The p110  isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110 (original) (raw)

2008, Proceedings of the National Academy of Sciences

The p110 isoforms of phosphoinositide 3-kinase (PI3K) are acutely regulated by extracellular stimuli. The class IA PI3K catalytic subunits (p110␣, p110␤, and p110␦) occur in complex with a Src homology 2 (SH2) domain-containing p85 regulatory subunit, which has been shown to link p110␣ and p110␦ to Tyr kinase signaling pathways. The p84/p101 regulatory subunits of the p110␥ class IB PI3K lack SH2 domains and instead couple p110␥ to G protein-coupled receptors (GPCRs). Here, we show, using smallmolecule inhibitors with selectivity for p110␤ and cells derived from a p110␤-deficient mouse line, that p110␤ is not a major effector of Tyr kinase signaling but couples to GPCRs. In macrophages, both p110␤ and p110␥ contributed to Akt activation induced by the GPCR agonist complement 5a, but not by the Tyr kinase ligand colony-stimulating factor-1. In fibroblasts, which express p110␤ but not p110␥, p110␤ mediated Akt activation by the GPCR ligands stromal cell-derived factor, sphingosine-1phosphate, and lysophosphatidic acid but not by the Tyr kinase ligands PDGF, insulin, and insulin-like growth factor 1. Introduction of p110␥ in these cells reduced the contribution of p110␤ to GPCR signaling. Taken together, these data show that p110␤ and p110␥ can couple redundantly to the same GPCR agonists. p110␤, which shows a much broader tissue distribution than the leukocyterestricted p110␥, could thus provide a conduit for GPCR-linked PI3K signaling in the many cell types where p110␥ expression is low or absent.