Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1

Nature Cell Biology volume 4, pages 251–255 (2002)Cite this article

Abstract

Genetic studies in Drosophila melanogaster underscore the importance of the insulin-signalling pathway in controlling cell, organ and animal size1. Effectors of this pathway include Chico (the insulin receptor substrate homologue), dPI(3)K, dPKB, dPTEN, and dS6K2. Mutations in any of these components have a striking effect on cell size and number3,4,5,6,7, with the exception of dS6K8. Mutants in dS6K affect cell size but not cell number, seemingly consistent with arguments that dS6K is a distal effector in the signalling pathway, directly controlled by dTOR, a downstream effector of dPI(3)K and dPKB1,9,10. Unexpectedly, recent studies showed that dS6K activity is unimpaired in chico-deficient larvae, suggesting that dS6K activation may be mediated through the dPI(3)K docking sites of the Drosophila insulin receptor11. Here, we show genetically, pharmacologically and biochemically that dS6K resides on an insulin signalling pathway distinct from that of dPKB, and surprisingly also from that of dPI(3)K. More striking, despite dPKB-dPI(3)K-independence, dS6K activity is dependent on the Drosophila homologue of the phosphoinositide-dependent protein kinase 1, dPDK1, demonstrating that both dPDK1, as well as dTOR, mediated dS6K activation is phosphatidylinositide-3,4,5-trisphosphate (PIP3)–independent.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genetic interaction analysis between dS6K and either dPDK1 or dPKB.
Figure 2: dS6K activation is dependent on amino acids and dTOR, but independent of dPKB.
Figure 3: dS6K activation in Drosophila Kc167 cells does not require increased PIP3 levels.
Figure 4: dS6K activation in Drosophila is dPI(3)K independent but requires dPDK1.

Similar content being viewed by others

References

  1. Edgar, B. A. Nature Cell Biol. 1, E191–E193 (1999).

    Article  CAS  Google Scholar 

  2. Thomas, G. Nature Cell Biol. 2, E71–E72 (2000).

    Article  CAS  Google Scholar 

  3. Böhni, R. et al. Cell 97, 865–875 (1999).

    Article  Google Scholar 

  4. Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E. & Waterfield, M. D. EMBO J. 15, 6584–6594 (1996).

    Article  CAS  Google Scholar 

  5. Stocker, H. & Hafen, E. Curr. Opin. Genet. Dev. 10, 529–535 (2000).

    Article  CAS  Google Scholar 

  6. Huang, H. et al. Development 126, 5365–5372 (1999).

    CAS  PubMed  Google Scholar 

  7. Goberdhan, D. C., Paricio, N., Goodman, E. C., Mlodzik, M. & Wilson, C. Genes Dev. 13, 3244–3258 (1999).

    Article  CAS  Google Scholar 

  8. Montagne, J. et al. Science 285, 2126–2129 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  11. Oldham, S., Montagne, J., Radimerski, T., Thomas, G. & Hafen, E. Genes Dev. 14, 2689–2694 (2000).

    Article  CAS  Google Scholar 

  12. Alessi, D. R. et al. Curr. Biol. 7, 261–269 (1997).

    Article  CAS  Google Scholar 

  13. Pullen, N. et al. Science 279, 707–710 (1998).

    Article  CAS  Google Scholar 

  14. Alessi, D. R., Kozlowski, M. T., Weng, Q. P., Morrice, N. & Avruch, J. Curr. Biol. 8, 69–81 (1998).

    Article  CAS  Google Scholar 

  15. Sekulic, A. et al. Cancer Res. 60, 3504–3513 (2000).

    CAS  PubMed  Google Scholar 

  16. Dennis, P. B., Pullen, N., Pearson, R. B., Kozma, S. C. & Thomas, G. J. Biol. Chem. 273, 14845–14852 (1998).

    Article  CAS  Google Scholar 

  17. Zhang, H., Stallock, J. P., Ng, J. C., Reinhard, C. & Neufeld, T. P. Genes Dev. 14, 2712–2724 (2000).

    Article  CAS  Google Scholar 

  18. Dufner, A., Andjelkovic, M., Burgering, B. M. T., Hemmings, B. A. & Thomas, G. Mol. Cell. Biol. 19, 4525–4534 (1999).

