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

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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 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.
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G protein, G protein-coupled receptor (GPCR), mitogen-activated protein kinase (MAPK), Regulator of G protein signaling (RGS), Signal transduction, G protein-coupled receptor kinases, Gαq, PB1 domain, PKCζ, ERK5
Bibliographic citation
Sánchez-Fernández, G., Cabezudo, S., Hernandez-Caballero, A., García-Hoz, C., Tall, G. G., Klett, J., Michnick, S. W., Mayor, F., & Ribas, C. (2016). Protein kinase C Ζ interacts with a novel binding region of GΑQ to act as a functional effector. Journal of Biological Chemistry, 291(18), 9513-9525.