Research ArticleImmunology

Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells

Sci. Signal.  16 Aug 2016:
Vol. 9, Issue 441, pp. ra82
DOI: 10.1126/scisignal.aae0453

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Mediating synergistic signaling

Phosphoinositide 3-kinase (PI3K) family members contain one of four different catalytic subunits and generate the second messenger PIP3 in response to stimulation. Whereas some PI3K isoforms mediate signaling from receptor tyrosine kinases (RTKs) and one isoform mediates signals from GPCRs, PI3Kβ transduces signals from both receptor types. Houslay et al. generated knock-in mice expressing a mutant PI3Kβ unable to transduce GPCR signals and measured the PIP3 responses of macrophages and neutrophils to RTK and GPCR agonists individually or in combination. Of all the PI3K isoforms, PI3Kβ uniquely induced synergistic increases in PIP3 concentration in response to simultaneous stimulation of both receptor types. Furthermore, effective responses of neutrophils to inflammatory stimuli depended on the ability of PI3Kβ to activate G proteins.

Abstract

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 (p110α, p110β, p110γ, or p110δ) that should be targeted in different therapeutic contexts. Previous studies have defined unique regulatory inputs for p110β, including direct interaction with Gβγ subunits, Rac, and Rab5. We generated mice with knock-in mutations of p110β that selectively blocked the interaction with Gβγ 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 p110β 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 p110α, p110β, and p110δ downstream of M-CSF alone and a nonredundant role for p110γ downstream of C5a alone. This role for p110β completely depended on direct interaction with Gβγ, suggesting that p110β transduces GPCR signals in the context of coincident activation by an RTK. The p110β-Gβγ interaction was also required for neutrophils to generate reactive oxygen species in response to the Fcγ receptor–dependent recognition of immune complexes and for their β2 integrin–mediated adhesion to fibrinogen or poly-RGD+, directly implicating heterotrimeric G proteins in these two responses.

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