Inhibition of Protein Phosphatase 2A Activity by PI3Kγ Regulates β-Adrenergic Receptor Function

Phosphoinositide 3-kinase gamma (PI3K gamma) is activated by G protein-coupled receptors (GPCRs). We show here that PI3K gamma inhibits protein phosphatase 2A (PP2A) at the beta-adrenergic receptor (beta AR, a GPCR) complex altering G protein coupling. PI3K gamma inhibition results in significant increase of beta AR-associated phosphatase activity leading to receptor dephosphorylation and resensitization preserving cardiac function. Mechanistically, PI3K gamma inhibits PP2A activity at the beta AR complex by phosphorylating an intracellular inhibitor of PP2A (I2PP2A) on serine residues 9 and 93, resulting in enhanced binding to PP2A. Indeed, enhanced phosphorylation of beta 2ARs is observed with a phosphomimetic I2PP2A mutant that was completely reversed with a mutant mimicking dephosphorylated state. siRNA depletion of endogenous I2PP2A augments PP2A activity despite active PI3K resulting in beta 2AR dephosphorylation and sustained signaling. Our study provides the underpinnings of a PI3K gamma-mediated regulation of PP2A activity that has significant consequences on receptor function with broad implications in cellular signaling.