p21-activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils

Itakura, A., Aslan, J.E., Kusanto, B.T., Phillips, K.G., Porter, J.E., Newton, P.K., Nan, X., Insall, R.H. , Chernoff, J. and McCarty, O.J.T. (2013) p21-activated kinase (PAK) regulates cytoskeletal reorganization and directional migration in human neutrophils. PLoS ONE, 8(9), e73063. (doi: 10.1371/journal.pone.0073063) (PMID:24019894) (PMCID:PMC3760889)

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 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Insall, Professor Robert
• Authors: Itakura, A., Aslan, J.E., Kusanto, B.T., Phillips, K.G., Porter, J.E., Newton, P.K., Nan, X., Insall, R.H., Chernoff, J., and McCarty, O.J.T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2013 The Authors
• First Published: First published in PLoS ONE 8(9):e73063
• Publisher Policy: Reproduced under a Creative Commons License