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Homer3 regulates the establishment of neutrophil polarity

Wu, J., Pipathsouk, A., Keizer-Gunnink, A., Fusetti, F., Alkema, W., Liu, S., Altschuler, S., Wu, L., Kortholt, A. & Weiner, O. D., 4-Mar-2015, In : Molecular Biology of the Cell. 26, 9, p. 1629-1639 11 p.

Research output: Contribution to journalArticleAcademicpeer-review

Most chemoattractants rely on activation of the heterotrimeric G-protein Gαi to regulate directional cell migration, but few links from Gαi to chemotactic effectors are known. Through affinity chromatography using primary neutrophil lysate, we identify Homer3 as a novel Gαi2-binding protein. RNAi-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 (PI3K) and Rac effectors. Chemoattractant-stimulated Homer3 knockdown cells also exhibit a normal initial magnitude of actin polymerization, but they 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.

Original languageEnglish
Pages (from-to)1629-1639
Number of pages11
JournalMolecular Biology of the Cell
Volume26
Issue number9
Publication statusPublished - 4-Mar-2015

    Keywords

  • NUCLEOTIDE EXCHANGE FACTOR, PROTEIN-COUPLED RECEPTORS, RAC ACTIVATION, MACROPHAGE-MIGRATION, ACTIN CYTOSKELETON, SIGNALING PATHWAY, MOUSE NEUTROPHILS, DENDRITIC SPINES, WAVE COMPLEX, SMALL GTPASE

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