Differential regulation of lipid and proteins kinase activities of phosphoinositide 3-kinase γ in vitro

G protein sensitive phosphoinositide 3-kinase gamma (PI3K gamma) has been characterised as a pleiotropic signalling protein expressing lipid kinase and protein kinase activities. Whereas the regulation of the lipid kinase activity has been investigated in detail, the regulatory features of PI3K gamma protein kinase activity are unknown. Here we report that G beta gamma subunits of heterotrimeric G proteins induce a biphasic response of PI3K gamma autophosphorylation in vitro, which contrasts the regulatory effects of the G proteins on PI3K gamma lipid kinase activity. In addition to autophosphorylation PI3K gamma is able to catalyse transphosphorylation of the adapter protein p101 and the protein kinase MEK-1. In the presence of the p101, G beta gamma affects PI3K gamma protein kinase activities in a complex manner. In summary, the differential regulatory effects of heterotrimeric G proteins on PI3K gamma lipid and protein kinase activities in vitro reflect the functional diversity of the enzyme observed in vivo.