Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase γ that is highly expressed in heart and interacts with PDE3B

Phosphoinositide 3- kinase (PI3K) gamma has been implicated in a vast array of physiological settings including the activation of different leukocyte species and the regulation of myocardial contractility. Activation of PI3K gamma is primarily mediated by G beta gamma subunits of heterotrimeric G proteins, which are recognized by a p101 regulatory subunit. Here, we describe the identification and characterization of a novel regulatory subunit of PI3K gamma, which we termed p87(PIKAP) (PI3K gamma adapter protein of 87 kDa). It is homologous to p101 in areas that we have recently shown that they mediate binding to the catalytic p110 gamma subunit and to G beta gamma. Like p101, p87(PIKAP) binds to both p110 gamma and G beta gamma and mediates activation of p110 gamma downstream of G protein-coupled receptors. In contrast to p101, p87(PIKAP) is highly expressed in heart and may therefore be crucial to PI3K gamma cardiac function. Moreover, p87(PIKAP) and p101 are both expressed in dendritic cells, macrophages, and neutrophils, raising the possibility of regulatory subunit-dependent differences in PI3K gamma signaling within the same cell type. We further provide evidence that p87(PIKAP) physically interacts with phosphodiesterase (PDE) 3B, suggesting that p87(PIKAP) is also involved in the recently described noncatalytic scaffolding interaction of p110 gamma with PDE3B. However, coexpression of PDE3B and PI3K gamma subunits was not sufficient to reconstitute the regulatory effect of PI3K gamma on PDE3B activity observed in heart, implying further molecules to be present in the complex regulating PDE3B in heart.