Biology Reference
In-Depth Information
Abstract
b-Arrestins regulate G protein-coupled receptors through receptor desensitization
while also acting as signaling scaffolds to facilitate numerous effector pathways.
Recent studies have provided evidence that b-arrestins play a key role in inflamma-
tory responses. Here, we summarize these advances on the roles of b-arrestins in
immune regulation and inflammatory responses under physiological and pathological
conditions, with an emphasis on translational implications of b-arrestins on human
diseases.
1. INTRODUCTION
b
-Arrestins are classically known to regulate G protein-coupled
receptor (GPCR) signaling through receptor desensitization and internali-
zation.
1
The structure and molecular characterization of
b
-arrestins have
been established.
2-4
Collaborating with GPCR kinases (GRKs),
5
b
-arrestins
are known for their role in desensitizing the
b
2-adrenergic receptor
(
b
2AR).
6
Much of the investigation on the role of
b
-arrestins has been asso-
ciated with the deactivation and desensitization of the GPCRs. GPCR
internalization is believed to occur through clathrin-mediated endocytosis,
which consists of three processes: receptor desensitization, sequestration of
receptors to clathrin-coated pits, and receptor internalization. These steps
are each regulated by distinct signaling events, and
b
-arrestins have a role
in these processes. In addition,
b
-arrestins have been shown to mediate
non-GPCR signaling pathways, such as through TGF-
b
receptor III.
7
Reports have also shown that
b
-arrestins facilitate the activation of
numerous effector pathways, such as the mitogen-activated protein kinases
(MAPKs) and Akt.
8
b
-Arrestin 2 serves as a scaffold to enhance MAPK
kinase kinase (cRaf-1) and MAPK kinase (MEK)-dependent activation of
extracellular signal-regulated kinase 2 (ERK2
9
) (reviewed in Refs.
10,11
).
Furthermore, evidence suggests that
b
-arrestins mediate signaling pathways
through transcriptional regulation (reviewed in Refs.
12
). For example,
b
-arrestin 1 is able to translocate from the cytosol to the nucleus and recruit
histone acetyltransferase p300, leading to enhanced local histone H4 acety-
lation and transcription of p27 and c-fos.
13
Extensive research demonstrates that
b
-arrestins have functions in devel-
opment,
14,15
cancer,
16,17
and chemotaxis.
18,19
During the past several years,
roles of
b
-arrestins in innate and adaptive immunity, as well as in inflamma-
tory responses, have been reported. Studies in mice with targeted deletion of
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