title: p21-Activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils.
abstract: 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 Ca(2+) 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.
authors.affiliation: Department of Cell and Developmental Biology, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Asako
authors.initials: A
authors.lastname: Itakura
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Aslan
authors.forename: Branden T
authors.initials: BT
authors.lastname: Kusanto
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Phillips
authors.forename: Juliana E
authors.initials: JE
authors.lastname: Porter
authors.forename: Paul K
authors.initials: PK
authors.lastname: Newton
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Nan
authors.forename: Robert H
authors.initials: RH
authors.lastname: Insall
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chernoff
authors.forename: Owen J T
authors.initials: OJ
authors.lastname: McCarty
mesh_terms: D015153:Blotting, Western; D002634:Chemotaxis, Leukocyte; D003599:Cytoskeleton / Q000378:metabolism*; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D006801:Humans; D008856:Microscopy, Fluorescence; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D021381:Protein Transport; D054462:p21-Activated Kinases / Q000378:metabolism*
chemical_list: D009240:N-Formylmethionine Leucyl-Phenylalanine; D054462:p21-Activated Kinases
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