The p101 subunit of PI3Kγ restores activation by Gβ mutants deficient in stimulating p110γ

G-protein-regulated PI3K gamma (phosphoinositide 3-kinase gamma) plays a crucial role in inflammatory and allergic processes. PI3K gamma, a dimeric protein formed by the non-catalytic p101 and catalytic p110 gamma subunits, is stimulated by receptor-released G beta gamma complexes. We have demonstrated previously that G beta gamma stimulates both monomeric p110 gamma and dimeric p110 gamma/p101 lipid kinase activity in vitro. In order to identify the G beta residues responsible for the G beta gamma-PI3K gamma interaction, we examined G beta(1), mutants for their ability to stimulate lipid and protein kinase activities and to recruit PI3K gamma to lipid vesicles. Our findings revealed different interaction profiles of G beta residues interacting with p110 gamma or p110 gamma/p101. Moreover, p101 was able to rescue the stimulatory activity of G beta(1) mutants incapable of modulating monomeric p110 gamma. In addition to the known adaptor function of p101, in the present paper we show a novel regulatory role of p101 in the activation of PI3K gamma.