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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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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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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DOI: https://doi.org/10.1038/ncb999