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.

  • Letter
  • Published:

The cytohesin Steppke is essential for insulin signalling in Drosophila

Nature volume 444, pages 945–948 (2006)Cite this article

Abstract

In metazoans, the insulin signalling pathway has a key function in regulating energy metabolism and organismal growth1. Its activation stimulates a highly conserved downstream kinase cascade that includes phosphatidylinositol-3-OH kinase (PI(3)K) and the serine–threonine protein kinase Akt. This study identifies a new component of insulin signalling in Drosophila, the steppke gene (step). step encodes a member of the cytohesin family of guanine nucleotide exchange factors (GEFs), which have been characterized as activators for ADP-ribosylation factor (ARF) GTPases2,3,4. In step mutant animals both cell size and cell number are reduced, resulting in decreased body size and body weight in larvae, pupae and adults. step acts upstream of PI(3)K and is required for the proper regulation of Akt and the transcription factor FOXO. Temporally controlled interference with the GEF activity of the Step protein by feeding the chemical inhibitor SecinH3 causes a block of insulin signalling and a phenocopy of the step mutant growth defect. Step represses its own expression and the synthesis of growth inhibitors such as the translational repressor 4E-BP. Our findings indicate a crucial role of an ARF–GEF in insulin signalling that has implications for understanding insulin-related disorders, such as diabetes and obesity.

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: step function is required for growth.
Figure 2: Mutations in step and inhibition of Step function impair insulin-dependent transcription.
Figure 3: Step acts upstream of PI(3)K and is involved in a negative feedback loop regulating step transcription.

Similar content being viewed by others

References

  1. Hafen, E. Cancer, type 2 diabetes, and ageing: news from flies and worms. Swiss Med. Wkly 134, 711–719 (2004)

    CAS  PubMed  Google Scholar 

  2. Jackson, C. L. & Casanova, J. E. Turning on ARF: the Sec7 family of guanine-nucleotide-exchange factors. Trends Cell Biol. 10, 60–67 (2000)

    Article  CAS  Google Scholar 

  3. Randazzo, P. A. et al. Cytohesins and centaurins: mediators of PI 3-kinase regulated Arf signalling. Trends Biochem. Sci. 26, 220–221 (2001)

    Article  CAS  Google Scholar 

  4. D’Souza-Schorey, C. & Chavrier, P. ARF proteins: roles in membrane traffic and beyond. Nature Rev. Mol. Cell Biol. 7, 347–358 (2006)

    Article  Google Scholar 

  5. Saltiel, A. R. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell 104, 517–529 (2001)

    Article  CAS  Google Scholar 

  6. Virkamaki, A., Ueki, K. & Kahn, C. R. Protein–protein interaction in insulin signalling and the molecular mechanisms of insulin resistance. J. Clin. Invest. 103, 931–943 (1999)

    Article  CAS  Google Scholar 

  7. 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  Google Scholar 

  8. Kolanus, W. et al. αLβ2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell 86, 233–242 (1996)

    Article  CAS  Google Scholar 

  9. Geiger, C. et al. Cytohesin-1 regulates β-2 integrin-mediated adhesion through both ARF-GEF function and interaction with LFA-1. EMBO J. 19, 2525–2536 (2000)

    Article  CAS  Google Scholar 

  10. Lietzke, S. E. et al. Structural basis of 3-phosphoinositide recognition by pleckstrin homology domains. Mol. Cell 6, 385–394 (2000)

    Article  CAS  Google Scholar 

  11. Gray, A., Van Der Kaay, J. & Downes, C. P. The pleckstrin homology domains of protein kinase B and GRP1 (general receptor for phosphoinositides-1) are sensitive and selective probes for the cellular detection of phosphatidylinositol 3,4-bisphosphate and/or phosphatidylinositol 3,4,5-trisphosphate. Biochem. J. 344, 929–936 (1999)

    Article  CAS  Google Scholar 

  12. Britton, J. S. & Edgar, B. A. Environmental control of the cell cycle in Drosophila: nutrition activates mitotic and endoreplicative cells by distinct mechanisms. Development 125, 2149–2157 (1998)

    CAS  PubMed  Google Scholar 

  13. Pierce, S. B. et al. dMyc is required for larval growth and endoreplication in Drosophila.. Development 131, 2317–2327 (2004)

    Article  CAS  Google Scholar 

  14. Hafner, M. et al. Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature doi:10.1038/nature05415 (this issue).

  15. Jünger, M. A. et al. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signalling. J. Biol. 2, 20 (2003)

    Article  Google Scholar 

  16. Puig, O., Marr, M. T., Ruhf, M. L. & Tjian, R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes Dev. 17, 2006–2020 (2003)

