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

Nature Cell Biology volume 5, pages 559–566 (2003)Cite this article

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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References

  1. Potter, C.J. & Xu, T. Mechanisms of size control. Curr. Opin. Genet. Dev. 11, 279–286 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Johnston, L.A. & Gallant, P. Control of growth and organ size in Drosophila. Bioessays 24, 54–64 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Marygold, S. & Leevers, S. Growth signaling: TSC takes its place. Curr. Biol. 12, R785–R787 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. McManus, E.J. & Alessi, D.R. TSC1–TSC2: a complex tale of PKB-mediated S6K regulation. Nature Cell Biol. 4, E214–E216 (2002).

    Article  CAS  PubMed  Google Scholar 

  5. Radimerski, T., Montagne, J., Hemmings-Mieszczak, M. & Thomas, G. Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev. 16, 2627–2632 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Oldham, S. & Hafen, E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol. 13, 79–85 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Leslie, N.R. & Downes, C.P. PTEN: The down side of PI 3-kinase signalling. Cell. Signal. 14, 285–295 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Wienecke, R., Konig, A. & DeClue, J.E. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J. Biol. Chem. 270, 16409–16414 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Xiao, G.H., Shoarinejad, F., Jin, F., Golemis, E.A. & Yeung, R.S. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J. Biol. Chem. 272, 6097–6100 (1997).

    Article  CAS  PubMed  Google Scholar 

  10. Böhni, R. et al. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell 97, 865–875 (1999).

    Article  PubMed  Google Scholar 

  11. Brogiolo, W. et al. An evolutionarily conserved function of the Drosophila insulin receptor and insulin-like peptides in growth control. Curr. Biol. 11, 213–221 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Yamagata, K. et al. rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J. Biol. Chem. 269, 16333–16339 (1994).

    CAS  PubMed  Google Scholar 

  13. Oldham, S., Montagne, J., Radimerski, T., Thomas, G. & Hafen, E. Genetic and biochemical characterization of dTOR, the Drosophila homolog of the target of rapamycin. Genes Dev. 14, 2689–2694 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang, H., Stallock, J.P., Ng, J.C., Reinhard, C. & Neufeld, T.P. Regulation of cellular growth by the Drosophila target of rapamycin dTOR. Genes Dev. 14, 2712–2724 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gao, X. et al. Tsc tumour suppressor proteins antagonize amino-acid-Tor signaling. Nature Cell Biol. 4, 699–704 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Britton, J.S., Lockwood, W.K., Li, L., Cohen, S.M. & Edgar, B.A. Drosophila's insulin/PI3-kinase pathway coordinates cellular metabolism with nutritional conditions. Dev. Cell 2, 239–249 (2002).

    Article  CAS  PubMed  Google Scholar 

  17. Tapon, N., Ito, N., Dickson, B.J., Treisman, J.E. & Hariharan, I.K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345–355 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Potter, C.J., Huang, H. & Xu, T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357–368 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Gao, X., Neufeld, T.P. & Pan, D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways. Dev. Biol. 221, 404–418 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Huang, H. et al. PTEN affects cell size, cell proliferation and apoptosis during Drosophila eye development. Development 126, 5365–5372 (1999).

    CAS  PubMed  Google Scholar 

  21. Gao, X. & Pan, D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 15, 1383–1392 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Radimerski, T. et al. dS6K regulated cell growth is dPKB/dPI3K independent, but requires dPDK1. Nature Cell Biol. 4, 251–255 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Haruta, T. et al. A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol. Endocrinol. 14, 783–794 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Montagne, J. et al. Drosophila S6 Kinase: A Regulator of Cell Size. Science 285, 2126–2129 (1999).

    CAS  PubMed  Google Scholar 

  25. Mach, K.E., Furge, K.A. & Albright, C.F. Loss of Rhb1, a Rheb-related GTPase in fission yeast, causes growth arrest with a terminal phenotype similar to that caused by nitrogen starvation. Genetics 155, 611–622 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Newsome, T.P., Asling, B. & Dickson, B.J. Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics. Development 127, 851–860 (2000).

    CAS  PubMed  Google Scholar 

  27. Nairz, K., Stocker, H., Schindelholz, B. & Hafen, E. High-resolution SNP mapping by denaturing HPLC. Proc. Natl Acad. Sci. USA 99, 10575–10580 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hay, B.A., Wassarman, D.A. & Rubin, G.M. Drosophila homologs of baculovirus inhibitor of apoptosis proteins function to block cell death. Cell 83, 1253–1262 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Staveley, B.E. et al. Genetic analysis of protein kinase B (AKT) in Drosophila. Curr. Biol. 8, 599–602 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Stocker, H. et al. Living with lethal concentrations of PIP3: A mutation in the PH domain of Akt/PKB restores the viability of flies lacking the tumor suppressor PTEN. Science 295, 2088–2091 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Oldham, S. et al. The Drosophila insulin/IGF receptor controls growth and size by modulating PtdInsP3 levels. Development 129, 4103–4109 (2002).

    CAS  PubMed  Google Scholar 

  32. Neufeld, T.P., Delacruz, A.F.A., Johnston, L.A. & Edgar, B.A. Coordination of Growth and Cell Division in the Drosophila Wing. Cell 93, 1183–1193 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Rintelen, F., Stocker, H., Thomas, G. & Hafen, E. PDK1 regulates growth through PKB and S6K in Drosophila. Proc. Natl Acad. Sci. USA 98, 15020–15025 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Andjelkovic, M. et al. Developmental regulation of expression and activity of multiple forms of the Drosophila RAC protein kinase. J. Biol. Chem. 270, 4066–4075 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Potter, C.J., Pedraza, L. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658–665 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

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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Authors and Affiliations

  1. Zoologisches Institut der Universität Zürich, Winterthurerstrasse 190, Zürich, 8057, Switzerland

    Hugo Stocker, Franz Wittwer, Priyanka Belawat & Ernst Hafen

  2. Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel, 4058, Switzerland

    Thomas Radimerski & George Thomas

  3. The Genetics Company, Inc., Wagistrasse 27, Zürich-Schlieren, 8952, Switzerland

    Benno Schindelholz, Pierre Daram & Sebastian Breuer

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  1. Hugo Stocker
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Correspondence to Ernst Hafen.

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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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