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In HEK 293 cells, isoproterenol treatment promotes the rapid and
sustained activation of Rac1 almost to the degree obtained from GTP
g
S
loading of the small G protein. Inhibition of
b
-arrestin 1 expression by
RNA interference has been shown to abrogate the ability of this agonist
to activate Rac1, a key event important for NADPH oxidase activation
and p38 phosphorylation.
22
These data suggest that
b
-arrestin is required
for
b
2
-adrenergic receptor signaling to this GTPase and that Rac1 acts
downstream of
b
-arrestin. The involvement of
b
-arrestins in the activation
of Rac proteins, therefore, remains a subject of great interest and requires
further studies to define the roles of
b
-arrestin isoforms in different cellular
contexts.
Interplay between arrestins and Rac2 has also been reported. One report
has proposed that Rac2 acts upstream and regulates the translocation of
arrestin 2, the major arrestin protein present in
Drosophila
, to activated
rhodopsin.
23
Similar to mammalian photoreceptors, translocation of arrestin
upon receptor activation resulted in desensitization of the photoresponse by
preventing further heterotrimeric G protein coupling. In control experi-
ments, arrestin was rapidly redistributed to the rhabdomeres upon light
exposure. In Rac2 null mutant photoreceptor cells, arrestin 2 remained dis-
tributed throughout the cell bodies after light exposure. In
Drosophila
,
relocalization of arrestin did not depend on any of the known components
of the phototransduction cascade. Altogether, these findings suggest that
light-dependent translocation of arrestin 2 occurs through a rhodopsin/
Rac2-dependent pathway in flies.
23
Whether this is an evolutionary con-
served mechanism remains to be addressed. In mammalian cells, our under-
standing of the mechanisms by which receptor activation results in arrestin
translocation remains poorly understood.
Finally, other examples of
b
-arrestin signaling to Rac-dependent path-
ways have been reported. Complex responses such as vascular permeability,
controlled by internalization of VE-cadherins, which like 7TM receptors are
membrane proteins, were shown to be dependent upon a
b
-arrestin/Rac1
axis. In this context, it was proposed that the vascular endothelial growth
factor receptor promoted endocytosis of VE-cadherin through a mechanism
involving Src,
b
-arrestin, Vav2, Rac, and PAK.
72
3.3. Cdc42 and filopodia formation
The human Cdc42 protein was initially purified from placental membranes
and named G
p
. This newly identified 21 kDa protein was considered an
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