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role is not currently known.Recently, it has beenproposed that a delicate inter-
play between different GRKs (e.g., 2 and 6) may regulate the balance of
G protein and
b
-arrestin-mediated signaling pathways downstream of
7TMRs.
75
10. OTHER RECEPTORS, OTHER FUNCTIONS
In addition to their paradigmatic roles in the regulation of classical
7TMRs,
b
-arrestins have also been found to regulate some receptors from
other diverse families. These include so-called atypical 7TMRs such as friz-
zled
76
and smoothened,
77
the receptor tyrosine kinases for IGF1
39
and
TrkA,
78
the nicotinic cholinergic receptor,
79
and even some cytokine
receptors such as the TGF-
b
RIII.
80
Depending on the particular receptor,
the
b
-arrestins may mediate endocytosis, signaling, or other functions.
Another role that has emerged for the
b
-arrestins in recent years is that of
an E3-ubiquitin ligase adaptor which facilitates interaction of ligases of widely
varying structures with their substrates. This role was first appreciated for the
b
2AR
81
though at the time the relevant ligase was unknown (it was subse-
quently shown to be NEDD4).
82
Later, it was shown that other 7TMRs
are regulated in this way by a variety of ligases (reviewed in Ref.
82
). More-
over, it is now known that diverse families of proteins are also ubiquitinated
by ligases using
b
-arrestins as adaptor proteins.
83
b
-Arrestin-mediated
ubiquitination has been shown to play roles in the internalization of mem-
brane proteins such as 7TMRs,
81
routing them to lysosomes for destruction,
in proteosomal degradation and signaling.
83
b
-Arrestins themselves are
ubiquitinated by MDM2, and this ubiquitination appears to be necessary
for their endocytic and at least some of their signaling functions.
81,84
Whether
this ubiquitination plays a role in
b
-arrestin—partner recognition and/or
other mechanisms is not clearly understood at present.
Recently, a much wider family of proteins containing predicted “arrestin
domains” has been discovered in organisms from yeast to mammals.
85
These
“arrestin-like” proteins have little or no sequence similarity to the mamma-
lian arrestins but are predicted to share the same fold. These proteins have
been referred to as “
a
-arrestins.”
86
Members include ARRDC1-5 and
TXNIP.
85
In yeast, there is a family of nine arrestin-related trafficking adap-
tors.
87
These proteins have some sequence similarities to ARRDCs and play
roles in the ubiquitination, endocytosis, and lysosomal trafficking of mem-
brane cargoes.
87
In mammalian cells, ARRDCs play various roles in traffick-
ing of membrane proteins which are still being defined.
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