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physiologically relevant concentrations of phosphatidic acid, a precursor of
the multifunctional lipid second messenger, lysophosphatidic acid (LPA).
3.2. Positive and negative regulation of arrestin-associated
kinases
The complexity of arrestin-dependent regulation of kinase activity can be
illustrated by two examples: its opposing effects on ERK1/2 and NF-
k
B sig-
naling and its bidirectional regulation of the PP2A-AKT-GSK3 cascade.
As previously discussed, ERK1/2 is recruited preferentially to the
receptor-bound conformation of arrestin2 and 3,
38
permitting GPCRs to
selectively activate ERK1/2 within receptor-arrestin signalsomes.
14,15
The resulting spatial compartmentalization of ERK1/2 leads to increased
phosphorylation of cytosolic targets,
35,47-49
while inhibiting its ability to
stimulate Elk-1-dependent transcription.
25,46
At the same, the dominant
effect of arrestins on nuclear factor (NF)-
k
B signaling is to dampen pathway
activity. In NF-
k
B signaling, phosphorylation of the inhibitory protein,
I
k
B
a
,byI
k
B
a
kinases accelerates its proteosomal degradation, permitting
nuclear translocation of NF-
k
B and increasedNF-
k
B transcriptional activity.
I
k
B
a
binds arrestin3, while both arrestin2 and 3 interact with I
k
B kinase
a
/
b
and NR-I
k
B-inducing kinase.
54,55
Downregulating arrestin2 expression
increases NF-
k
B activation by tumor necrosis factor
a
(TNF
a
), consistent
with the hypothesis that arrestins tonically inhibit NF-
k
B signaling by
protecting I
k
B
a
from degradation.
19
In HEK293 cells, downregulating
arrestin expression attenuates toll-like receptor (TLR)4-mediated ERK1/2
activation while simultaneously enhancing NF-
k
B reporter activity,
suggesting that arrestins exert opposing effects on the ERK1/2 and NF-
k
B
pathways.
56
The situation with respect to PP2A-AKT-GSK3 signaling is similarly
complex.
b
-Catenin and Akt signaling is regulated by an arrestin3 sig-
nalsome complex composed of the catalytic subunit of PP2A, Akt, and gly-
cogen synthase kinase 3
b
(GSK3
b
).
23
As with NF-
k
B, the dominant arrestin
effect is to dampen
b
-catenin signaling. Within the arrestin3 complex, PP2A
maintains Akt in an inactive state by dephosphorylating Thr
308
. Since Akt
phosphorylation of GSK3
b
inhibits its activity, keeping Akt inactive
increases GSK3
a
/
b
activity. GSK3
b
, in turn, phosphorylates
b
-catenin,
accelerating its degradation and inhibiting
b
-catenin-dependent transcrip-
tion. Predictably, brain extracts from arrestin3 null mice show higher levels
of
b
-catenin expression, presumably reflecting the loss of tonic arrestin-
mediated Akt inhibition.
57
On the other hand, a phosphoproteomic screen
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