PKB kinase; phospho-site mutant tuberin (S939/T1462)
Target	TSC2 (tuberin) phosphorylation; S6K1 activation
Model	Mouse and human cell lines; in vitro
Effect	Akt phosphorylates tuberin (inhibitory); non-phosphorylatable tuberin blocks S6K1 activation

In the Atlas

Links in the pathway map

Supports Akt/PKB inhibits TSC1/TSC2

Cite this paper

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Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J., & Cantley, L. C. (2002). Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Molecular Cell. https://doi.org/10.1016/s1097-2765(02)00568-3

@article{MAN2002,
  author       = {Manning, B. D. and Tee, A. R. and Logsdon, M. N. and Blenis, J. and Cantley, L. C.},
  title        = {{Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway}},
  journal      = {Molecular Cell},
  year         = {2002},
  doi          = {10.1016/s1097-2765(02)00568-3},
  note         = {PMID: 12150915},
}

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 MAN2002) [Data set]. https://mtor-atlas.org/study/MAN2002/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_MAN2002,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record MAN2002},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/MAN2002/},
  doi          = {10.5281/zenodo.22059963}
}

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