G Protein-coupled Scaffolding♦

♦ See referenced article, J. Biol. Chem. 2010, 285, 13480–13489

G protein-coupled receptors (GPCR), along with their coupled heterotrimeric G proteins, mediate a wide range of signaling pathways such as mitogen-activated protein kinase (MAPK) signaling associated with cell proliferation, migration, and apoptosis. The MAPK family member ERK5, for example, has been shown to be stimulated by G_q-coupled GPCR, although the mechanism is unknown. In this Paper of the Week, however, Carlota García-Hoz and colleagues use multiple biochemical approaches to demonstrate that the Gα_q subunit promotes ERK5 activation by acting as a scaffold that brings key elements together. They found that Gα_q interacts independently with the atypical protein kinase PKCζ, essential for ERK5 activity, and the ERK5 activator MEK5 to form a transient ternary complex. Interestingly, this scaffold activity was independent of the interaction of Gα_q with its classical effector phospholipase Cβ (PLCβ).This study provides the first demonstration that Gα protein subunits can serve as molecular scaffolds, bringing together two signaling proteins into proper proximity and orientation to promote their interaction, subsequently releasing the assembled PKCζ-MEK5 complex for downstream activity. These findings have broad implications in highly dynamic cell signaling.

Illustrated model for the proposed formation and release of the Gα_q-PKCζ-MEK5 complex.