p21-Activated Kinase (PAK) Regulates Cytoskeletal Reorganization and Directional Migration in Human Neutrophils

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere73063
JournalPLoS One
Volume8
Issue number9
DOIs
StatePublished - Sep 3 2013

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p21-Activated Kinases
neutrophils
phosphotransferases (kinases)
Neutrophils
guanosinetriphosphatase
rho GTP-Binding Proteins
methionyl-leucyl-phenylalanine
Actins
actin
Actomyosin
Monomeric GTP-Binding Proteins
GTP Phosphohydrolases
Chemotactic Factors
Pathogens
Aptitude
chemoattractants
chemotaxis
Chemotaxis
Adhesion
Innate Immunity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

p21-Activated Kinase (PAK) Regulates Cytoskeletal Reorganization and Directional Migration in Human Neutrophils. / Itakura, Asako; Aslan, Joseph; Kusanto, Branden T.; Phillips, Kevin G.; Porter, Juliana E.; Newton, Paul K.; Nan, Xiaolin; Insall, Robert H.; Chernoff, Jonathan; McCarty, Owen.

In: PLoS One, Vol. 8, No. 9, e73063, 03.09.2013.

Research output: Contribution to journalArticle

Itakura, Asako ; Aslan, Joseph ; Kusanto, Branden T. ; Phillips, Kevin G. ; Porter, Juliana E. ; Newton, Paul K. ; Nan, Xiaolin ; Insall, Robert H. ; Chernoff, Jonathan ; McCarty, Owen. / p21-Activated Kinase (PAK) Regulates Cytoskeletal Reorganization and Directional Migration in Human Neutrophils. In: PLoS One. 2013 ; Vol. 8, No. 9.
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