Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 118

receptors or G protein-dependent GPCR signaling is able to translocate to
the nucleus and elicit a transcriptional response, ERK1/2 activated through
the arrestin pathway is confined to the cytosol and silent in Elk-1 reporter
assays. 25,46 Arrestin-bound ERK1/2 performs other functions, for example,
regulating arrestin-clathrin interaction during GPCR endocytosis 47,48 and
localized actin cytoskeletal reorganization during chemotaxis. 49 Similarly,
arrestin-bound ERK1/2 mediates AngII-stimulated phosphorylation of
the cytosolic targets, Mnk1 and eIF4E, leading to increased rates of mRNA
translation. 35 Thus, by compartmentalizing signaling, arrestin scaffolding
can change the functional consequences of pathway activation, even when
the pathway is subject to convergent regulation by multiple mechanisms.
2.4. The arrestin-regulated kinome
Before considering the multitude of individual kinase and phosphatase path-
ways regulated by arrestins, it is worth examining the scope of arrestin-
dependent effects on protein phosphorylation globally. Taking advantage
of the ability of the biased angiotensin AT 1A receptor agonist, [Sar 1 ,Ile 4 ,
Ile 8 ]-AngII (SII), to promote arrestin recruitment and arrestin-dependent
signaling independent of significant G protein activation, 32,50 two studies
have surveyed the arrestin-dependent “kinome” using whole-cell quantita-
tive phosphoproteomic approaches. These studies point to the existence of a
robust arrestin-dependent signaling network with far-reaching regulatory
functions.
In AT 1A receptor-expressing HEK293 cells, Xiao et al. 51 identified 171
unique proteins whose phosphorylation increased, and 53 whose phosphor-
ylation decreased, upon stimulation with SII, including 38 protein kinases
and 3 phosphatases. A subsequent bioinformatic network analysis based
on these results suggested that much of the arrestin-dependent signaling
network was focused on regulation of cytoskeletal rearrangement. Using
a similar strategy, Christensen et al. 52 performed a side-by-side global
phosphoproteomic comparison of angiotensin II and SII, thus revealing
the extent to which arrestin-dependent kinase regulation contributes to
the overall response. These investigators detected over 1183 regulated
protein phosphorylation sites out of 10,000 sites surveyed using high-
resolution LTQ-Orbitrap mass spectrometry. Of these, 756 (64%) were
unique to angiotensin II, 369 (34%) were regulated by both angiotensin
II and SII, and 58 (5%) were unique to SII. Analysis of consensus phosphor-
ylation sites indicated a striking difference between the kinases regulated by