b-Arrestins: Modulators of Small GTPase Activation and Function - Progress in Molecular Biology and Translational Science - page 160

six members of the arrestin subfamily were identified and named arrestin
domain-containing protein (Adc) A-F. It was reported that AdcA interacted
with GDP-bound ARF a , an homologue of human ARF proteins, further
demonstrating the importance of these two proteins across species. 15
Interestingly, activation of ARF6 by ARNO was reported to cause
b -arrestin release from its membrane docking site to promote luteinizing
hormone/choriogonadotropin receptor desensitization using a cell-free
plasma membrane model of ovarian cells. 16 Indeed, the addition of recom-
binant ARNO promoted binding of b -arrestin to the third intracellular loop
of the active receptor thereby limiting signaling to heterotrimeric G a s pro-
tein and adenylate cyclase. Further studies revealed that in this system,
ARNO is readily detected in follicular membranes. Its activation to promote
b -arrestin release from the plasma membrane pool was demonstrated to be
independent of PI-3 kinase and G bg but required PIP2. 16

5.2. Remodeling of the actin cytoskeleton via -arrestin

b

and ARF6
A role for b -arrestin and ARF6 in other receptor-mediated cellular
responses was also observed. Stimulation of the calcium-sensing receptor
leads to increased intracellular calcium levels, membrane ruffling and ulti-
mately chemotaxis. These responses were blocked by expression of a dom-
inant negative b -arrestin mutant or transfection of specific b -arrestin
siRNA, expression of a catalytically inactive ARNO construct, and expres-
sion of a dominant negative form of ARF6 as well as a truncated form of
ELMO. Furthermore, ARNO and b -arrestin were shown to
coimmunoprecipitate independent of receptor stimulation and to colocalize
in HEK293 cells. 17 This chapter was the first suggesting that the b -arrestin/
ARNO/ARF6/ELMO signaling axis was involved in 7TM receptor-
dependent cell shape changes. As many other receptors are known to pro-
mote actin remodeling in a b -arrestin and ARF6-dependent manner, the
b -arrestin/GEF/ARF6 signaling axis may represent a general mechanism.
Together, these newly identified ARF-dependent signaling events con-
tribute to the understanding of the molecular mechanisms by which
b -arrestin regulates receptor endocytosis and trafficking.

6. RAN FAMILY GTPases
The last family of Ras proteins comprises the Ras-like nuclear protein
(Ran). Only one isoform has been identified, and its main role has been