期刊
MOLECULAR BIOLOGY OF THE CELL
卷 23, 期 13, 页码 2457-2467出版社
AMER SOC CELL BIOLOGY
DOI: 10.1091/mbc.E12-01-0062
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资金
- Ministry of Education, Science, Sports and Culture of Japan
- Novartis Foundation for the Promotion of Science
- Takeda Foundation for the Promotion of Natural Science
- Special Coordination Funds for Promoting Science and Technology from the Japan Science and Technology Agency
Most chemoattractants for neutrophils bind to the G alpha(i) family of heterotrimeric G protein-coupled receptors (GPCRs) and release G beta gamma subunits to activate chemotaxis and superoxide production. GIT2, a GTPase-activating protein for Arf1, forms a complex with G beta gamma 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 PI3K gamma. 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 PI3K gamma activity with chemotaxis and superoxide production in GPCR signaling.
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