p21-Activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils.
p21-Activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils.
复制标题
DOI：
10.1371/journal.pone.0073063
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
McCarty OJ
中科院分区：
文献类型：
--
作者：
Itakura A;Aslan JE;Kusanto BT;Phillips KG;Porter JE;Newton PK;Nan X;Insall RH;Chernoff J;McCarty OJ
中性粒细胞作为先天免疫的第一道防线，部分原因是它们能够迅速迁移到来自入侵病原体的趋化因子。作为一种迁移功能，中性粒细胞趋化性是由小gtpase的Rho家族调节的。然而，Rho gtpase在迁移中性粒细胞中协调细胞骨架动力学的机制仍然不明确。在这项研究中，我们表征了Rho GTPases下游的p21活化激酶（PAK）在人类中性粒细胞的细胞骨架重塑和趋化过程中的作用。我们发现，在f-Met-Leu-Phe （fMLP）刺激中性粒细胞时，PAK被激活，PAK在受刺激的中性粒细胞富含肌动蛋白的前沿积聚，这表明PAK在rac依赖性肌动蛋白重塑中起作用。使用PAK抑制剂PF3758309治疗，rhoa介导的肌动球蛋白收缩力和表面粘附的完整性被破坏。此外，抑制PAK活性会在fMLP梯度下损害中性粒细胞形态极化和定向迁移，并与Ca2+信号失调有关。这些结果表明，PAK是rho家族gtpase在中性粒细胞细胞骨架重组中的重要效应因子，在驱动人类中性粒细胞高效定向迁移中起关键作用。
Neutrophils serve as a first line of defense in innate immunity owing in part to their ability to rapidly migrate towards chemotactic factors derived from invading pathogens. As a migratory function, neutrophil chemotaxis is regulated by the Rho family of small GTPases. However, the mechanisms by which Rho GTPases orchestrate cytoskeletal dynamics in migrating neutrophils remain ill-defined. In this study, we characterized the role of p21-activated kinase (PAK) downstream of Rho GTPases in cytoskeletal remodeling and chemotactic processes of human neutrophils. We found that PAK activation occurred upon stimulation of neutrophils with f-Met-Leu-Phe (fMLP), and PAK accumulated at the actin-rich leading edge of stimulated neutrophils, suggesting a role for PAK in Rac-dependent actin remodeling. Treatment with the pharmacological PAK inhibitor, PF3758309, abrogated the integrity of RhoA-mediated actomyosin contractility and surface adhesion. Moreover, inhibition of PAK activity impaired neutrophil morphological polarization and directional migration under a gradient of fMLP, and was associated with dysregulated Ca2+ signaling. These results suggest that PAK serves as an important effector of Rho-family GTPases in neutrophil cytoskeletal reorganization, and plays a key role in driving efficient directional migration of human neutrophils.
登录
查看更多内容
影响因子：
5.3
作者：
Manser, E;Huang, HY;Lim, L
通讯作者：
Lim, L
影响因子：
11.2
作者：
Chow HY;Jubb AM;Koch JN;Jaffer ZM;Stepanova D;Campbell DA;Duron SG;O'Farrell M;Cai KQ;Klein-Szanto AJ;Gutkind JS;Hoeflich KP;Chernoff J
通讯作者：
Chernoff J
影响因子：
5.3
作者：
Coniglio, Salvatore J.;Zavarella, Salvatore;Symons, Marc H.
通讯作者：
Symons, Marc H.
影响因子：
56.9
作者：
KNAUS, UG;MORRIS, S;BOKOCH, GM
通讯作者：
BOKOCH, GM
影响因子：
56.9
作者：
Li, Z;Jiang, HP;Wu, DQ
通讯作者：
Wu, DQ