Gαq Acts as an Adaptor Protein in Protein Kinase Cζ (PKCζ)-mediated ERK5 Activation by G Protein-coupled Receptors (GPCR)

Abstract

Gq-coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of different cellular functions. These receptors can regulate a highly interconnected network of biochemical routes that control the activity of several members of the mitogen-activated protein kinase (MAPK) family. The ERK5 MAPK has been shown to be activated by Gq-coupled GPCR via unknown mechanisms. We find that the atypical protein kinase C (PKCζ), previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor-mediated ERK5 stimulation, plays a crucial role in the activation of the ERK5 pathway by Gq-coupled GPCR. Stimulation of ERK5 by Gq-coupled GPCR is abolished upon pharmacological inhibition of PKCζ as well as in embryonic fibroblasts obtained from PKCζ-deficient mice. Both PKCζ and MEK5 associate to Gαq upon activation of GPCR, thus forming a ternary complex that seems essential for the activation of ERK5. These data put forward a novel function of Gαq as a scaffold protein involved in the modulation of the ERK5 cascade by GPCR that could be relevant in Gq-mediated physiological functions. Gq-coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of different cellular functions. These receptors can regulate a highly interconnected network of biochemical routes that control the activity of several members of the mitogen-activated protein kinase (MAPK) family. The ERK5 MAPK has been shown to be activated by Gq-coupled GPCR via unknown mechanisms. We find that the atypical protein kinase C (PKCζ), previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor-mediated ERK5 stimulation, plays a crucial role in the activation of the ERK5 pathway by Gq-coupled GPCR. Stimulation of ERK5 by Gq-coupled GPCR is abolished upon pharmacological inhibition of PKCζ as well as in embryonic fibroblasts obtained from PKCζ-deficient mice. Both PKCζ and MEK5 associate to Gαq upon activation of GPCR, thus forming a ternary complex that seems essential for the activation of ERK5. These data put forward a novel function of Gαq as a scaffold protein involved in the modulation of the ERK5 cascade by GPCR that could be relevant in Gq-mediated physiological functions.