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2015 ; 26
(9
): 1629-39
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Homer3 regulates the establishment of neutrophil polarity
#MMPMID25739453
Wu J
; Pipathsouk A
; Keizer-Gunnink A
; Fusetti F
; Alkema W
; Liu S
; Altschuler S
; Wu L
; Kortholt A
; Weiner OD
Mol Biol Cell
2015[May]; 26
(9
): 1629-39
PMID25739453
show ga
Most chemoattractants rely on activation of the heterotrimeric G-protein G?i to
regulate directional cell migration, but few links from G?i to chemotactic
effectors are known. Through affinity chromatography using primary neutrophil
lysate, we identify Homer3 as a novel G?i2-binding protein. RNA
interference-mediated knockdown of Homer3 in neutrophil-like HL-60 cells impairs
chemotaxis and the establishment of polarity of phosphatidylinositol
3,4,5-triphosphate (PIP3) and the actin cytoskeleton, as well as the persistence
of the WAVE2 complex. Most previously characterized proteins that are required
for cell polarity are needed for actin assembly or activation of core chemotactic
effectors such as the Rac GTPase. In contrast, Homer3-knockdown cells show normal
magnitude and kinetics of chemoattractant-induced activation of phosphoinositide
3-kinase and Rac effectors. Chemoattractant-stimulated Homer3-knockdown cells
also exhibit a normal initial magnitude of actin polymerization but fail to
polarize actin assembly and intracellular PIP3 and are defective in the
initiation of cell polarity and motility. Our data suggest that Homer3 acts as a
scaffold that spatially organizes actin assembly to support neutrophil polarity
and motility downstream of GPCR activation.