Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils (original) (raw)

Nature Cell Biology volume 4, pages 513–518 (2002)Cite this article

Abstract

In gradients of external chemo-attractant, mammalian neutrophilic leukocytes (neutrophils)1 and Dictyostelium discoideum amoebae2 adopt a polarized morphology and selectively accumulate lipid products of phosphatidylinositol-3-OH kinases (PI(3)Ks), including PtdIns(3,4,5)P3, at their up-gradient edges; the internal PtdIns(3,4,5)P3 gradient substantially exceeds that of the external attractant. An accompanying report3 presents evidence for a positive feedback loop that amplifies the gradient of internal signal: PtdIns(3,4,5)P3 at the leading edge stimulates its own accumulation by inducing activation of one or more Rho GTPases (Rac, Cdc42, and/or Rho), which in turn increase PtdIns(3,4,5)P3 accumulation. Here we show that interruption of this feedback by treatment with PI(3)K inhibitors reduces the size and stability of pseudopods and causes cells to migrate in jerky trajectories that deviate more from the up-gradient direction than do those of controls. Moreover, amplification of the internal PtdIns(3,4,5)P3 gradient is markedly impaired by latrunculin or jasplakinolide, toxins that inhibit polymerization4,5 or depolymerization6 of actin, respectively. Thus reciprocal interplay between PtdIns(3,4,5)P3 and polymerized actin initiates and maintains the asymmetry of intracellular signals responsible for cell polarity and directed motility.

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

Access options

Subscribe to this journal

Receive 12 print issues and online access

$209.00 per year

only $17.42 per issue

Buy this article

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

Additional access options:

Similar content being viewed by others

References

  1. Servant, G. et al. Science 287, 1037–1040 (2000).
    Article CAS Google Scholar
  2. Meili, R. et al. EMBO J. 18, 2092–2105 (1999).
    Article CAS Google Scholar
  3. Weiner, O. D. et al. Nature Cell Biol. DOI: 10.1038/ncb811.
  4. Coue, M., Brenner, S. L., Spector, I. & Korn, E. D. FEBS Lett. 213, 316–318 (1987).
    Article CAS Google Scholar
  5. Spector, I., Shochet, N. R., Kashman, Y. & Groweiss, A. Science 219, 493–495 (1983).
    Article CAS Google Scholar
  6. Bubb, M. R., Senderowicz, A. M., Sausville, E. A., Duncan, K. L. & Korn, E. D. J. Biol. Chem. 269, 14869–14871 (1994).
    CAS PubMed Google Scholar
  7. Rickert, P., Weiner, O. D., Wang, F., Bourne, H. R. & Servant, G. Trends Cell Biol. 10, 466–473 (2000).
    Article CAS Google Scholar
  8. Chung, C. Y., Funamoto, S. & Firtel, R. A. Trends Biochem. Sci. 26, 557–566 (2001).
    Article CAS Google Scholar
  9. Haugh, J. M., Codazzi, F., Teruel, M. & Meyer, T. J. Cell Biol. 151, 1269–1280 (2000).
    Article CAS Google Scholar
  10. Funamoto, S., Milan, K., Meili, R. & Firtel, R. A. J. Cell Biol. 153, 795–810 (2001).
    Article CAS Google Scholar
  11. Knall, C., Worthen, G. S. & Johnson, G. L. Proc. Natl Acad. Sci. USA 94, 3052–3057 (1997).
    Article CAS Google Scholar
  12. Hirsch, E., et al. Science 287, 1049–1053 (2000).
    Article CAS Google Scholar
  13. Niggli, V. & Keller, H. Eur. J. Pharmacol. 335, 43–52 (1997).
    Article CAS Google Scholar
  14. Li, Z., et al. Science 287, 1046–1049 (2000).
    Article CAS Google Scholar
  15. Sasaki, T., et al. Science 287, 1040–1046 (2000).
    Article CAS Google Scholar
  16. Niggli, V. FEBS Lett. 473, 217–221 (2000).
    Article CAS Google Scholar
  17. Foxman, E. F., Campbell, J. J. & Butcher, E. C. J. Cell Biol. 139, 1349–1360 (1997).
    Article CAS Google Scholar
  18. Sheikh, S., Gratzer, W. B., Pinder, J. C. & Nash, G. B. Biochem. Biophys. Res. Commun. 238, 910–915 (1997).
    Article CAS Google Scholar
  19. Stephens, L. R. et al. Cell 89, 105–114 (1997).
    Article CAS Google Scholar
  20. Naccache, P. H. et al. J. Biol. Chem. 275, 23636–23641 (2000).
    Article CAS Google Scholar
  21. Hannigan, M. et al. Proc. Natl Acad. Sci. USA 99, 3603–3608 (2002).
    Article CAS Google Scholar
  22. Ayscough, K. R. Curr. Biol. 10, 1587–1590 (2000).
    Article CAS Google Scholar
  23. Ayscough, K. R. & Drubin, D. G. Curr. Biol. 8, 927–930 (1998).
    Article CAS Google Scholar
  24. Peyrollier, K. et al. Biochem. J. 352, 617–622 (2000).
    Article CAS Google Scholar
  25. Servant, G., Weiner, O. D., Neptune, E. R., Sedat, J. W. & Bourne, H. R. Mol. Biol. Cell. 10, 1163–1178 (1999).
    Article CAS Google Scholar
  26. Weiner, O. D. et al. Nature Cell Biol. 1, 75–81 (1999).
    Article CAS Google Scholar

Download references

Acknowledgements

We thank members of the Bourne laboratory for valuable discussions. This work was supported by National Institutes of Health grants GM-27800 and CA-54427 to H.R.B., an NIH training grant HL07713 to F.W., and a grant from the Leukemia and Lymphoma Society to S.S.

Author information

Author notes

  1. Orion D. Weiner
    Present address: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave/ C-1, Boston, MA 02115, USA
  2. Guy Servant
    Present address: Senomyx, Inc., 11099 N. Torrey Pines Drive, Suite 160, La Jolla, CA 92037, USA

Authors and Affiliations

  1. Departments of Cellular and Molecular Pharmacology and Medicine and the Cardiovascular Research Institute, University of California, San Francisco, 94143-0450, CA, USA
    Fei Wang, Paul Herzmark & Supriya Srinivasan
  2. University of California School of Medicine, S-1212, Box 0450, 513 Parnassus avenue, San Francisco, 94143, CA, USA
    Henry R. Bourne

Authors

  1. Fei Wang
    You can also search for this author inPubMed Google Scholar
  2. Paul Herzmark
    You can also search for this author inPubMed Google Scholar
  3. Orion D. Weiner
    You can also search for this author inPubMed Google Scholar
  4. Supriya Srinivasan
    You can also search for this author inPubMed Google Scholar
  5. Guy Servant
    You can also search for this author inPubMed Google Scholar
  6. Henry R. Bourne
    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toHenry R. Bourne.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

About this article

Cite this article

Wang, F., Herzmark, P., Weiner, O. et al. Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils.Nat Cell Biol 4, 513–518 (2002). https://doi.org/10.1038/ncb810

Download citation

Associated content

Leading the way

Nature Cell Biology News & Views 01 Jul 2002