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Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling

Nature Cell Biology volume 4, pages 699–704 (2002)Cite this article

Abstract

Target of Rapamycin (TOR) mediates a signalling pathway that couples amino acid availability to S6 kinase (S6K) activation, translational initiation and cell growth1,2. Here, we show that tuberous sclerosis 1 (Tsc1) and Tsc2, tumour suppressors that are responsible for the tuberous sclerosis syndrome3,4, antagonize this amino acid–TOR signalling pathway. We show that Tsc1 and Tsc2 can physically associate with TOR and function upstream of TOR genetically. In Drosophila melanogaster and mammalian cells, loss of Tsc1 and Tsc2 results in a TOR-dependent increase of S6K activity. Furthermore, although S6K is normally inactivated in animal cells in response to amino acid starvation, loss of Tsc1–Tsc2 renders cells resistant to amino acid starvation. We propose that the Tsc1–Tsc2 complex antagonizes the TOR-mediated response to amino acid availability. Our studies identify Tsc1 and Tsc2 as regulators of the amino acid–TOR pathway and provide a new paradigm for how proteins involved in nutrient sensing function as tumour suppressors.

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Figure 1: Genetic epistasis analysis places TOR downstream of Tsc1–Tsc2.
Figure 2: Tsc1–Tsc2 associate with TOR and negatively regulate S6K activity in a TOR-dependent manner.
Figure 3: Tsc1–Tsc2 regulate amino-acid signalling in S2 cells.
Figure 4: Tsc1–Tsc2 regulate amino acid signalling in mammalian cells.

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Acknowledgements

We would like to thank M. Brown, E. Chen, J. Chen, J. Stull and K. Wharton for critical reading of the manuscript. We thank E. Hafen and T. Neufeld for fly stocks, N. Ito and M. Stewart for antibodies, P. Jones for amino acid measurement and the University of Texas Southwestern Molecular and Cellular Imaging Facility for assistance with eye sections. D.J.P. is Virginia Murchison Linthicum Endowed Scholar in Medical Science, and is supported by the National Institutes of Health (GM62323) and American Heart Association (0130222N).

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Author notes

  1. Xinsheng Gao and Yong Zhang: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, 75390-9040, TX, USA

    Xinsheng Gao, Yong Zhang, Peter Arrazola & Duojia Pan

  2. Department of Experimental Pathology, Cancer Institute, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo, 170-8455, Japan

    Okio Hino & Toshiyuki Kobayashi

  3. Department of Surgery, Division of Medical Genetics, University of Washington, Seattle, 98195, WA, USA

    Raymond S. Yeung

  4. Department of Biochemistry, Peking University, Beijing, 100871, China

    Binggeng Ru

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  1. Xinsheng Gao
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Correspondence to Duojia Pan.

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Gao, X., Zhang, Y., Arrazola, P. et al. Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling. Nat Cell Biol 4, 699–704 (2002). https://doi.org/10.1038/ncb847

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