TY - JOUR
T1 - DOCK8 protein regulates macrophage migration through Cdc42 protein activation and LRAP35a protein interaction
AU - Shiraishi, Akira
AU - Uruno, Takehito
AU - Sanematsu, Fumiyuki
AU - Ushijima, Miho
AU - Sakata, Daiji
AU - Hara, Toshiro
AU - Fukui, Yoshinori
N1 - Funding Information:
This work was supported by a grant-in-aid for scientific research on innovative areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; grants-in-aid for scientific research from the Japan Society for the Promotion of Science; the Leading Advanced Projects for Medical Innovation; and the Research on Development of New Drugs from Japan Agency for Medical Research and Development. The authors declare that they have no conflicts of interest with the contents of this article. We thank T. Kitamura for providing the pMX vector and platinum-E packaging cells, A. Inayoshi and A. Aosaka for technical assistance, and Brian Quinn for English editing.
Publisher Copyright:
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2017/2/10
Y1 - 2017/2/10
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M116.736306
DO - 10.1074/jbc.M116.736306
M3 - Article
C2 - 28028174
AN - SCOPUS:85012079901
SN - 0021-9258
VL - 292
SP - 2191
EP - 2202
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 6
ER -