    Article  CAS  Google Scholar 

  17. Bernal, A. & Kimbrell, D. A. Drosophila Thor participates in host immune defense and connects a translational regulator with innate immunity. Proc. Natl Acad. Sci. USA 97, 6019–6024 (2000)

    Article  ADS  CAS  Google Scholar 

  18. Chen, C., Jack, J. & Garofalo, R. S. The Drosophila insulin receptor is required for normal growth. Endocrinology 137, 846–856 (1996)

    Article  CAS  Google Scholar 

  19. Zinke, I., Schutz, C. S., Katzenberger, J. D., Bauer, M. & Pankratz, M. J. Nutrient control of gene expression in Drosophila: microarray analysis of starvation and sugar-dependent response. EMBO J. 21, 6162–6173 (2002)

    Article  CAS  Google Scholar 

  20. Verdu, J., Buratovich, M. A., Wilder, E. L. & Birnbaum, M. J. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nature Cell Biol. 1, 500–506 (1999)

    Article  CAS  Google Scholar 

  21. Leevers, S. J., Weinkove, D., MacDougall, L. K., Hafen, E. & Waterfield, M. D. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 15, 6584–6594 (1996)

    Article  CAS  Google Scholar 

  22. Goberdhan, D. C., Paricio, N., Goodman, E. C., Mlodzik, M. & Wilson, C. Drosophila tumor suppressor PTEN controls cell size and number by antagonizing the Chico/PI3-kinase signaling pathway. Genes Dev. 13, 3244–3258 (1999)

    Article  CAS  Google Scholar 

  23. Weinkove, D., Neufeld, T. P., Twardzik, T., Waterfield, M. D. & Leevers, S. J. Regulation of imaginal disc cell size, cell number and organ size by Drosophila class I(A) phosphoinositide 3-kinase and its adaptor. Curr. Biol. 9, 1019–1029 (1999)

    Article  CAS  Google Scholar 

  24. 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  Google Scholar 

  25. Stocker, H. et al. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295, 2088–2091 (2002)

    Article  ADS  CAS  Google Scholar 

  26. Furuyama, T., Nakazawa, T., Nakano, I. & Mori, N. Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues. Biochem. J. 349, 629–634 (2000)

    Article  CAS  Google Scholar 

  27. Xuan, Z. & Zhang, M. Q. From worm to human: bioinformatics approaches to identify FOXO target genes. Mech. Ageing Dev. 126, 209–215 (2005)

    Article  CAS  Google Scholar 

  28. Kaufmann, E. & Knochel, W. Five years on the wings of fork head. Mech. Dev. 57, 3–20 (1996)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank W. Kolanus for valuable discussions on cytohesins; M. Famulok for providing the Step inhibitor SecinH3 and for sharing unpublished results; S. Cohen and M. Günther Behr for reagents; A. Schmitz for help with pAkt quantifications; C. Müller for technical assistance; and the members of the Famulok and Hoch laboratories for helpful comments. This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Sonderforschungsbereiche 645 (to M.H.) and 704 (to M.H. and B.F.). Author Contributions T.B. and I.Z. performed the growth and body size analysis in step mutants. T.B. analysed the insulin signalling activity in step and chico mutants and under starvation using quantitative RT–PCR. B.F. performed the cell cycle analysis, cell size analysis in step mutants, pAkt quantifications, in vitro and in vivo FOXO localization studies, in vitro growth inhibition analysis, step enhancer analysis and ectopic FOXO expression experiments. I.Z. generated the in vivo chemical genetics data and the Dp110-CAAX rescue experiment. I.Z. and B.F. contributed to the step rescue experiment. M.H. supervised the research project, and assisted in the experimental design. All authors discussed the experimental results. B.F. and M.H. wrote the manuscript.

Author information

Author notes

  1. Bernhard Fuss, Thomas Becker and Ingo Zinke: These authors contributed equally to this work.

Authors and Affiliations

  1. LIMES-Institute, Program Unit Development and Genetics, Laboratory for Molecular Developmental Biology, University of Bonn, Meckenheimer Allee 169, Bonn, D-53115, Germany

    Bernhard Fuss, Thomas Becker, Ingo Zinke & Michael Hoch

Authors
  1. Bernhard Fuss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Thomas Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ingo Zinke
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Hoch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Hoch.

Ethics declarations

Competing interests

Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains complete Supplementary Information including Supplementary Methods, Supplementary Figures 1-7 and Supplementary Tables (PDF 947 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fuss, B., Becker, T., Zinke, I. et al. The cytohesin Steppke is essential for insulin signalling in Drosophila. Nature 444, 945–948 (2006). https://doi.org/10.1038/nature05412

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature05412

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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