Arrestin Pathways as Drug Targets - Progress in Molecular Biology and Translational Science - page 472

activation. 75 In vivo, cardiomyocyte-specific overexpression of AT 1 -i2m
leads to greater cardiomyocyte hypertrophy, bradycardia, and fetal cardiac
gene expression than comparable overexpression of the wild-type receptor.
Conversely, overexpressed wild-type AT 1A receptors produce greater
cardiomyocyte apoptosis and interstitial fibrosis than the G protein-
uncoupled mutant, suggesting that G protein-dependent and arrestin-
dependent AT 1A receptor signals mediate different aspects of the hypertro-
phic response. 76

4.4. Cell survival and apoptosis
A widely conserved and apparently critical set of arrestin-mediated signals
involves

the regulation of pro-survival and anti-apoptotic signaling.

In -catenin signaling (see

Chapter 11 ), the capacity of arrestin3 to scaffold a PP2A-AKT-GSK3 com-
plex probably allows it to serve as a positive regulator of PI3K/AKT-
dependent survival signaling. Activation of AT 1A receptors by SII promotes
G protein-independent phosphorylation of the PP2A inhibitor, I2PP2A,
leading to inhibition of arrestin-bound PP2A and increased phosphorylation
of Thr308, the activating phosphorylation site on AKT. 40 Arrestin-
dependent activation of the ERK1/2 substrate p90RSK also reportedly acts
in concert with PI3K-AKT to downregulate phospho-BAD, inducing anti-
apoptotic cytoprotective effects in rat vascular smooth muscle cells. 77
Finally, arrestin scaffolding of the ubiquitin ligase, Mdm2, modulates
p53-dependent apoptosis. Besides controlling GPCR endocytosis through
arrestin ubiquitination (see Chapter 7 ), Mdm2 is a major negative regulator
of the p53 tumor suppressor, since ubiquitination of p53 promotes its deg-
radation by the proteosome. Arrestin binding to Mdm2 prevents self-
ubiquitination and p53 ubiquitination. Decreasing p53 ubiquitination
increases its abundance, leading to enhanced apoptotic p53 signaling. As a
result, overexpressing arrestin3 enhances, and downregulating arrestin3
expression attenuates, p53-mediated apoptosis. 78
Functional genomic analysis of the actions of (D-Trp 12 ,Tyr 34 )-bPTH
(7-34) on bone in vivo suggest that arrestin-dependent anti-apoptotic signal-
ing underlies the observed expansion of the osteoblast pool and increase in
trabecular bone mass. 31,44 In vitro , both (D-Trp 12 ,Tyr 34 )-bPTH(7-34) and
PTH(1-34) protect wild type, but not arrestin3-null, osteoblasts from a pro-
apoptotic etoposide challenge. 44 In addition to its proliferative effects, the
arrestin-selective AT 1A receptor agonist, SII, is likewise anti-apoptotic in

addition to chronically dampening b