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reported to regulate the function of the GTPases themselves as well as their
regulatory factors, GEFs and GAPs.
3.1. Rho and
-arrestin modulation of stress fiber formation
Three Rho GTPases have been identified in higher vertebrates: RhoA,
RhoB, and RhoC. Despite their 85% homology of sequence, they play dis-
tinct roles. Over the years, much attention has focused on RhoA in the con-
text of receptor modulation of actin reorganization. The identification of
Rho-dependent signaling pathways leading to specific cellular responses
has largely relied on the use of dominant negative mutants and biochemical
inhibitors such as the exoenzyme C3 transferase. LPA was the first agonist
identified to activate Rho leading to stress fiber formation and cell migra-
tion.
53
Several other agonists acting via 7TM receptors, such as sphingosine
1-phosphate, bombesin, thrombin, endothelin, and Ang II, were also
reported to promote Rho activation.
54-56
Efforts to identify the molecular
mechanisms leading to activation of this GTPase have implicated hetero-
trimeric G proteins as key molecules. Specifically, G
a
12/13
were identified
as heterotrimeric G protein isoforms mediating Rho activation,
57
and it was
proposed that G
a
subunits directly bind RhoGEFs to modulate their
activity.
58-60
The potential of G
a
q/11
to mediate Rho activation has also
been reported
8,61
and the identity of the G protein implicated in Rho acti-
vation following 7TM receptor stimulation remains of great interest.
The role of
b
-arrestins in mediating RhoA activation has been studied in
the context of Ang II stimulation of HEK293 cells stably expressing the
AT
1A
R.
8
Knockdown of
b
-arrestin 1, but not
b
-arrestin 2, by siRNA,
impaired the ability of Ang II stimulation to promote GTP loading of RhoA
by about 60% and reduced stress fiber formation. The involvement of
b
-arrestins was further supported by experiments where an AT
1
R ligand
known to mediate biased signaling via
b
-arrestin, [Sarcosine
1
-Ile
4
-Ile
8
]-
Ang II, was effective in promoting RhoA activation. The authors concluded
that in concert with G
a
q/11
,
b
-arrestin 1 was critical for RhoA activation
and formation of stress fibers. The molecular mechanism by which
G proteins and
b
-arrestin coordinate Rho activation remains to be defined.
Whether
b
-arrestin 1 acts as a scaffold to promote the recruitment of GEFs
to the receptor has not been investigated. Two Rho GEFs, Lbc and LARG,
were previously reported to interact with G
a
q/11
.
62,63
b
-Arrestin 1 may play
a role in translocation of these GEFs, to the receptor/G
q
complex to pro-
mote RhoA activation.
8
The role of
b
-arrestins
b
in Ang II-mediated
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