Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 113

the receptor and G protein, arrestin binding can be viewed as the dividing
line between two mutually exclusive and temporally discrete GPCR-
signaling states.
The first discovered, and still the most diverse, of the arrestin-signaling
functions is the regulation of protein and lipid phosphorylation. This chapter
discusses the characteristics of arrestins that enable them to function as
adapters and scaffolds for protein kinases, their roles as both positive and
negative regulators of kinase activity, and the numerous protein and lipid
kinase, and protein phosphatase effectors controlled by arrestins. Subsequent
chapters in this volume cover the other major classes of arrestin-regulated
effectors, including small G proteins, ubiquitin ligases, and regulators of
cytoskeletal dynamics. How these signals affect physiological function in
embryologic development, intermediary metabolism, vision, cancer, bone,
and the cardiovascular, immune, and central nervous systems are then
discussed separately.

2. ARRESTINS AS GPCR EFFECTORS
The fundamental duality of arrestin function is well illustrated by a
simple experiment. When angiotensin II-stimulated phosphatidylinositol
production was assayed in COS-7 cells expressing the angiotensin AT 1A
receptor, overexpression of either arrestin2 or 3 led to a reduction in the
maximal response, an entirely predictable effect of a protein known to pro-
mote uncoupling of AT 1A receptors from the Gq/11-phospholipase C b
effector pathway. Yet when angiotensin II-stimulated ERK1/2 activation
was assayed under identical conditions, arrestin overexpression led to a par-
adoxical increase in the response. 25 Such a result could not be a reflection of
arrestin-dependent termination of G protein signaling, but rather suggested
that the arrestin itself was somehow coupling the AT 1A receptor to the
ERK1/2 cascade.

2.1. Adaptors or scaffolds?
The nonvisual arrestins clearly function as adapter proteins in the context of
clathrin-dependent GPCR endocytosis, binding to agonist-bound GPCRs
while at the same time engaging clathrin and the b 2-adaptin subunit of the
AP-2 complex. 2,3 To transmit signals, in many cases they also function as
scaffolds. Scaffolding proteins perform at least three functions in cells: to
increase the efficiency of signaling between successive components of an
enzymatic cascade, ensure signaling fidelity by dampening cross talk