TY - JOUR
T1 - Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils
AU - Wang, Fei
AU - Herzmark, Paul
AU - Weiner, Orion D.
AU - Srinivasan, Supriya
AU - Servant, Guy
AU - Bourne, Henry R.
N1 - Funding Information:
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. Correspondence and requests for material should be addressed to H.R.B. Supplementary information is available on Nature Cell Biology’s website (http://cellbio.nature.com).
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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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U2 - 10.1038/ncb810
DO - 10.1038/ncb810
M3 - Article
C2 - 12080345
AN - SCOPUS:0036308458
SN - 1465-7392
VL - 4
SP - 513
EP - 518
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 7
ER -