Abstract
Insulin signalling is a potent inhibitor of cell growth and has been proposed to function, at least in part, through the conserved protein kinase TOR (target of rapamycin). Recent studies suggest a that the tuberous sclerosis complex Tsc1–Tsc2 may couple insulin signalling to Tor activity. However, the regulatory mechanism involved remains unclear, and additional components are most probably involved. In a screen for novel regulators of growth, we identified Rheb (Ras homologue enriched in brain), a member of the Ras superfamily of GTP-binding proteins. Increased levels of Rheb in Drosophila melanogaster promote cell growth and alter cell cycle kinetics in multiple tissues. In mitotic tissues, overexpression of Rheb accelerates passage through G1–S phase without affecting rates of cell division, whereas in endoreplicating tissues, Rheb increases DNA ploidy. Mutation of Rheb suspends larval growth and prevents progression from first to second instar. Genetic and biochemical tests indicate that Rheb functions in the insulin signalling pathway downstream of Tsc1–Tsc2 and upstream of TOR. Levels of rheb mRNA are rapidly induced in response to protein starvation, and overexpressed Rheb can drive cell growth in starved animals, suggesting a role for Rheb in the nutritional control of cell growth.
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Acknowledgements
We thank S. Grewal for critical reading of the manuscript. This work was supported by grants from the National Institutes of Health (GM20590 to L.J.S, GM62323 to D.J.P., and GM51186 and GM61805 to B.A.E.) and the American Cancer Society (RSG0303601DDC to D.J.P.).
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Supplementary information
Fig S1. Histogram of clone size distribution.
Fig S2. Transcriptional regulation of components of the insulin/PI3K signaling (PDF 99 kb)
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Saucedo, L., Gao, X., Chiarelli, D. et al. Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat Cell Biol 5, 566–571 (2003). https://doi.org/10.1038/ncb996
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DOI: https://doi.org/10.1038/ncb996