    Article  CAS  Google Scholar 

  19. Rintelen, F., Stocker, H., Thomas, G. & Hafen, E. Proc. Natl Acad. Sci. USA, 98, 15020–15025 (2001).

    Article  CAS  Google Scholar 

  20. Hara, K. et al. J. Biol. Chem. 273, 14484–14494 (1998).

    Article  CAS  Google Scholar 

  21. Staveley, B. E. et al. Curr. Biol. 8, 599–602 (1998).

    Article  CAS  Google Scholar 

  22. Scanga, S. E. et al. Oncogene 19, 3971–3977 (2000).

    Article  CAS  Google Scholar 

  23. Haruta, T. et al. Mol. Endocrinol. 14, 783–794 (2000).

    Article  CAS  Google Scholar 

  24. Majewski, M. et al. Proc. Natl Acad. Sci. USA 97, 4285–4290 (2000).

    Article  CAS  Google Scholar 

  25. Van der Kaay, J., Cullen, P. J. & Downes, C. P. Methods Mol. Biol. 105, 109–125 (1998).

    CAS  PubMed  Google Scholar 

  26. Verdu, J., Buratovich, M. A., Wilder, E. L. & Birnbaum, M. J. Nature Cell Biol. 1, 500–506 (1999).

    Article  CAS  Google Scholar 

  27. Miron, M. et al. Nature Cell Biol. 3, 596–601 (2001).

    Article  CAS  Google Scholar 

  28. Weinkove, D., Neufeld, T. P., Twardzik, T., Waterfield, M. D. & Leevers, S. J. Curr. Biol. 9, 1019–1029 (1999).

    Article  CAS  Google Scholar 

  29. Yano, S., Tokumitsu, H. & Soderling, T. R. Nature 396, 584–587 (1998).

    Article  CAS  Google Scholar 

  30. Alessi, D. et al. EMBO J. 23, 6541–6551 (1996).

    Article  Google Scholar 

  31. Conus, N. M., Hemmings, B. A. & Pearson, R. B. J. Biol. Chem. 273, 4776–4782 (1998).

    Article  CAS  Google Scholar 

  32. Montagne, J., Radimerski, T. & Thomas, G. Sci. STKE 2001, E36 (2001).

  33. Hidalgo, M. & Rowinsky, E. K. Oncogene 19, 6680–6686 (2000).

    Article  CAS  Google Scholar 

  34. Alessi, D. R. et al. Curr. Biol. 7, 776–789 (1997).

    Article  CAS  Google Scholar 

  35. Rørth, P. Proc. Natl Acad. Sci. USA 93, 12418–12422 (1996).

    Article  Google Scholar 

  36. Radimerski, T. et al. Biochemistry 39, 5766–5774 (2000).

    Article  CAS  Google Scholar 

  37. Andjelkovic, M. et al. J. Biol. Chem. 270, 4066–4075 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Leevers for providing fly stocks, B. Hemmings for providing the dPKB antibody, P. Dennis for critical reading of the manuscript, R. Guggenheim and D. Mathys for SEM. This work was supported by grants from the Roche Research Foundation to T.R. and G.T. and from the Swiss Cancer League to E.H. and G.T.

Author information

Authors and Affiliations

  1. Friedrich Miescher Institute, Novartis Research Foundation, Maulbeerstrasse 66, Basel, 4058, Switzerland

    Thomas Radimerski, Jacques Montagne & George Thomas

  2. Zoology Institute, University of Zürich, Winterthurerstrasse 190, Zürich, 8057, Switzerland

    Felix Rintelen, Hugo Stocker & Ernst Hafen

  3. Department of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, Scotland, UK

    Jeroen van der Kaay & C. Peter Downes

Authors
  1. Thomas Radimerski
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jacques Montagne
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Felix Rintelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hugo Stocker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jeroen van der Kaay
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. C. Peter Downes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ernst Hafen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. George Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to George Thomas.

Supplementary information

Figure S1

Model of the signalling events leading to the activation of dS6K and dPKB in Drosophila. (PDF 90 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Radimerski, T., Montagne, J., Rintelen, F. et al. dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. Nat Cell Biol 4, 251–255 (2002). https://doi.org/10.1038/ncb763

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb763

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing