| First Author | Houslay DM | Year | 2016 |
| Journal | Sci Signal | Volume | 9 |
| Issue | 441 | Pages | ra82 |
| PubMed ID | 27531651 | Mgi Jnum | J:259189 |
| Mgi Id | MGI:6142415 | Doi | 10.1126/scisignal.aae0453 |
| Citation | Houslay DM, et al. (2016) Coincident signals from GPCRs and receptor tyrosine kinases are uniquely transduced by PI3Kbeta in myeloid cells. Sci Signal 9(441):ra82 |
| abstractText | 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 (p110alpha, p110beta, p110gamma, or p110delta) that should be targeted in different therapeutic contexts. Previous studies have defined unique regulatory inputs for p110beta, including direct interaction with Gbetagamma subunits, Rac, and Rab5. We generated mice with knock-in mutations of p110beta that selectively blocked the interaction with Gbetagamma 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 p110beta 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 p110alpha, p110beta, and p110delta downstream of M-CSF alone and a nonredundant role for p110gamma downstream of C5a alone. This role for p110beta completely depended on direct interaction with Gbetagamma, suggesting that p110beta transduces GPCR signals in the context of coincident activation by an RTK. The p110beta-Gbetagamma interaction was also required for neutrophils to generate reactive oxygen species in response to the Fcgamma receptor-dependent recognition of immune complexes and for their beta2 integrin-mediated adhesion to fibrinogen or poly-RGD+, directly implicating heterotrimeric G proteins in these two responses. |
