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A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity

Nature Cell Biology volume 4, pages 509–513 (2002)Cite this article

Abstract

When presented with a gradient of chemoattractant, many eukaryotic cells respond with polarized accumulation of the phospholipid PtdIns(3,4,5)P3. This lipid asymmetry is one of the earliest readouts of polarity in neutrophils, Dictyostelium discoideum and fibroblasts. However, the mechanisms that regulate PtdInsP3 polarization are not well understood. Using a cationic lipid shuttling system, we have delivered exogenous PtdInsP3 to neutrophils. Exogenous PtdInsP3 elicits accumulation of endogenous PtdInsP3 in a positive feedback loop that requires endogenous phosphatidylinositol-3-OH kinases (PI(3)Ks) and Rho family GTPases. This feedback loop is important for establishing PtdInsP3 polarity in response to both chemoattractant and to exogenous PtdInsP3; it may function through a self-organizing pattern formation system. Emergent properties of positive and negative regulatory links between PtdInsP3 and Rho family GTPases may constitute a broadly conserved module for the establishment of cell polarity during eukaryotic chemotaxis.

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Figure 1: PtdInsP3–histone induces translocation of PH-Akt–GFP.
Figure 2: Surface plots of PH-Akt–GFP distribution in neutrophil-differentiated HL-60 cells.
Figure 3: PI(3)K and Rho GTPase inhibitors block PtdInsP3–histone-induced PH-Akt–GFP translocation.
Figure 4: Endogenous PI(3)K and Rho GTPases are not required for PtdInsP3–histone uptake.

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Acknowledgements

We thank S. Ozaki and J. Chen for NBD–PtdInsP3 synthesis, C. Kelley and M. Warny for the kind gift of Clostridium difficile toxin B, R. Tsien's lab for the PtdInsP3-AM used in early experiments, V. Niggli for advice on using this compound with neutrophils, F. Wang for protocols for the PtdInsP3 antibody, Echelon for the gift of phospholipids and histones, and C. Bargmann, C. Carpenter and C. Kenyon for helpful discussions. This work was in part supported by grants from the National Institutes of Health to H.R.B., L.C.C. (GM41890), M.W.K. (GM26825), P.O.N. (GM62734-03), and G.D.P. (NS29632). O.D.W. was supported by a Howard Hughes Medical Institute predoctoral fellowship and the Damon Runyon Cancer Research Fund.

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Authors and Affiliations

  1. Department of Cell Biology, Harvard Medical School, 240 Longwood Ave/ C-1, Boston, 02115, MA, USA

    Orion D. Weiner & Marc W. Kirschner

  2. Department of Cell Biology, Division of Signal Transduction, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, 02115, MA, USA

    Orion D. Weiner & Lewis C. Cantley

  3. Echelon Research Laboratories, 420 Chipeta Way, Suite 180, Salt Lake City, UT, 84108

    Paul O. Neilsen

  4. Department of Medicinal Chemistry, University of Utah, 419 Wakara Way, Suite 205, Salt Lake City, 84108, UT, USA

    Glenn D. Prestwich

  5. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143-0450, CA, USA

    Henry R. Bourne

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  1. Orion D. Weiner
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Correspondence to Henry R. Bourne.

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Weiner, O., Neilsen, P., Prestwich, G. et al. A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity. Nat Cell Biol 4, 509–513 (2002). https://doi.org/10.1038/ncb811

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