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DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis

¹ Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
² Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan
³ Division of Microbiology, Department of Pathology and Immunology, Akita University School of Medicine, Akita 010-8543, Japan
⁴ International Medical Center of Japan, Tokyo 162-8655, Japan

Correspondence to Yoshinori Fukui: fukui{at}bioreg.kyushu-u.ac.jp

Neutrophils are highly motile leukocytes, and they play important roles in the innate immune response to invading pathogens. Neutrophil chemotaxis requires Rac activation, yet the Rac activators functioning downstream of chemoattractant receptors remain to be determined. We show that DOCK2, which is a mammalian homologue of Caenorhabditis elegans CED-5 and Drosophila melanogaster Myoblast City, regulates motility and polarity during neutrophil chemotaxis. Although DOCK2-deficient neutrophils moved toward the chemoattractant source, they exhibited abnormal migratory behavior with a marked reduction in translocation speed. In DOCK2-deficient neutrophils, chemoattractant-induced activation of both Rac1 and Rac2 were severely impaired, resulting in the loss of polarized accumulation of F-actin and phosphatidylinositol 3,4,5-triphosphate (PIP₃) at the leading edge. On the other hand, we found that DOCK2 associates with PIP₃ and translocates to the leading edge of chemotaxing neutrophils in a phosphatidylinositol 3-kinase (PI3K)–dependent manner. These results indicate that during neutrophil chemotaxis DOCK2 regulates leading edge formation through PIP₃-dependent membrane translocation and Rac activation.

Abbreviations used in this paper: BM, bone marrow; fMLP, N-formyl-methionyl-leucyl-phenylalanine; GEF, guanine nucleotide exchange factor; HEK, human embryonic kidney; PH, pleckstrin homology; PI3K, phosphatidylinositol 3-kinase; PIP₃, phosphatidylinositol 3,4,5-triphosphate; SOD, superoxide dismutase.

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