p84, a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110γ

A variety of genetic and inhibitor studies have shown that phosphoinositide 3-kinase gamma (PI3K gamma) plays an essential role in a number of physiological responses, including neutrophil chemotaxis, mast cell degranulation, and cardiac function [1-6]. PI3K gamma is currently thought to be composed of a p110 gamma catalytic subunit and a single regulatory subunit, p101. The binding of p110 gamma to p101 dramatically increases the activation of the complex by G beta gamma subunits and, hence, is thought to be critical for the coupling of PI3K gamma to G protein coupled receptors [7-9]. Here, we characterize a new regulatory subunit for PI3K gamma. p84 is present in human, mouse, chicken, frog, and fugu genomes and is located beside the p101 locus. It is broadly expressed in cells of the murine immune system. Both recombinant and endogenous p84 bind p110 gamma specifically and with high affinity. Binding of p84 to p110 gamma substantially increases the ability of G beta gamma to stimulate phosphatidylinositol (3,4,5)-tris-phosphate (PtdIns(3,4,5)P-3) production both in vitro and in vivo. However, the p84/p110 gamma heterodimer is approximately 4-fold less sensitive to G beta gamma s than p101/p110 gamma. Endogenous murine p84 expression is substantially reduced in the absence of p110 gamma expression. We conclude that p110 gamma has two potential regulatory subunits in vivo, p84 and p101.