期刊
SCIENCE
卷 324, 期 5925, 页码 384-387出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1170179
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Toray Science Foundation
- CREST program of Japan Science and Technology Agency
- Global Center of Excellence program of the Japan Society for the Promotion of Science
- NIH [R01GM71520]
- Grants-in-Aid for Scientific Research [19059004, 21200075] Funding Source: KAKEN
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.
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