Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis

Akihiko Nishikimi; Hideo Fukuhara; Wenjuan Su; Tsunaki Hongu; Shunsuke Takasuga; Hisashi Mihara; Qinhong Cao; Fumiyuki Sanematsu; Motomu Kanai; Hiroshi Hasegawa; Yoshihiko Tanaka; Masakatsu Shibasaki; Yasunori Kanaho; Takehiko Sasaki; Michael A Frohman; Yoshinori Fukui

doi:10.1126/science.1170179

Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis

Science. 2009 Apr 17;324(5925):384-7. doi: 10.1126/science.1170179. Epub 2009 Mar 26.

Authors

Akihiko Nishikimi¹, Hideo Fukuhara, Wenjuan Su, Tsunaki Hongu, Shunsuke Takasuga, Hisashi Mihara, Qinhong Cao, Fumiyuki Sanematsu, Motomu Kanai, Hiroshi Hasegawa, Yoshihiko Tanaka, Masakatsu Shibasaki, Yasunori Kanaho, Takehiko Sasaki, Michael A Frohman, Yoshinori Fukui

Affiliation

¹ Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.

Abstract

During chemotaxis, activation of the small guanosine triphosphatase Rac is spatially regulated to organize the extension of membrane protrusions in the direction of migration. In neutrophils, Rac activation is primarily mediated by DOCK2, an atypical guanine nucleotide exchange factor. Upon stimulation, we found that DOCK2 rapidly translocated to the plasma membrane in a phosphatidylinositol 3,4,5-trisphosphate-dependent manner. However, subsequent accumulation of DOCK2 at the leading edge required phospholipase D-mediated synthesis of phosphatidic acid, which stabilized DOCK2 there by means of interaction with a polybasic amino acid cluster, resulting in increased local actin polymerization. When this interaction was blocked, neutrophils failed to form leading edges properly and exhibited defects in chemotaxis. Thus, intracellular DOCK2 dynamics are sequentially regulated by distinct phospholipids to localize Rac activation during neutrophil chemotaxis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

1-Butanol / pharmacology
Actins / metabolism
Animals
Cell Line
Cell Membrane / metabolism*
Cell Polarity
Chemotaxis, Leukocyte*
Enzyme Inhibitors / pharmacology
GTPase-Activating Proteins / chemistry
GTPase-Activating Proteins / genetics
GTPase-Activating Proteins / metabolism*
Guanine Nucleotide Exchange Factors
Humans
Mice
Neutrophils / cytology
Neutrophils / drug effects
Neutrophils / physiology*
Phosphatidic Acids / metabolism*
Phosphatidic Acids / pharmacology
Phosphatidylinositol Phosphates / metabolism*
Phospholipase D / genetics
Phospholipase D / metabolism
Protein Binding
Pseudopodia / metabolism
Recombinant Fusion Proteins / metabolism
Signal Transduction
rac GTP-Binding Proteins / metabolism

Substances

Actins
DOCK2 protein, mouse
Enzyme Inhibitors
GTPase-Activating Proteins
Guanine Nucleotide Exchange Factors
Phosphatidic Acids
Phosphatidylinositol Phosphates
Recombinant Fusion Proteins
phosphatidylinositol 3,4,5-triphosphate
1-Butanol
phospholipase D2
Phospholipase D
rac GTP-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding