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Rheb is an essential regulator of S6K in controlling cell growth in Drosophila

Abstract

Understanding the mechanisms through which multicellular organisms regulate cell, organ and body growth is of relevance to developmental biology and to research on growth-related diseases such as cancer. Here we describe a new effector in growth control, the small GTPase Rheb (Ras homologue enriched in brain). Mutations in the Drosophila melanogaster Rheb gene were isolated as growth-inhibitors, whereas overexpression of Rheb promoted cell growth. Our genetic and biochemical analyses suggest that Rheb functions downstream of the tumour suppressors Tsc1 (tuberous sclerosis 1)–Tsc2 in the TOR (target of rapamycin) signalling pathway to control growth, and that a major effector of Rheb function is ribosomal S6 kinase (S6K).

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Figure 1: Growth defects caused by Rheb mutations.
Figure 2: Clonal analysis of Rheb function.
Figure 3: Epistatic relationship of Rheb with the InR/dPI(3)K and the TOR signalling pathways.
Figure 4: Rheb affects the kinase activities of S6K and PKB.

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Acknowledgements

We thank R. Bopp, D. El Tounsy Garner, P. Wüstemann, P. Gast, E. Niederer and C. Hugentobler for technical assistance; N. Tapon, I. Hariharan, B. Edgar, T. Xu, B. Dickson and the Bloomington Stock Center for flies; B. Hemmings and A. Hajnal for antibodies; K. Basler for critically reading the manuscript, and B. Edgar, D. Pan and N. Tapon for communicating results prior to publication. This work was supported by grants from the Swiss National Science Foundation (to E.H.), the Swiss Cancer League (to G.T. and E.H.) and the Roche Research Foundation (to T.R.).

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Correspondence to Ernst Hafen.

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The authors declare no competing financial interests.

Supplementary information

Figure S1 Mutations in the highly conserved dRheb protein result in growth impairment.

Figure S2 Unusual behaviour of cells lacking or overexpressing dRheb. (PDF 406 kb)

Figure S3 Alternative positions of dRheb in the growth regulatory network.

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Stocker, H., Radimerski, T., Schindelholz, B. et al. Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat Cell Biol 5, 559–566 (2003). https://doi.org/10.1038/ncb995

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