Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 111

family nonreceptor tyrosine kinases, mitogen-activated protein kinases, protein kinase B
(AKT), glycogen synthase kinase 3, protein phosphatase 2A, nuclear factor-kB, and
several others, imposing spatial and temporal control on their function. While many
arrestin-bound kinases and phosphatases are involved in the control of cytoskeletal
rearrangement, vesicle endocytosis, exocytosis, and cell migration, other signals reach
into the nucleus, affecting cell proliferation, apoptosis, and survival. Indeed, the
kinase/phosphatasenetwork regulatedby arrestinsmaybe fully as diverse as that regulated
by heterotrimeric G proteins.
1. INTRODUCTION
By the mid-1990s, the central roles of visual and nonvisual arrestins in
G protein-coupled receptor (GPCR) desensitization were well under-
stood. 1 The at-the-time startling discovery that arrestins, like the hetero-
trimeric G proteins, functioned as discrete GPCR effectors arose from
two lines of research. The first was the study of the mechanisms of GPCR
endocytosis, which led to the discovery that upon binding to activated
receptors, the two nonvisual arrestins, arrestin2 and 3 ( b -arrestin1 and 2),
act as adapter proteins linking the receptor to components of the
clathrin-dependent endocytic machinery. 2,3 The second line of research
involved the study of the mechanisms by which GPCRs regulated the non-
receptor tyrosine protein kinase c-Src and the small GTPase Ras pathway. 4,5
The realization that nonvisual arrestins form relatively stable arrestin-GPCR
complexes that persist over a timescale of minutes to hours as receptors tran-
sit the endocytic vesicle compartment, combined with the observation that
arrestin2 bound directly to activated c-Src and recruited it into a mul-
tiprotein “signalsome” complex with the receptor, 6 evolved into what
has amounted to a reenvisioning of GPCR signal transduction. Rather than
functioning solely as ligand-activated guanine nucleotide exchange factors
for heterotrimeric G protein, GPCRs have become multifunctional signal-
ing platforms that transmit “pluridimensional” intracellular signals via both
G protein and non-G protein effectors. 7 And rather than serving simply as
terminators of receptor-G protein coupling, arrestins have become versatile
signaling platforms whose binding confers additional GPCR-signaling
capability. 8-10
It is now known that arrestins function as ligand-regulated scaffolds,
bringing a host of arrestin-bound proteins to agonist-occupied GPCRs,
among them Src family nonreceptor tyrosine kinases 4,11,12 ; components