title: GBF1 bears a novel phosphatidylinositol-phosphate binding module, BP3K, to link PI3Kγ activity with Arf1 activation involved in GPCR-mediated neutrophil chemotaxis and superoxide production.
abstract: Most chemoattractants for neutrophils bind to the Gα(i) family of heterotrimeric G protein-coupled receptors (GPCRs) and release Gβγ subunits to activate chemotaxis and superoxide production. GIT2, a GTPase-activating protein for Arf1, forms a complex with Gβγ and is integral for directional sensing and suppression of superoxide production. Here we show that GBF1, a guanine nucleotide exchanging factor for Arf-GTPases, is primarily responsible for Arf1 activation upon GPCR stimulation and is important for neutrophil chemotaxis and superoxide production. We find that GBF1 bears a novel module, namely binding to products of phosphatidyl inositol 3-kinase (PI3K), which binds to products of PI3Kγ. Through this binding, GBF1 is translocated from the Golgi to the leading edge upon GPCR stimulation to activate Arf1 and recruit p22phox and GIT2 to the leading edge. Moreover, GBF1-mediated Arf1 activation is necessary to unify cell polarity during chemotaxis. Our results identify a novel mechanism that links PI3Kγ activity with chemotaxis and superoxide production in GPCR signaling.
authors.affiliation: Priority Organization for Innovation and Excellence, Kumamoto University, Kumamoto, Japan. mazaki@kumamoto-u.ac.jp
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Mazaki
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Hisataka
authors.initials: H
authors.lastname: Sabe
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D002462:Cell Membrane / Q000378:metabolism; D016764:Cell Polarity; D002633:Chemotaxis; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D004789:Enzyme Activation; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015870:Gene Expression; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology / Q000502:physiology*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*
chemical_list: C120445:GBF1 protein, human; C430213:GIT2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D018129:Phosphatidylinositol Phosphates; D043562:Receptors, G-Protein-Coupled; D013481:Superoxides; D019255:NADPH Oxidases; C086986:CYBA protein, human; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546760:PIK3CG protein, human; D020823:ADP-Ribosylation Factor 1