Arrestins and Protein Ubiquitination - Progress in Molecular Biology and Translational Science - page 170

b-arrestin ubiquitination. This posttranslational modification of b-arrestin is appended
by specific E3 ubiquitin ligases and reversed by deubiquitinases, which are also recruited
in a receptor- and agonist-specific manner. b-Arrestin ubiquitination allows it to form
protein complexes with activated 7TMRs, endocytic proteins such as clathrin, and phos-
phorylated ERK1/2. b-Arrestin ubiquitination is dependent on its activated conformation
and likely regulates timing and subcellular localization of various protein interactions
during receptor trafficking and signaling. b-Arrestins also serve as adaptors that escort
E3 ubiquitin ligases to mediate ubiquitination of a wide list of substrate proteins includ-
ing 7TMRs and provide an added layer of regulation for defining substrate specificity in
the cellular ubiquitination pathway.

1. INTRODUCTION
1.1. Arrestins: Adaptors for receptors and effectors
Arrestins are multifunctional adaptor proteins that bind to diverse cell-
surface receptors and regulate transmembrane signal transduction. 1-3 The
arrestin gene family contains four members and is divided into two groups
based on sequence identity, function, and tissue distribution: (1) visual
arrestins that regulate the opsins: arrestin 1 (or S antigen) and arrestin 4
(X-arrestin, cone arrestin, or C-arrestin) and (2) nonvisual arrestins:
b -arrestins 1 and 2 (arrestin 2 and arrestin 3). 4-7 Arrestin 1 is highly expressed
in the retinal rods, whereas arrestin 4 is highly expressed in retinal cones. The
two b -arrestins share 78% amino acid identity and are expressed ubiqui-
tously; at least one b -arrestin isoform is required for normal survival of
mouse neonates because genetic deletion of both b -arrestin isoforms confers
perinatal lethality. 8,9 The b -arrestins function as prototypical adaptors for the
vast majority of heptahelical cell-surface receptors known as the seven-
transmembrane receptors (G protein-coupled receptors or GPCRs). 10
Upon agonist stimulation, the 7TMRs activate heterotrimeric G proteins
leading to changes in the cellular levels of second-messenger molecules
(e.g., cAMP, inositol phosphate, Ca 2 þ ), which bind and activate signaling
kinases, ion channels, and other proteins leading to specific cellular
responses. 11 However, concomitant processes, namely, phosphorylation
within receptor intracellular domains by the serine-threonine kinases called
G protein-coupled-receptor kinases (GRKs) and subsequent recruitment of
cytoplasmic b -arrestins to plasma membrane-localized 7TMRs, cause
desensitization of G protein signaling ( Fig. 7.1 ; Ref. 12 ).
About a decade after the initial characterization, it became evident that
b -arrestins are important adaptors for the internalization of activated