| First Author | Deladeriere A | Year | 2015 |
| Journal | Sci Signal | Volume | 8 |
| Issue | 360 | Pages | ra8 |
| PubMed ID | 25605974 | Mgi Jnum | J:238900 |
| Mgi Id | MGI:5824488 | Doi | 10.1126/scisignal.2005564 |
| Citation | Deladeriere A, et al. (2015) The regulatory subunits of PI3Kgamma control distinct neutrophil responses. Sci Signal 8(360):ra8 |
| abstractText | Neutrophils, which migrate toward inflamed sites and kill pathogens by producing reactive oxygen species (ROS), are important in the defense against bacterial and fungal pathogens, but their inappropriate regulation causes various chronic inflammatory diseases. Phosphoinositide 3-kinase gamma (PI3Kgamma) functions downstream of proinflammatory G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptors (GPCRs) in neutrophils and is a therapeutic target. In neutrophils, PI3Kgamma consists of a p110gamma catalytic subunit, which is activated by the guanosine triphosphatase Ras, and either a p84 or p101 regulatory subunit. Loss or inhibition of p110gamma or expression of a Ras-insensitive variant p110gamma (p110gamma(DASAA/DASAA)) impairs PIP3 production, Akt phosphorylation, migration, and ROS formation in response to GPCR activation. The p101 subunit binds to, and mediates PI3Kgamma activation by, G protein betagamma subunits, and p101(-/-) neutrophils have a similar phenotype to that of p110gamma(-/-) neutrophils, except that ROS responses are normal. We found that p84(-/-) neutrophils displayed reduced GPCR-stimulated PIP3 and Akt signaling, which was indistinguishable from that of p101(-/-) neutrophils. However, p84(-/-) neutrophils produced less ROS and exhibited normal migration in response to GPCR stimulation. These data suggest that p84-containing PI3Kgamma controls GPCR-dependent ROS production. Thus, the PI3Kgamma regulatory subunits enable PI3Kgamma to mediate distinct neutrophil responses, which may occur by targeting PIP3 signaling into spatially distinct domains. |
