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:

A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation

Nature Cell Biology volume 8, pages 1407–1414 (2006)Cite this article

Abstract

Signalling by the TGF-β superfamily member and BMP orthologue Decapentaplegic (Dpp) is crucial for multiple developmental programmes and has to be tightly regulated. Here, we demonstrate that the Drosophila Dpp pathway is negatively regulated by eukaryotic translation initiation factor 4A (eIF4A), which mediates activation-dependent degradation of the Dpp signalling components Mad and Medea. eIF4A mutants exhibit increased Dpp signalling and accumulation of Mad and phospho-Mad. Overexpression of eIF4A decreases Dpp signalling and causes loss of Mad and phospho-Mad. Furthermore, eIF4A physically associates with Mad and Medea, and promotes their degradation following activation of Dpp signalling in a translation-independent manner. Finally, we show that eIF4A acts synergistically with, but independently of, the ubiquitin ligase DSmurf, indicating that a dual system controls SMAD degradation. Thus, in addition to being an obligatory component of the cap-dependent translation initiation complex, eIF4A has a novel function as a specific inhibitor of Dpp signalling that mediates the degradation of SMAD homologues.

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: Levels of eIF4A affect Dpp signalling and Mad protein levels.
Figure 2: Physical association of eIF4A with Mad and Medea.
Figure 3: eIF4A promotes Dpp signalling-dependent Mad and Medea degradation.
Figure 4: eIF4A acts synergistally with and independently of DSmurf.

Similar content being viewed by others

References

  1. Li, J., Li, W. X. & Gelbart, W. M. A genetic screen for maternal-effect suppressors of decapentaplegic identifies the eukaryotic translation initiation factor 4A in Drosophila. Genetics 171, 1629–1641 (2006).

    Article  Google Scholar 

  2. Wharton, K. A., Ray, R. P. & Gelbart, W. M. An activity gradient of decapentaplegic is necessary for the specification of dorsal pattern elements in the Drosophila embryo. Development 117, 807–822 (1993).

    CAS  PubMed  Google Scholar 

  3. Galloni, M. & Edgar, B. A. Cell-autonomous and non-autonomous growth-defective mutants of Drosophila melanogaster. Development 126, 2365–2375 (1999).

    CAS  PubMed  Google Scholar 

  4. Newfeld, S. J. et al. Mothers against dpp participates in a DDP/TGF-β responsive serine-threonine kinase signal transduction cascade. Development 124, 3167–3176 (1997).

    CAS  PubMed  Google Scholar 

  5. Sekelsky, J. J., Newfeld, S. J., Raftery, L. A., Chartoff, E. H. & Gelbart, W. M. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139, 1347–1358 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Brummel, T. J. et al. Characterization and relationship of Dpp receptors encoded by the saxophone and thick veins genes in Drosophila. Cell 78, 251–261 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Penton, A. et al. Identification of two bone morphogenetic protein type I receptors in Drosophila and evidence that Brk25D is a decapentaplegic receptor. Cell 78, 239–250 (1994).

    Article  CAS  PubMed  Google Scholar 

  8. Xie, T., Finelli, A. L. & Padgett, R. W. The Drosophila saxophone gene: a serine-threonine kinase receptor of the TGF-β superfamily. Science 263, 1756–1759 (1994).

    Article  CAS  PubMed  Google Scholar 

  9. Nellen, D., Affolter, M. & Basler, K. Receptor serine/threonine kinases implicated in the control of Drosophila body pattern by decapentaplegic. Cell 78, 225–237 (1994).

    Article  CAS  PubMed  Google Scholar 

  10. Dorfman, R. & Shilo, B. Z. Biphasic activation of the BMP pathway patterns the Drosophila embryonic dorsal region. Development 128, 965–972 (2001).

    CAS  PubMed  Google Scholar 

  11. Podos, S. D., Hanson, K. K., Wang, Y. C. & Ferguson, E. L. The DSmurf ubiquitin-protein ligase restricts BMP signaling spatially and temporally during Drosophila embryogenesis. Dev. Cell 1, 567–578 (2001).

    Article  CAS  PubMed  Google Scholar 

  12. Brand, A. H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  PubMed  Google Scholar 

  13. Nellen, D., Burke, R., Struhl, G. & Basler, K. Direct and long-range action of a DPP morphogen gradient. Cell 85, 357–368 (1996).

    Article  CAS  PubMed  Google Scholar 

  14. Hudson, J. B., Podos, S. D., Keith, K., Simpson, S. L. & Ferguson, E. L. The Drosophila Medea gene is required downstream of dpp and encodes a functional homolog of human Smad4. Development 125, 1407–1420 (1998).

    CAS  PubMed  Google Scholar 

  15. Wisotzkey, R. G. et al. Medea is a Drosophila Smad4 homolog that is differentially required to potentiate DPP responses. Development 125, 1433–1445 (1998).

    CAS  PubMed  Google Scholar 

  16. Liang, Y. Y. et al. dSmurf selectively degrades decapentaplegic-activated MAD, and its overexpression disrupts imaginal disc development. J. Biol. Chem. 278, 26307–26310 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Lachance, P. E., Miron, M., Raught, B., Sonenberg, N. & Lasko, P. Phosphorylation of eukaryotic translation initiation factor 4E is critical for growth. Mol. Cell. Biol. 22, 1656–1663 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haerry, T. E., Khalsa, O., O'Connor, M. B. & Wharton, K. A. Synergistic signaling by two BMP ligands through the SAX and TKV receptors controls wing growth and patterning in Drosophila. Development 125, 3977–3987 (1998).

    CAS  PubMed  Google Scholar 

  19. Gustafson, K. & Boulianne, G. L. Distinct expression patterns detected within individual tissues by the GAL4 enhancer trap technique. Genome 39, 174–182 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Inoue, H. et al. Interplay of signal mediators of decapentaplegic (Dpp): molecular characterization of mothers against dpp, Medea, and daughters against dpp. Mol. Biol. Cell 9, 2145–2156 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank S. Matics for technical assistance, M. Kawabata, P. Lasko, P. ten Dijke, C. Proud, W. Gelbart, D. Bohmann, Y. Sun, J. Zhao, J. Jiang, C. Proschel, and the Bloomington Drosophila Stock Center for various reagents and Drosophila strains. We thank Y. Sun for insightful discussions regarding possible mechanisms of eIF4A involvement in Dpp signalling and comments on the manuscript. J.L. was a recipient of the Wilmot Cancer Research Fellowship from the James P. Wilmot Foundation. This study was supported, in part, by grants from the National Institutes of Health (R01GM65774; R01GM077046) and an American Cancer Society Research Scholar Grant (RSG-06-196-01-TBE) to W.X.L.

Author information

Authors and Affiliations

  1. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, 14642, NY, USA

    Jinghong Li & Willis X. Li

Authors
  1. Jinghong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Willis X. Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.L. coplanned the project, performed experiments and analysed data. W.X.L. planned the project and wrote the paper.

Corresponding author

Correspondence to Willis X. Li.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary Figures S1, S2, S3, S4 and S5 (PDF 880 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, J., Li, W. A novel function of Drosophila eIF4A as a negative regulator of Dpp/BMP signalling that mediates SMAD degradation. Nat Cell Biol 8, 1407–1414 (2006). https://doi.org/10.1038/ncb1506

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1506

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