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Input from Ras is required for maximal PI(3)K signalling in Drosophila

Nature Cell Biology volume 8, pages 1298–1302 (2006)Cite this article

Abstract

Class I phosphoinositide 3-kinases (PI(3)Ks) are activated through associated adaptor molecules in response to G protein-coupled and tyrosine kinase receptor signalling1. They contain Ras-binding domains (RBDs) and can also be activated through direct association with active GTP-bound Ras2,3,4,5,6,7,8,9,10. The ability of Ras to activate PI(3)K has been established in vitro and by overexpression analysis, but its relevance for normal PI(3)K function in vivo is unknown. The Drosophila class I PI(3)K, Dp110, is activated by nutrient-responsive insulin signalling and modulates growth, oogenesis and metabolism11,12,13,14,15. To investigate the importance of Ras-mediated PI(3)K activation for normal PI(3)K function, we replaced Dp110 with Dp110RBD, which is unable to bind to Ras but otherwise biochemically normal. We found that Ras-mediated Dp110 regulation is dispensable for viability. However, egg production, which requires large amounts of growth, is dramatically lowered in Dp110RBD flies. Furthermore, insulin cannot maximally activate PI(3)K signalling in Dp110RBD imaginal discs and Dp110RBD flies are small. Thus, Dp110 integrates inputs from its phosphotyrosine-binding adaptor and Ras to achieve maximal PI(3)K signalling in specific biological situations.

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Figure 1: Dp110RBD does not bind Ras1, but is otherwise biochemically similar to wild-type Dp110.
Figure 2: The interaction between Dp110 and Ras1 is not essential for Drosophila viability.
Figure 3: Myc–Dp110RBD flies cannot maximally activate PI(3)K signalling.

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References

  1. Vanhaesebroeck, B. et al. Synthesis and function of 3-phosphorylated inositol lipids. Annu. Rev. Biochem. 70, 535–602 (2001).

    Article  CAS  Google Scholar 

  2. Marte, B. M., Rodriguez-Viciana, P., Wennstrom, S., Warne, P. H. & Downward, J. R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways. Curr. Biol. 7, 63–70 (1997).

    Article  CAS  Google Scholar 

  3. Pacold, M. E. et al. Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase γ. Cell 103, 931–943 (2000).

    Article  CAS  Google Scholar 

  4. Rodriguez-Viciana, P., Sabatier, C. & McCormick, F. Signaling specificity by Ras family GTPases is determined by the full spectrum of effectors they regulate. Mol. Cell Biol. 24, 4943–4954 (2004).

    Article  CAS  Google Scholar 

  5. Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).

    Article  CAS  Google Scholar 

  6. Rodriguez-Viciana, P. et al. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89, 457–467 (1997).

    Article  CAS  Google Scholar 

  7. Rodriguez-Viciana, P., Warne, P. H., Vanhaesebroeck, B., Waterfield, M. D. & Downward, J. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J. 15, 2442–2451 (1996).

    Article  CAS  Google Scholar 

  8. Rubio, I., Rodriguez-Viciana, P., Downward, J. & Wetzker, R. Interaction of Ras with phosphoinositide 3-kinase γ. Biochem. J. 326, 891–895 (1997).

    Article  CAS  Google Scholar 

  9. Suire, S., Hawkins, P. & Stephens, L. Activation of phosphoinositide 3-kinase γ by Ras. Curr. Biol. 12, 1068–1075 (2002).

    Article  CAS  Google Scholar 

  10. Vanhaesebroeck, B. et al. P110δ, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl Acad. Sci. USA 94, 4330–4335 (1997).

    Article  CAS  Google Scholar 

  11. Drummond-Barbosa, D. & Spradling, A. C. Stem cells and their progeny respond to nutritional changes during Drosophila oogenesis. Dev. Biol. 231, 265–278 (2001).

    Article  CAS  Google Scholar 

  12. LaFever, L. & Drummond-Barbosa, D. Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science 309, 1071–1073 (2005).

