The role of DOCK2 and its regulatory mechanism in the innate immune system

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Neutrophils are highly motile leukocytes and 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. In this study, we have analyzed the role of DOCK2 in chemotactic response of neutrophils. 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. In addition to this, we revealed that DOCK2 is a Rac activator critical for migration of plasmacytoid dendritic cells. Our results thus indicate that DOCK2 plays an important role not only in the acquired, but also in the innate immune system.