Journal
SCIENCE SIGNALING
Volume 9, Issue 441, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aae0453
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Funding
- Biotechnology and Biological Sciences Research Council (BBSRC) UK [BB/J004456/1]
- Welcome Trust [WT085889MA]
- NIH [GM112524]
- European Research Council (RASTARGET)
- BBSRC PhD studentship
- BBSRC [BBS/E/B/000C0411] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BBS/E/B/000C0411, 1128445] Funding Source: researchfish
- Cancer Research UK [15680] Funding Source: researchfish
- The Francis Crick Institute [10071, 10074, 10070] Funding Source: researchfish
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Class I phosphoinositide 3-kinases (PI3Ks) catalyze production of the lipid messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which plays a central role in a complex signaling network regulating cell growth, survival, and movement. This network is overactivated in cancer and inflammation, and there is interest in determining the PI3K catalytic subunit (p110 alpha, p110 beta, p110 gamma, or p110 delta) that should be targeted in different therapeutic contexts. Previous studies have defined unique regulatory inputs for p110b, including direct interaction with G beta gamma subunits, Rac, and Rab5. We generated mice with knock-in mutations of p110 beta that selectively blocked the interaction with G beta gamma and investigated its contribution to the PI3K isoform dependency of receptor tyrosine kinase (RTK) and G protein (heterotrimeric guanine nucleotide-binding protein)coupled receptor (GPCR) responses in primary macrophages and neutrophils. We discovered a unique role for p110b in supporting synergistic PIP3 formation in response to the coactivation of macrophages by macrophage colony-stimulating factor (M-CSF) and the complement protein C5a. In contrast, we found partially redundant roles for p110 alpha, p110 beta, and p110 delta downstream of M-CSF alone and a nonredundant role for p110 gamma downstream of C5a alone. This role for p110 beta completely depended on direct interaction with Gb gamma, suggesting that p110 beta transduces GPCR signals in the context of coincident activation by an RTK. The p110 beta-Gb gamma interaction was also required for neutrophils to generate reactive oxygen species in response to the Fc gamma receptor-dependent recognition of immune complexes and for their beta(2) integrin-mediated adhesion to fibrinogen or poly-RGD(+), directly implicating heterotrimeric G proteins in these two responses.
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