PLoS ONE (Jan 2013)

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

  • Asako Itakura,
  • Joseph E Aslan,
  • Branden T Kusanto,
  • Kevin G Phillips,
  • Juliana E Porter,
  • Paul K Newton,
  • Xiaolin Nan,
  • Robert H Insall,
  • Jonathan Chernoff,
  • Owen J T McCarty

DOI
https://doi.org/10.1371/journal.pone.0073063
Journal volume & issue
Vol. 8, no. 9
p. e73063

Abstract

Read online

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.