Protein kinase C zeta Interacts with a novel binding region of Galfaq to act as a functional effector

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 Galfaq and protein kinase C zeta (PKCzeta), leading to the stimulation of the ERK5 pathway independent of the canonical effector PLCbeta. We report herein that the activation-dependent Galfaq/PKCzeta complex involves the basic PB1-type II domain of PKCzeta and a novel interaction module in Galfaq different from the classical effector-binding site. Point mutations in this Galfaq region completely abrogate ERK5 phosphorylation, indicating that Galfaq/PKCzeta association is required for the activation of the pathway. Indeed, PKCzeta was demonstrated to directly bind ERK5 thus acting as a scaffold between Galfaq and ERK5 upon GPCR activation. The inhibition of these protein complexes by G protein-coupled receptor kinase 2, a known Galfaq modulator, led to a complete abrogation of ERK5 stimulation. Finally, we reveal that Galfaq/PKCzeta complexes link Galfaq to apoptotic cell death pathways. Our data suggest that the interaction between this novel region in Galfaq and the effector PKCzeta is a key event in Galfaq signaling.

g protein; g protein-coupled receptor (gpcr); mitogen-activated protein kinase (mapk); regulator of g protein signaling (rgs); signal transduction; erk5g protein-coupled receptor kinases; g(alfa)q; pb1 domain; pkcç

Protein kinase C zeta Interacts with a novel binding region of Galfaq to act as a functional effector Articles