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Science 324 (5925): 384-387

Copyright © 2009 by the American Association for the Advancement of Science

Sequential Regulation of DOCK2 Dynamics by Two Phospholipids During Neutrophil Chemotaxis

Akihiko Nishikimi,1,2 Hideo Fukuhara,1 Wenjuan Su,3 Tsunaki Hongu,4 Shunsuke Takasuga,5 Hisashi Mihara,6 Qinhong Cao,1* Fumiyuki Sanematsu,1 Motomu Kanai,6 Hiroshi Hasegawa,4 Yoshihiko Tanaka,1,2 Masakatsu Shibasaki,6 Yasunori Kanaho,4 Takehiko Sasaki,5 Michael A. Frohman,3 Yoshinori Fukui1,2{dagger}

Abstract: During chemotaxis, activation of the small guanosine triphosphatase Rac is spatially regulated to organize the extension of membrane protrusions in the direction of migration. In neutrophils, Rac activation is primarily mediated by DOCK2, an atypical guanine nucleotide exchange factor. Upon stimulation, we found that DOCK2 rapidly translocated to the plasma membrane in a phosphatidylinositol 3,4,5-trisphosphate–dependent manner. However, subsequent accumulation of DOCK2 at the leading edge required phospholipase D–mediated synthesis of phosphatidic acid, which stabilized DOCK2 there by means of interaction with a polybasic amino acid cluster, resulting in increased local actin polymerization. When this interaction was blocked, neutrophils failed to form leading edges properly and exhibited defects in chemotaxis. Thus, intracellular DOCK2 dynamics are sequentially regulated by distinct phospholipids to localize Rac activation during neutrophil chemotaxis.

1 Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
2 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, Tokyo 102-0075, Japan.
3 Department of Pharmacology, Center for Developmental Genetics, Stony Brook University, Stony Brook, NY 11794–5140, USA.
4 Graduate School of Comprehensive Human Sciences, Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan.
5 Division of Microbiology, Department of Pathology and Immunology, Akita University School of Medicine, Akita 010-8543, Japan.
6 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan.

* Present address: College of Biological Sciences, China Agricultural University, Beijing 100193, China.

{dagger} To whom correspondence should be addressed. E-mail: fukui{at}bioreg.kyushu-u.ac.jp


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