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cells and fine-tuning GRK2 levels. Because GRK2 also phosphorylates mul-
tiple substrates in addition to 7TMRs, these effects would have a broader
impact in cell signaling.
77,90,91
cAMP in cells is rapidly degraded by phosphodiesterases (PDE), and
upon
b
2
AR stimulation, the recruited
b
-arrestin2 was shown to scaffold
PDE4 isoforms to prime cAMP degradation in membrane microdomains,
increasing the efficiency of desensitization.
92
Intriguingly, PDE4D5 is rap-
idly and transiently ubiquitinated in response to agonist stimulation of
b
2
ARs, and this is mediated by Mdm2 scaffolded by
b
-arrestin2.
93
PDE4D5 ubiquitination serves to enhance its interaction with
b
-arrestin2,
while simultaneously decreasing interaction with the alternate scaffold
RACK1,
thus
increasing
the
fidelity of
specific protein-protein
interactions.
93
b
-Arrestins act as 7TMR-regulated scaffolds forMAPKactivation as shown
for both the JNK3 and ERK1/2 pathways.
94
For JNK3 activation,
b
-arrestin
brings together the upstream MAPKKK (ASK1) and the MAPKK (MKK4),
thus increasing proximity of the individual components of this kinase
cascade.
26,27
During H
2
O
2
-induced apoptosis,
b
-arrestins promote
ubiquitination and 26S proteasomal degradation of bound ASK1 by recruiting
the U-box containing E3 ubiquitin ligase C-terminus of Hsc70-interacting
protein (CHIP).
95
CHIP activity requires the additional molecular chaperones
Hsp-90 and HSc-70. In the above stress-induced pathway,
b
-arrestins act to
suppress apoptosis by decreasing ASK1 levels.
Recent studies have shown that chronic
b
2
AR activation by catechol-
amines triggers DNA damage and downregulation of p53.
96
The molecular
mechanism involves
b
-arrestin1-dependent ubiquitination of p53 by the E3
ubiquitin ligase Mdm2 leading to p53 degradation, which results in impaired
apoptosis of cells carrying DNA damage and accumulation of DNA damage.
This study exemplifies the emerging role of
b
-arrestin1 as an E3-ligase adap-
tor in the nucleus and highlights the pathophysiological consequences of
obliterating this
b
-arrestin function
in vivo
.
5. ARRESTINS AND SEVEN-TRANSMEMBRANE
RECEPTOR DEUBIQUITINATION
Plasma membrane-localized
b
2
ARs can bind to two closely related
DUBs, USP33 and USP20 (also known as VDU2). Agonist stimulation
of the
b
2
AR leads to ubiquitination and lysosomal degradation of the
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