Journal
SCIENCE SIGNALING
Volume 13, Issue 656, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aaz4003
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) UK [BB/J004456/1, BB/P013384/1]
- Medical Research Council MRC [MR/K018167/1]
- Amgen Scholars Programme Award
- Swiss National Science Foundation fellowship [PA00P3_134202]
- European Commission [275880]
- Swiss National Science Foundation (SNF) [PA00P3_134202] Funding Source: Swiss National Science Foundation (SNF)
- BBSRC [BBS/E/B/000C0415, BBS/E/B/0000C238, BB/I003916/1, BB/I008489/1, BBS/E/B/000C0411, BBS/E/B/000C0431] Funding Source: UKRI
- MRC [MC_U105184308, MR/K018167/1] Funding Source: UKRI
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The PI3K gamma isoform is activated by Gi-coupled GPCRs in myeloid cells, but the extent to which the two endogenous complexes of PI3K gamma, p101/p110 gamma and p84/p110 gamma, receive direct regulation through G beta gamma or indirect regulation through RAS and the sufficiency of those inputs is controversial or unclear. We generated mice with point mutations that prevent G beta gamma binding to p110 gamma (RK552DD) or to p101 (VVKR777AAAA) and investigated the effects of these mutations in primary neutrophils and in mouse models of neutrophilic inflammation. Loss of G beta gamma binding to p110 gamma substantially reduced the activation of both p101/p110 gamma and p84/p110 gamma in neutrophils by various GPCR agonists. Loss of G beta gamma binding to p101 caused more variable effects, depending on both the agonist and cellular response, with the biggest reductions seen in PIP3 production by primary neutrophils in response to LTB4 and MIP-2 and in the migration of neutrophils during thioglycolate-induced peritonitis or MIP2-induced ear pouch inflammation. We also observed that p101(VVKR777AAAA) neutrophils showed enhanced p84-dependent ROS responses to fMLP and C5a, suggesting that competition may exist between p101/p110 gamma and p84/p110 gamma for G beta gamma subunits downstream of GPCR activation. GPCRs did not activate p110 gamma in neutrophils from mice lacking both the p101 and p84 regulatory subunits, indicating that RAS binding to p110 gamma is insufficient to support GPCR activation in this cell type. These findings define a direct role for G beta gamma subunits in activating both of the endogenous PI3K gamma complexes and indicate that the regulatory PI3K gamma subunit biases activation toward different GPCRs.
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