title: DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis.
abstract: 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.
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kunisaki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Nishikimi
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takii
authors.forename: Mayuko
authors.initials: M
authors.lastname: Noda
authors.forename: Ayumi
authors.initials: A
authors.lastname: Inayoshi
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Watanabe
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasazuki
authors.forename: Takehiko
authors.initials: T
authors.lastname: Sasaki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D000199:Actins / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D016764:Cell Polarity; D002634:Chemotaxis, Leukocyte; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009479:Neuropeptides / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D018129:Phosphatidylinositol Phosphates; D051057:Proto-Oncogene Proteins c-akt; D011993:Recombinant Fusion Proteins; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C471356:DOCK2 protein, mouse; C510359:ELMO1 protein, mouse; C484602:Rac1 protein, mouse; C060974:phosphatidylinositol 3,4,5-triphosphate