Submitted March 30, 2006
Accepted August 7, 2006
Rho GTPase CDC42 regulates directionality and
random movement via distinct MAPK pathways in neutrophils
Kathleen Szczur, Haiming Xu, Simon Atkinson, Yi Zheng, and Marie-Dominique Filippi*
Cincinnati Children's Research Foundation, University Cincinnati College of Medicine, Cincinnati, OH
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
* Corresponding author; email: marie-dominique.filippi{at}cchmc.org.
Neutrophil transmigration into tissue is a multiple step process that results from a coordinated rearrangement of the cytoskeleton and adhesion complexes. Assembly and disassembly of actin and adhesion structures dictate motility behavior while polarity and gradient sensing provide directionality to the cell movement. Here, using mice deficient in the CDC42 regulator CDC42 GTPase Activating Protein, we demonstrate that CDC42 activity separately regulates neutrophil motility and directionality. CDC42GAP-/- neutrophils showed increased motility while directed migration was defective. Podosome-like structures present at the leading edge in wild type neutrophils were significantly reduced in CDC42GAP-/- cells. CDC42GAP-/- neutrophils also showed increased lateral and tail filopodia-like formation, and excess membrane protrusions. We further suggest that CDC42GAP-mediated ERK activity regulates motility associated with podosome-like structures at the cell leading edge while CDC42GAP-induced p38MAPK phosphorylation regulates directed migration by antagonizing filopodia assembly. Overall, this study reveals that CDC42 activity regulates both motility and directionality in neutrophils but via distinct MAPK pathways.
