Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils
Lipid products of PI(3)Ks maintain persistent cell polarity and directed motility in neutrophils
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DOI：
10.1038/ncb810
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发表时间：
2002-07-01
影响因子：
21.3
通讯作者：
Bourne, HR
中科院分区：
文献类型：
--
作者：
Wang, F;Herzmark, P;Bourne, HR
在外部化学引诱剂的梯度中，哺乳动物嗜中性白细胞（中性粒细胞）（1）和盘状网柄藻（Dictyosteelium discoideum amoeicum）2采用极化形态，并选择性地在其上梯度边缘积累磷脂酰肌醇-3-OH激酶（PI（3）Ks）的脂质产物，包括PtdIns（3，4，5）P-3;内部PtdIns（3，4，5）P-3梯度显著超过外部引诱剂的梯度。随附的报告3提供了放大内部信号梯度的正反馈回路的证据：前沿的PtdIns（3，4，5）P-3通过诱导一种或多种Rho GTP酶（Rac、Cdc 42和/或Rho）的激活来刺激其自身的积累，这反过来又增加了PtdIns（3，4，5）P-3的积累。在这里，我们表明，中断这种反馈与PI（3）K抑制剂治疗减少伪足的大小和稳定性，并导致细胞迁移在颠簸的轨迹，偏离更多的向上梯度方向比那些控制。此外，内部PtdIns（3，4，5）P-3梯度的扩增明显受到latrunculin或jasplakinastrin的损害，这两种毒素分别抑制肌动蛋白的聚合（4，5）或解聚（6）。因此，PtdIns（3，4，5）P-3和聚合肌动蛋白之间的相互作用启动并维持负责细胞极性和定向运动的细胞内信号的不对称性。
In gradients of external chemo-attractant, mammalian neutrophilic leukocytes (neutrophils)(1) and Dictyostelium discoideum amoebae 2 adopt a polarized morphology and selectively accumulate lipid products of phosphatidylinositol-3-OH kinases (PI(3) Ks), including PtdIns(3,4,5) P-3, at their up-gradient edges; the internal PtdIns(3,4,5) P-3 gradient substantially exceeds that of the external attractant. An accompanying report 3 presents evidence for a positive feedback loop that amplifies the gradient of internal signal: PtdIns(3,4,5) P-3 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) P-3 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) P-3 gradient is markedly impaired by latrunculin or jasplakinolide, toxins that inhibit polymerization (4,5) or depolymerization(6) of actin, respectively. Thus reciprocal interplay between PtdIns(3,4,5) P-3 and polymerized actin initiates and maintains the asymmetry of intracellular signals responsible for cell polarity and directed motility.