Brief Communication abstract
Nature Cell Biology 4, 513 - 518 (2002)
Published online: 24 June 2002 | doi:10.1038/ncb810
Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils
Fei Wang1, Paul Herzmark1, Orion D. Weiner3, Supriya Srinivasan1, Guy Servant4 & Henry R. Bourne2
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.
- Departments of Cellular and Molecular Pharmacology and Medicine and the Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0450, USA
- S-1212, Box 0450, University of California School of Medicine, 513 Parnassus avenue, San Francisco, CA 94143, USA
- Present address: Department of Cell Biology, Harvard Medical School, 240 Longwood Ave/ C-1, Boston, MA 02115, USA
- Present address: Senomyx, Inc., 11099 N. Torrey Pines Drive, Suite 160, La Jolla, CA 92037, USA
Correspondence to: Henry R. Bourne2 e-mail: bourne@cmp.ucsf.edu
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