Brief Communication abstract
Nature Cell Biology 4, 699 - 704 (2002)
Published online: 12 August 2002 | doi:10.1038/ncb847
Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling
Xinsheng Gao1,5, Yong Zhang1,5, Peter Arrazola1, Okio Hino2, Toshiyuki Kobayashi2, Raymond S. Yeung3, Binggeng Ru4 & Duojia Pan1
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.
- Department of Physiology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75390-9040, USA
- Department of Experimental Pathology, Cancer Institute, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan
- Department of Surgery, Division of Medical Genetics, University of Washington, Seattle, WA 98195, USA
- Department of Biochemistry, Peking University, Beijing, 100871, China
- These authors contributed equally to this work
Correspondence to: Duojia Pan1 e-mail: dpan@mednet.swmed.edu
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