Publication Date:
2009-03-28
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761877/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3761877/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nishikimi, Akihiko -- Fukuhara, Hideo -- Su, Wenjuan -- Hongu, Tsunaki -- Takasuga, Shunsuke -- Mihara, Hisashi -- Cao, Qinhong -- Sanematsu, Fumiyuki -- Kanai, Motomu -- Hasegawa, Hiroshi -- Tanaka, Yoshihiko -- Shibasaki, Masakatsu -- Kanaho, Yasunori -- Sasaki, Takehiko -- Frohman, Michael A -- Fukui, Yoshinori -- R01 GM084251/GM/NIGMS NIH HHS/ -- R01GM71520/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2009 Apr 17;324(5925):384-7. doi: 10.1126/science.1170179. Epub 2009 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19325080" target="_blank"〉PubMed〈/a〉
Keywords:
1-Butanol/pharmacology
;
Actins/metabolism
;
Animals
;
Cell Line
;
Cell Membrane/*metabolism
;
Cell Polarity
;
*Chemotaxis, Leukocyte
;
Enzyme Inhibitors/pharmacology
;
GTPase-Activating Proteins/chemistry/genetics/*metabolism
;
Humans
;
Mice
;
Neutrophils/cytology/drug effects/*physiology
;
Phosphatidic Acids/*metabolism/pharmacology
;
Phosphatidylinositol Phosphates/*metabolism
;
Phospholipase D/genetics/metabolism
;
Protein Binding
;
Pseudopodia/metabolism
;
Recombinant Fusion Proteins/metabolism
;
Signal Transduction
;
rac GTP-Binding Proteins/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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