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:

Osmotic stress activates phosphatidylinositol-3,5-bisphosphate synthesis

Nature volume 390, pages 187–192 (1997)Cite this article

Abstract

Inositol phospholipids play multiple roles in cell signalling systems. Two widespread eukaryotic phosphoinositide-based signal transduction mechanisms, phosphoinositidase C-catalysed phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) hydrolysis and 3-OH kinase-catalysed PtdIns(4,5)P2 phosphorylation, make the second messengers inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) sn-1,2-diacylglycerol and PtdIns(3,4,5)P3 (refs 1,2,3,4,5,6,7). In addition, PtdIns(4,5)P2 and PtdIns3P have been implicated in exocytosis and membrane trafficking8. We now show that when the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe are hyperosmotically stressed, they rapidly synthesize phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P2) by a process that involves activation of a PtdIns3P 5-OH kinase. This PtdIns(3,5)P2 accumulation only occurs in yeasts that have an active vps34-encoded PtdIns 3-OH kinase, showing that this latter kinase makes the PtdIns3P needed for PtdIns(3,5)P2 synthesis and indicating that PtdIns(3,5)P2 may have a role in sorting vesicular proteins. PtdIns(3,5)P2 is also present in mammalian and plant cells: in monkey Cos-7 cells, its labelling is inversely related to the external osmotic pressure. The stimulation of a PtdIns3P 5-OH kinase-catalysed synthesis of PtdIns(3,5)P2, a molecule that might be a new type of phosphoinositide ‘second messenger’, thus appears to be central to a widespread and previously uncharacterized regulatory pathway.

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: Identiffication of a novel yeast PtdIns(4,5)P2 as PtdIns(3,5)P2.
Figure 2: Increased PtdIns(3,5)P2 synthesis in S.
Figure 3: Demonstration of the presence of PtdIns(3,5)P2 in S.
Figure 4: Scheme to illustrate the likely relationships between the stress-activated synthesis of PtdIns(3,5)P2 described here (boxed, le.

Similar content being viewed by others

References

  1. Creba, J. A. et al. Rapid breakdown of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate in rat hepatocytes stimulated by vasopressin and other Ca2+-mobilising hormones. Biochem. J. 212, 733–747 (1983).

    Article  CAS  Google Scholar 

  2. Berridge, M. J. Inositol trisphosphate and diacylglycerol: two interacting second messengers. Annu. Rev. Biochem. 56, 159–193 (1987).

    Article  CAS  Google Scholar 

  3. Berridge, M. J. Inositol trisphosphate and calcium signalling. Nature 361, 315–325 (1993).

    Article  CAS  ADS  Google Scholar 

  4. Nishizuka, Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 308, 693–697 (1984).

    Article  CAS  ADS  Google Scholar 

  5. Nishizuka, Y. The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature 334, 661–665 (1990).

    Article  ADS  Google Scholar 

  6. Stephens, L., Jackson, T. R. & Hawkins, P. T. Agonist-stimulated synthesis of phosphatidylinositol (3,4,5)-trisphosphate: a new intracellular signalling system? Biochim. Biophys. Acta 1179, 27–75 (1993).

    Article  CAS  Google Scholar 

  7. Toker, A. & Cantley, L. C. Signalling through the lipid products of phosphoinositide-3-OH kinase. Nature 387, 673–676 (1997).

    Article  CAS  ADS  Google Scholar 

  8. De Camilli, P., Emr, S. D., McPherson, P. S. & Novick, P. Phosphoinositides as regulators in membrane traffic Science 271, 1533–1539 (1996).

    Article  CAS  ADS  Google Scholar 

  9. Letcher, A. J., Stephens, L. R. & Irvine, R. F. in Methods in Inositide Research (ed. Irvine, R. F.) 31–37 (Raven, London, (1990)).

    Google Scholar 

  10. Stephens, L. R., Hughes, K. T. & Irvine, R. F. Pathway of phosphatidylinositol (3,4,5)-trisphosphate synthesis in activated neutrophils. Nature 351, 33–39 (1991).

    Article  CAS  ADS  Google Scholar 

  11. Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P. & Cantley, L. C. PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57, 167–175 (1989).

    Article  CAS  Google Scholar 

  12. Graziani, A., Ling, L. E., Endemann, G. & Cantley, L. C. Purification and characterisation of human erythrocyte phosphatidylinositol 4-kinase: phosphatidylinositol 4-kinase and phosphatidylinositol 3-phosphate 4-kinase are distinct enzymes. Biochem. J. 284, 39–45 (1992).

    Article  CAS  Google Scholar 

  13. Whiteford, C. A., Brearley, C. A. & Ulug, E. T. Phosphatidylinositol 3,5-bisphosphate defines a new phosphatidylinositol 3-kinase pathway in resting mouse fibroblasts. Biochem. J. 323, 597–601 (1997).

