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

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.

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Figure 1: Migration toward a point source of chemo-attractant.
Figure 2: PI(3)K inhibitors impair gradient interpretation.
Figure 3: The effects of latrunculin on chemotactic signal amplification.
Figure 4: The effects of jasplakinolide on chemotactic signal amplification.

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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.

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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

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Correspondence to Henry R. Bourne.

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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

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