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Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins

Abstract

Mutations in the TSC1 or TSC2 genes cause tuberous sclerosis, a benign tumour syndrome in humans1,2. Tsc2 possesses a domain that shares homology with the GTPase-activating protein (GAP) domain of Rap1-GAP2, suggesting that a GTPase might be the physiological target of Tsc2. Here we show that the small GTPase Rheb (Ras homologue enriched in brain) is a direct target of Tsc2 GAP activity both in vivo and in vitro. Point mutations in the GAP domain of Tsc2 disrupted its ability to regulate Rheb without affecting the ability of Tsc2 to form a complex with Tsc1. Our studies identify Rheb as a molecular target of the TSC tumour suppressors.

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Figure 1: Tsc2 regulates Rheb activity in vivo.
Figure 2: In vitro Rheb GAP activity of Tsc2 and genetic interaction between Tsc1 and Rheb.

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References

  1. van Slegtenhorst, M. et al. Science 277, 805–808 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. The European Chromosome 16 Tuberous Sclerosis Consortium. Cell 75, 1305–1315 (1993).

  3. Gao, X. & Pan, D. Genes Dev. 15, 1383–1392 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Potter, C.J., Huang, H. & Xu, T. Cell 105, 357–368 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Tapon, N., Ito, N., Dickson, B.J., Treisman, J.E. & Hariharan, I.K. Cell 105, 345–355 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Gao, X. et al. Nature Cell Biol. 4, 699–704 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K.L. Nature Cell Biol. 4, 648–657 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Radimerski, T., Montagne, J., Hemmings-Mieszczak, M. & Thomas, G. Genes Dev. 16, 2627–2632 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tee, A.R. et al. Proc. Natl Acad. Sci. USA 99, 13571–13576 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Maheshwar, M.M. et al. Hum. Mol. Genet. 6, 1991–1996 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Saucedo, L.J. et al. Nature Cell Biol. 5, 566–571 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Stocker H. et al. Nature Cell Biol. 5, 559–565 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Xiao, G.-H., Shoarinejad, F., Jin, F., Golemis, E.A. & Yeung, R.S. J. Biol. Chem. 272, 6097–6100 (1997).

    Article  CAS  PubMed  Google Scholar 

  14. Wienecke, R., Konig, A. & DeClue, J.E. J. Biol. Chem. 270, 16409–16414 (1995).

    Article  CAS  PubMed  Google Scholar 

  15. Yamagata, K. et al. J. Biol. Chem. 269, 16333–16339 (1994).

    CAS  PubMed  Google Scholar 

  16. Im, E. et al. Oncogene 21, 6356–6365 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Langille, S.E. et al. J. Biol. Chem. 274, 27099–27104 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Matsumoto, S., Bandyopadhyay, A., Kwiatkowski, D.J., Maitra, U. & Matsumoto, T. Genetics 161, 1053–1063 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Brinkmann, T. et al. J. Biol. Chem. 277, 12525–12531 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Garrett, M.D., Self, A.J., van Oers, C. & Hall, A. J. Biol. Chem. 264, 10–13 (1989).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to thank E. Chen and K. Wharton for critical reading of the manuscript, G. Tall for advice on in vitro GAP assays and M. White for the GST–DRas1 construct. D.J.P. is Virginia Murchison Linthicum Endowed Scholar in Medical Science. This work was supported by grants from the National Institutes of Health (GM20590 to L.J.S.; GM51186 to B.A.E. and GM62323 to D.J.P.), American Heart Association (0130222N to D.J.P.) and the American Cancer Society (RSG0303601DDC to D.J.P.).

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Correspondence to Duojia Pan.

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Zhang, Y., Gao, X., Saucedo, L. et al. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 5, 578–581 (2003). https://doi.org/10.1038/ncb999

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