p84, a New Gβγ-Activated Regulatory Subunit of the Type IB Phosphoinositide 3-Kinase p110γ

Summary A variety of genetic and inhibitor studies have shown that phosphoinositide 3-kinase γ (PI3Kγ) plays an essential role in a number of physiological responses, including neutrophil chemotaxis, mast cell degranulation, and cardiac function [1–6]. PI3Kγ is currently thought to be composed of a p110γ catalytic subunit and a single regulatory subunit, p101. The binding of p110γ to p101 dramatically increases the activation of the complex by Gβγ subunits and, hence, is thought to be critical for the coupling of PI3Kγ to G protein coupled receptors [7–9]. Here, we characterize a new regulatory subunit for PI3Kγ. 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 p110γ specifically and with high affinity. Binding of p84 to p110γ substantially increases the ability of Gβγ to stimulate phosphatidylinositol (3,4,5)-trisphosphate (PtdIns(3,4,5) P 3 ) production both in vitro and in vivo. However, the p84/p110γ heterodimer is approximately 4-fold less sensitive to Gβγs than p101/p110γ. Endogenous murine p84 expression is substantially reduced in the absence of p110γ expression. We conclude that p110γ has two potential regulatory subunits in vivo, p84 and p101.