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Itakura A , Aslan JE , Kusanto BT , Phillips KG , Porter JE , Newton PK , Nan XL , Insall RH , Chernoff J , McCarty OJT
p21-Activated Kinase (PAK) Regulates Cytoskeletal Reorganization and Directional Migration in Human Neutrophils
Plos One. 2013 Sep;8(9) :e73063
PMID: WOS:000324338200036    PMCID: PMC 3760889   
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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.
Itakura, Asako Aslan, Joseph E. Kusanto, Branden T. Phillips, Kevin G. Porter, Juliana E. Newton, Paul K. Nan, Xiaolin Insall, Robert H. Chernoff, Jonathan McCarty, Owen J. T.