Phosphoinositide 3-kinase gamma is a mediator of Gbetagamma-dependent Jun kinase activation

Jun kinases (JNK) are involved in the stress response of mammalian cells. Stimulation of JNK can be induced by stress factors and by agonists of tyrosine kinase and G protein-coupled receptors. G protein-dependent receptors stimulate JNK via Gbetagamma subunits of heterotrimeric G proteins, but the subsequent signaling reaction has been undefined. Here we demonstrate JNK activation in COS-7 cells by Gbetagamma-stimulated phosphoinositide 3-kinase gamma (PI3Kgamma). Signal transduction from PI3Kgamma to JNK can be suppressed by dominant negative mutants of Ras, Rac, and the protein kinase PAK. These results identify PI3Kgamma as a mediator of Gbetagamma-dependent regulation of JNK activity.