DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis.
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.
Kunisaki
Yuya
Y
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Nishikimi
Akihiko
A
Tanaka
Yoshihiko
Y
Takii
Ryosuke
R
Noda
Mayuko
M
Inayoshi
Ayumi
A
Watanabe
Ken-ichi
K
Sanematsu
Fumiyuki
F
Sasazuki
Takehiko
T
Sasaki
Takehiko
T
Fukui
Yoshinori
Y
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
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