Arrestin-dependent ERK activation and its disruption

Abstract

Regulation of the ERK1/2 cascade is one of the most studied functions of arrestins and illustrates many of the features that enable them to function as GPCR-regulated scaffolds. While all four arrestins can bind the component kinases of the ERK cascade; c-Raf1, MEK1/2 and ERK1/2, their binding is dependent on arrestin conformation, such that inactive ERK1/2 can be sequestered by a microtubule-bound pool of arrestin, while activated ERK1/2 binds with high affinity only to the GPCR-bound arrestin conformation. The result is both a dampening of basal pathway activity, and the arrestin-dependent activation of a spatially and temporally constrained pool of ERK1/2 that differs in function from ERK1/2 activated by G protein-dependent mechanisms or classical receptor tyrosine kinase growth factor receptors. Arrestin-bound ERK1/2 performs numerous functions in cells, among them contributing to the regulation of GPCR internalization and trafficking, control of cell proliferation and non-proliferative cell growth, and regulation of cytoskeletal dynamics involved in cell migration and chemotaxis. The finding that arrestin binding of c-Raf1 and MEK1/2 can be disrupted by point mutations that eliminate its ability to activate ERK1/2 without disrupting its other functions indicates that the two major functions of arrestins, GPCR desensitization and signaling, are dissociable, and offers tools to probe arrestin's diverse cellular functions.