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Blood, 15 December 2006, Vol. 108, No. 13, pp. 4205-4213. Prepublished online as a Blood First Edition Paper on August 24, 2006; DOI 10.1182/blood-2006-03-013789. This Article Full Text Full Text (PDF) Supplemental Figure and Videos All Versions of this Article: blood-2006-03-013789v1 108/13/4205    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Szczur, K. Articles by Filippi, M.-D. Search for Related Content PubMed PubMed Citation Articles by Szczur, K. Articles by Filippi, M.-D. Related Collections Phagocytes Cell Adhesion and Motility Cytoskeleton Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  PHAGOCYTES 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 From the Department of Experimental Hematology, Cincinnati Children's Research Foundation, University Cincinnati College of Medicine, OH; and Department of Medicine, Indiana University School of Medicine, Indianapolis, IN. 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 (CDC42GAP), 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 extracellular signal–regulated kinase (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 mitogen-activated protein kinase (MAPK) pathways. 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