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Abstract

Heterotrimeric G proteins play an essential role in the initiation of G protein-coupled receptor (GPCR) signaling through specific interactions with a variety of cellular effectors. We have recently reported that GPCR activation promotes a direct interaction between G alpha q and protein kinase C zeta (PKC zeta), leading to the stimulation of the ERK5 pathway independent of the canonical effector PLC beta. We report herein that the activation-dependent G alpha q/PKC zeta complex involves the basic PB1-type II domain of PKC zeta and a novel interaction module in G alpha q different from the classical effector-binding site. Point mutations in this G alpha q region completely abrogate ERK5 phosphorylation, indicating that G alpha q/PKC zeta association is required for the activation of the pathway. Indeed, PKC zeta was demonstrated to directly bind ERK5 thus acting as a scaffold between G alpha q and ERK5 upon GPCR activation. The inhibition of these protein complexes by G protein-coupled receptor kinase 2, a known G alpha q modulator, led to a complete abrogation of ERK5 stimulation. Finally, we reveal that G alpha q/PKC zeta complexes link G alpha q to apoptotic cell death pathways. Our data suggest that the interaction between this novel region in G alpha q and the effector PKC zeta is a key event in G alpha q signaling.