title: Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kβ in myeloid cells.
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.
authors.affiliation: Inositide Laboratory, Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Houslay
authors.affiliation: Inositide Laboratory, Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.affiliation: Inositide Laboratory, Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK.
authors.forename: Tamara
authors.initials: T
authors.lastname: Chessa
authors.affiliation: Inositide Laboratory, Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK.
authors.forename: Suhasini
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Department of Hematology and Oncology, Freiburg University Medical Centre, Albert-Ludwigs-Universität, Freiburg, Hugstetter Str. 55 79106, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Fritsch
authors.affiliation: Signal Transduction Laboratory, Francis Crick Institute, Lincoln's Inn Fields, London WC2A 3LY, UK.
authors.forename: Julian
authors.initials: J
authors.lastname: Downward
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer 230, Bronx, NY 10461, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.affiliation: Inositide Laboratory, Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK. phillip.hawkins@babraham.ac.uk len.stephens@babraham.ac.uk.
authors.forename: Len R
authors.initials: LR
authors.lastname: Stephens
authors.affiliation: Inositide Laboratory, Babraham Institute, Babraham Research Campus, Babraham, Cambridge CB223AT, UK. phillip.hawkins@babraham.ac.uk len.stephens@babraham.ac.uk.
authors.forename: Phillip T
authors.initials: PT
authors.lastname: Hawkins
mesh_terms: D000818:Animals; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D043562:Receptors, G-Protein-Coupled; D019869:Phosphatidylinositol 3-Kinases; D020696:rab5 GTP-Binding Proteins; D020744:rac GTP-Binding Proteins