    Article  CAS  Google Scholar 

  14. Schuller, C., Brewster, J. L., Alexander, M., Gustin, M. & Ruis, H. The Hog pathway controls osmotic regulation of transcription via the stress-response element (stre) of the Saccharomyces cerevisiae ctt1 gene. EMBO J. 13, 4382–4389 (1994).

    Article  CAS  Google Scholar 

  15. Wurgler-Murphy, S. M. & Saito, H. Two-component signal transducers and MAPK cascades. Trends Biochem. Sci. 22, 172–176 (1997).

    Article  CAS  Google Scholar 

  16. Doughney, C., McPherson, M. A. & Dormer, R. L. Metabolism of inositol 1,3,4,5-tetrakisphosphate by human erythrocyte membranes. Biochem. J. 251, 927–929 (1988).

    Article  CAS  Google Scholar 

  17. Schu, P. V. et al. Phosphatidylinositol 3-kinase encoded by yeast vps34 gene essential for protein sorting. Science 260, 88–91 (1993).

    Article  CAS  ADS  Google Scholar 

  18. Vanhaesebrock, B., Leevers, S. J., Panayatou, G. & Waterfield, M. D. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem. Sci. 22, 267–272 (1997).

    Article  Google Scholar 

  19. Einspahr, K. J., Peeler, R. C. & Thompson, G. A. Rapid changes in polyphosphoinositide metabolism associated with the response of Dunaliella salina to hypo-osmotic shock. J. Biol. Chem. 263, 5775–5779 (1988).

    CAS  PubMed  Google Scholar 

  20. Yamamoto, A. et al. Novel PI(4)P 5-kinase homologue, Fab1p, essential for normal vacuole function and morphology in yeast. Mol. Biol. Cell 6, 525–539 (1995).

    Article  CAS  Google Scholar 

  21. Divecha, N. & Irvine, R. F. Phospholipid signalling. Cell 80, 269–278 (1995).

    Article  CAS  Google Scholar 

  22. Wickerham, L. J. Acritical evaluation of the nitrogen assimilation tests commonly used in the classification of yeasts. J. Bacteriol. 52, 293–301 (1946).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Stephens, L. R., Hawkins, P. T. & Downes, C. P. Metabolic and structural evidence for the existence of a third species of polyphosphoinositide in cells, D-phosphatidyl-myo-inositol 3-phosphate. Biochem. J. 259, 267–276 (1989).

    Article  CAS  Google Scholar 

  24. Wreggett, K. & Irvine, R. F. Automated isocratic hplc of inositol phosphate isomers. Biochem. J. 262, 997–1000 (1989).

    Article  CAS  Google Scholar 

  25. Jenkinson, S. in Methods in Molecular Biology: Signal Transduction Protocols (eds Kendall, D. A. & Hill, S. J.) Vol. 41, 151–166 (Humana, Totowa, NJ, (1995)).

    Book  Google Scholar 

  26. Barker, C. J. et al. Inositol 1,2,3-trisphosphate and inositol 1,2- and/or 2,3-bisphosphate are normal constituents of mammalian cells. Biochem. J. 306, 557–564 (1995).

    Article  CAS  Google Scholar 

  27. Woscholski, R., Waterfield, M. D. & Parker, P. J. Purification and biochemical characterization of a mammalian phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase. J. Biol. Chem. 270, 31001–31007 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Royal Society (R.H.M. and L.R.S.), the MRC (R.H.M.), and the Beit Memorial Trust (S.K.D.) for financial support. We also thank S. Emr and M. J. Gustin for yeast strains and for discussion.

Author information

Author notes

  1. Stephen K. Dove, Frank T. Cooke, Lee G. Sayers and Peter J. Parker: These authors contributed equally to this work

Authors and Affiliations

  1. Centre for Clinical Research in Immunology and Signalling,

    Stephen K. Dove & Robert H. Michell

  2. Departments of Biochemistry,

    Stephen K. Dove & Robert H. Michell

  3. Departments of Rheumatology, University of Birmingham, Birmingham, B15 2TT, UK

    Michael R. Douglas

  4. Imperial Cancer Research Fund Laboratories, PO Box 123, Lincoln's Inn Fields, WC2A 3PX, London, UK

    Frank T. Cooke, Lee G. Sayers & Peter J. Parker

Authors
  1. Stephen K. Dove
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Frank T. Cooke
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael R. Douglas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lee G. Sayers
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peter J. Parker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert H. Michell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Stephen K. Dove.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dove, S., Cooke, F., Douglas, M. et al. Osmotic stress activates phosphatidylinositol-3,5-bisphosphate synthesis. Nature 390, 187–192 (1997). https://doi.org/10.1038/36613

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/36613

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