Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling

Xinsheng Gao, Yong Zhang, Peter Arrazola, Okio Hino, Toshiyuki Kobayashi, Raymond S. Yeung, Binggeng Ru, Duojia Pan

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)699-704
Number of pages6
JournalNature Cell Biology
Volume4
Issue number9
DOIs
StatePublished - Sep 2002
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology

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  • Cite this

    Gao, X., Zhang, Y., Arrazola, P., Hino, O., Kobayashi, T., Yeung, R. S., Ru, B., & Pan, D. (2002). Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nature Cell Biology, 4(9), 699-704. https://doi.org/10.1038/ncb847