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CXCR4 promotes the interaction of
b
-arrestin 1 with the ubiquitin ligase
AIP4.
26
Interestingly, AIP4 can also bind CXCR4 directly. Two serine res-
idues within the C-terminal tail of CXCR4 are essential for this interaction
and the subsequent ubiquitination of CXCR4.
27
CXCR4-bound
b
-arrestin
1 recruits endosomal sorting complex required for transport (ESCRT)-0 via
an initial interaction between ubiquitin and hepatocyte growth factor-
regulated tyrosine kinase substrate (Hrs), and possibly between
b
-arrestin
1 and STAM-1. Scaffolding of AIP4 modulates the ubiquitination of Hrs
and its subsequent dissociation following an internal interaction between
ubiquitin and the ubiquitin-binding domain of Hrs, thereby controlling
the amount of CXCR4 that will be degraded.
28
Another aspect of arrestin function pertains to their capacity to recruit,
on the endocytic vesicles, G protein-independent signaling machinery and
serve thus as signal transducers on their own. The first kinase scaffold that
was identified comprises mitogen-activated protein kinase (MAPK) mod-
ules: Raf-1, MEK1/2, ERK1/2; and ASK1, MKK4, and Jnk3. Arrestins sig-
nal also to other kinases such as Src kinase, protein kinase B/Akt, and PI(3)
kinase.
24,29-35
The role of
b
-arrestins in the regulation of GPCR signaling, endocytosis,
and degradation has also been demonstrated for other plasma membrane
(PM) proteins; for example, atypical 7TM receptors, tyrosine kinases, and
ion exchangers.
36-39
This extended repertoire of targets, together with
the variety of interfaces that
b
-arrestins are able to scaffold, explains their
important roles in multiple cellular processes in the retina, nervous system,
immune system, bone remodeling, and cancer.
32
A consequence of arrestin
recruiting signaling molecules, some of them involved in actin reorganiza-
tion, is their contribution in cell polarity and migration.
30,40
b
-Arrestins
have been implicated in networks belonging to the Wingless, Hedgehog,
Notch, and TGF
b
pathways, and their ablation has major developmental
consequences.
41
b
-Arrestins partially localize on the centrosome and the pri-
mary cilium.
42-44
Within cilia,
b
-arrestins participate in the GPCR-
dependent signaling pathways related to the sensory function of this antenna.
2.2. Crystal structure of arrestins
The crystal structure of visual arrestins and
b
-arrestins was solved not long
after their discovery.
1-8
Arrestin proteins are structured as two head-to-tail
oriented modules, the arrestin-N (PFAM signature PF00339) and arrestin-C
(PFAM signature PF02752) domains connected by a flexible hinge
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