Sequential Regulation of DOCK2 Dynamics by Two Phospholipids During Neutrophil Chemotaxis

被引:213
作者
Nishikimi, Akihiko [1 ,2 ]
Fukuhara, Hideo [1 ]
Su, Wenjuan [3 ]
Hongu, Tsunaki [4 ]
Takasuga, Shunsuke [5 ]
Mihara, Hisashi [6 ]
Cao, Qinhong [1 ]
Sanematsu, Fumiyuki [1 ]
Kanai, Motomu [6 ]
Hasegawa, Hiroshi [4 ]
Tanaka, Yoshihiko [1 ,2 ]
Shibasaki, Masakatsu [6 ]
Kanaho, Yasunori [4 ]
Sasaki, Takehiko [5 ]
Frohman, Michael A. [3 ]
Fukui, Yoshinori [1 ,2 ]
机构
[1] Kyushu Univ, Med Inst Bioregulat, Dept Neurosci & Immunol, Div Immunogenet, Fukuoka 8128582, Japan
[2] Japan Sci & Technol Agcy, Core Res Evolut Sci & Technol, Tokyo 1020075, Japan
[3] SUNY Stony Brook, Dept Pharmacol, Ctr Dev Genet, Stony Brook, NY 11794 USA
[4] Univ Tsukuba, Inst Basic Med Sci, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058575, Japan
[5] Akita Univ, Sch Med, Dept Pathol & Immunol, Div Microbiol, Akita 0108543, Japan
[6] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo 1130033, Japan
基金
日本学术振兴会; 日本科学技术振兴机构;
关键词
PHOSPHATIDIC-ACID; CELL-MIGRATION; DOWNSTREAM ACTIVATION; RAC ACTIVATION; MOTILITY; POLARITY; PROTEINS; COMPLEX; ROLES; ARF6;
D O I
10.1126/science.1170179
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:384 / 387
页数:4
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