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ubiquitination is internalized at a normal rate but not degraded in lysosomes.
CXCR4 ubiquitination is mediated by the HECT domain E3 ligase
atrophin-interacting protein 4 (AIP4, also known as Itch), but here arrestins
may not be functioning as E3 ligase adaptors; depletion of
b
-arrestin1 has no
effect on CXCR4 ubiquitination.
52,73
Further, AIP4 can bind directly to
CXCR4: this binding involves WW domains in AIP4 and phosphorylated
serines in the CXCR4 carboxyl tail.
74
On the other hand, the N-terminus of
b
-arrestin1 can bind to the WW domains of AIP4 and
b
-arrestin1 depletion
blocks CXCR4 lysosomal degradation, suggesting that arrestin-AIP4 inter-
action regulates postendocytic sorting of CXCR4.
52
In later studies, how-
ever,
b
-arrestin1 was reported to inhibit degradation of ubiquitinated
CXCR4 by interacting with signal-transducing adaptor molecule-1, a com-
ponent of the postendocytic sorting complexes collectively called as
endosomal sorting complex required for transport 0 (ESCRT 0).
75,76
Although
b
-arrestins may not act as ubiquitin ligase adaptors for CXCR4,
they may be required for this function toward an endocytic protein or cofac-
tor at a downstream sorting step during CXCR4 lysosomal trafficking.
For other 7TMRs,
b
-arrestins have been shown to be required for recep-
tor ubiquitination, but the E3 ligase(s) involved is not known.
b
-Arrestin2 is
required for the ubiquitination of V2R, which occurs on lysine 268 in the
third intracellular loop of the receptor.
77
V2R ubiquitination is dispensable
for internalization as well as for slow agonist-independent protein turnover,
but it is required for rapid degradation of the receptor upon agonist stimu-
lation.
77
Ubiquitination of the
m
-opioid receptor is induced by the agonist
[D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin and requires
b
-arrestin1, but
not
b
-arrestin2 expression.
78
Although a growing number of 7TMRs have
been reported to be regulated by ubiquitination,
34,79
conclusive evidence
regarding the role of
b
-arrestins in this process remains an open question.
4.2. Other receptors
As indicated above, the endocytic functions of
b
-arrestins are not limited to
regulation of 7TMRs; rather, they play critical roles in mediating endocy-
tosis of other cell-surface receptors including growth factor receptors.
80
In
the case of the insulin-like growth factor 1 receptor (IGF-1R),
b
-arrestin1
functions as an essential adaptor to promote receptor internalization via
clathrin-coated vesicles.
81
In addition,
b
-arrestin1 escorts the E3 ubiquitin
ligase Mdm2 to mediate ubiquitination of the IGF-1R leading to receptor
degradation.
82
This role is specific for
b
-arrestin1 because depletion of
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