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首页> 外文学位 >Signaling of chemotactic-receptor stimulated F-actin polymerization in the human neutrophil.
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Signaling of chemotactic-receptor stimulated F-actin polymerization in the human neutrophil.

机译：趋化受体刺激人嗜中性粒细胞中F-肌动蛋白聚合的信号。

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摘要

The motility responses of the human neutrophil are essential in the body's defense against pathogens. Neutrophil motility is critically dependent on its ability to sense its environment and dynamically control its cellular actin cytoskeleton accordingly. The rearrangement of the cytoskeleton is associated with the temporary extension and stabilization of lamellipodia in the direction of movement. Lamella extension, and other migratory responses of the cell, is initiated by different membrane associated receptors that signal a variety of molecules grouped in signaling pathways. The receptor-generated signals eventually converge in the polymerization of F-actin, which is manifested as lamella formation and an overall rearrangement of the actin cytoskeleton. The precise mechanisms of the coupling and modulation of the signals generated from the different membrane receptors to the processes controlling cell migration are not yet entirely elucidated. However, it is known that the migration of the neutrophil is dependent on the p110 catalytic subunit of phosphoinositide 3-kinase γ. Here we present the first direct evidence for the existence of two distinct signaling pathways leading to F-actin polymerization in the pseudopod region: one pathway is dependent on the catalytic activity of the p110 subunit of the phosphoinositide 3-kinases and the other involves the regulatory p85α subunit. The p110-dependent signaling of F-actin polymerization also involves the activation of protein kinase C ζ and protein kinase B. The p85α-dependent pathway also includes the small GTPase RhoA, ROCK, Src family tyrosine kinases, NADPH and protein kinase A. These distinct pathways are chemotactic-receptor specific and utilize different isoforms of the phosphoinositide 3-kinases, some of which are differentially regulated by the growth factor, granulocyte-macrophage colony-stimulating factor, and insulin. Furthermore, in certain physiological conditions the p85α-dependent pathway may play a leading role in the polymerization of F-actin and overall cell migration. The results presented here were accomplished utilizing both single cell micropipet manipulation techniques and bulk biochemistry methods to characterize the motility responses of neutrophils, establishing links between the biochemical environment of the cell and the underlying signaling responses of activated neutrophils.
机译：人类嗜中性粒细胞的运动反应对于机体抵御病原体至关重要。中性粒细胞的运动性主要取决于其感知环境并相应地动态控制其细胞肌动蛋白细胞骨架的能力。细胞骨架的重排与片状脂膜在运动方向上的暂时延伸和稳定有关。薄层扩展以及其他细胞迁移反应是由不同的膜相关受体引发的，这些受体发出信号的多种分子在信号通路中分组。受体产生的信号最终收敛于F-肌动蛋白的聚合反应，这表现为薄片形成和肌动蛋白细胞骨架的整体重排。尚未完全阐明不同膜受体产生的信号与控制细胞迁移过程的耦合和调制的精确机制。然而，已知中性粒细胞的迁移取决于磷酸肌醇3-激酶γ的p110催化亚基。在这里，我们提供了在伪足区域中导致F-肌动蛋白聚合的两个不同信号通路存在的第一个直接证据：一个通路取决于磷酸肌醇3-激酶的p110亚基的催化活性，另一个通路涉及调节p85α亚基。 F-肌动蛋白聚合反应的p110依赖性信号转导还涉及蛋白激酶Cζ和蛋白激酶B的激活。p85α依赖性途径还包括小的GTPase RhoA，ROCK，Src家族酪氨酸激酶，NADPH和蛋白激酶A。不同的途径是趋化受体特异性的，并利用磷酸肌醇3-激酶的不同同工型，其中一些受生长因子，粒细胞-巨噬细胞集落刺激因子和胰岛素的调节。此外，在某些生理条件下，p85α依赖性途径可能在F-肌动蛋白的聚合和整个细胞迁移中起主导作用。此处介绍的结果是利用单细胞微量移液器操作技术和批量生化方法表征嗜中性粒细胞的运动反应，在细胞的生化环境与活化嗜中性粒细胞的潜在信号传导反应之间建立联系而实现的。

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  • 作者

    Chodniewicz, David.;

  • 作者单位

    Duke University.;

  • 授予单位 Duke University.;
  • 学科 Biology Cell.; Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2003
  • 页码 217 p.
  • 总页数 217
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞生物学;预防医学、卫生学;
  • 关键词

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