    Article  CAS  Google Scholar 

  13. Leevers, S. J. & Hafen, E. Growth regulation by insulin and TOR signaling in Drosophila. in Cell Growth: Control of Cell Size (eds. Hall, M. N., Raff, M. & Thomas, G.) 167–192 (Cold Spring Harbour Laboratory Press, Cold Spring Harbour, 2004).

    Google Scholar 

  14. 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 

  15. Wu, Q. & Brown, M. R. Signaling and function of insulin-like peptides in insects. Annu. Rev. Entomol. 51, 1–24 (2006).

    Article  CAS  Google Scholar 

  16. Lizcano, J. M. et al. Insulin-induced Drosophila S6 kinase activation requires phosphoinositide 3-kinase and protein kinase B. Biochem. J. 374, 297–306 (2003).

    Article  CAS  Google Scholar 

  17. Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).

    Article  CAS  Google Scholar 

  18. Weinkove, D., Leevers, S. J., MacDougall, L. K. & Waterfield, M. D. p60 is an adaptor for the Drosophila phosphoinositide 3-kinase, Dp110. J. Biol. Chem. 272, 14606–14610 (1997).

    Article  CAS  Google Scholar 

  19. 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 

  20. Colicelli, J. Human RAS superfamily proteins and related GTPases. Sci. STKE re13 (2004).

  21. Karim, F. D. & Rubin, G. M. Ectopic expression of activated Ras1 induces hyperplastic growth and increased cell death in Drosophila imaginal tissues. Development 125, 1–9 (1998).

    CAS  PubMed  Google Scholar 

  22. Prober, D. A. & Edgar, B. A. Ras1 promotes cellular growth in the Drosophila wing. Cell 100, 435–446 (2000).

    Article  CAS  Google Scholar 

  23. Prober, D. A. & Edgar, B. A. Interactions between Ras1, dMyc, and dPI3K signaling in the developing Drosophila wing. Genes Dev. 16, 2286–2299 (2002).

    Article  CAS  Google Scholar 

  24. Diaz-Benjumea, F. J. & Hafen, E. The sevenless signalling cassette mediates Drosophila EGF receptor function during epidermal development. Development 120, 569–578 (1994).

    CAS  PubMed  Google Scholar 

  25. Strutt, H. & Strutt, D. EGF signaling and ommatidial rotation in the Drosophila eye. Curr. Biol. 13, 1451–1457 (2003).

    Article  CAS  Google Scholar 

  26. Kypta, R. M., Su, H. & Reichardt, L. F. Association between a transmembrane protein tyrosine phosphatase and the cadherin-catenin complex. J. Cell Biol. 134, 1519–1529 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank R. Williams for advice on mutation of the RBD, M. White for pGEX–Ras1, H. Stocker and E. Hafen for hypomorphic Dp110 mutants, and L. Foukas, B. Vanhaesebroeck, B. Baum, N. Tapon and M. Giannakou for advice, reagents and helpful discussions. We thank the Cancer Research UK London Research Institute (CRUK LRI) Equipment Park and Fly Facility for technical support and M. Cully, J. Downward, C. Marshall, S. Marygold, N. Tapon and B. Vanhaesebroeck for advice on manuscript preparation. This work was supported by Cancer Research UK, The Ludwig Institute for Cancer Research and the BBSRC.

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  1. Growth Regulation Laboratory, Cancer Research UK London Research Institute,, PO Box 123, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK

    Mariam H. Orme, Saif Alrubaie, Gemma L. Bradley, Cherryl D. Walker & Sally J. Leevers

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  1. Mariam H. Orme
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Correspondence to Sally J. Leevers.

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Orme, M., Alrubaie, S., Bradley, G. et al. Input from Ras is required for maximal PI(3)K signalling in Drosophila. Nat Cell Biol 8, 1298–1302 (2006). https://doi.org/10.1038/ncb1493

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