title: DOCK8 Protein Regulates Macrophage Migration through Cdc42 Protein Activation and LRAP35a Protein Interaction.
abstract: DOCK8 is an atypical guanine nucleotide exchange factor for Cdc42, and its mutations cause combined immunodeficiency in humans. Accumulating evidence indicates that DOCK8 regulates the migration and activation of various subsets of leukocytes, but its regulatory mechanism is poorly understood. We here report that DOCK8-deficient macrophages exhibit a migration defect in a 2D setting. Although DOCK8 deficiency in macrophages did not affect the global Cdc42 activation induced by chemokine stimulation, rescue experiments revealed that the guanine nucleotide exchange factor activity of DOCK8 was required for macrophage migration. We found that DOCK8 associated with LRAP35a, an adaptor molecule that binds to the Cdc42 effector myotonic dystrophy kinase-related Cdc42-binding kinase, and facilitated its activity to phosphorylate myosin II regulatory light chain. When this interaction was disrupted in WT macrophages, they showed a migration defect, as seen in DOCK8-deficient macrophages. These results suggest that, during macrophage migration, DOCK8 links Cdc42 activation to actomyosin dynamics through the association with LRAP35a.
authors.affiliation: From the Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation.|Department of Pediatrics, Graduate School of Medical Sciences, and.
authors.forename: Akira
authors.initials: A
authors.lastname: Shiraishi
authors.affiliation: From the Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation.|Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Takehito
authors.initials: T
authors.lastname: Uruno
authors.affiliation: From the Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation.|Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Fumiyuki
authors.initials: F
authors.lastname: Sanematsu
authors.affiliation: From the Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation.
authors.forename: Miho
authors.initials: M
authors.lastname: Ushijima
authors.affiliation: From the Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation.
authors.forename: Daiji
authors.initials: D
authors.lastname: Sakata
authors.affiliation: the Fukuoka Children's Hospital, Fukuoka 813-0017, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: From the Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, fukui@bioreg.kyushu-u.ac.jp.|Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan and.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism / Q000502:physiology*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011485:Protein Binding; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C581598:Cdc42 protein, mouse; C545324:Dock8 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; C000621004:Lrap35a protein, mouse; D020764:cdc42 GTP-Binding Protein
keywords: Cdc42; actomyosin dynamics; cell migration; guanine nucleotide exchange factor (GEF); macrophage; signal transduction