b-Arrestins: Modulators of Small GTPase Activation and Function - Progress in Molecular Biology and Translational Science - page 162

7.2. Identification of the mechanisms whereby -arrestins

b

regulate GTPase function
In order to better understand the biological significance of the role of
b -arrestins in small GTPase activation, we must better define the molecular
mechanisms underlying their actions. We now know that b -arrestins can
colocalize and interact with some small G proteins. In addition, their deple-
tion in cells impacts the activation of some small GTPases. Although for
years investigators have been examining the role b -arrestin plays in
GTPase-mediated events, we can only draw simple schematic diagrams to
propose a model ( Fig. 6.2 ). Sustained agonist stimulation leads to conforma-
tional changes of receptor structure and translocation of b -arrestins from the
cytosol to the plasma membrane. As scaffold proteins, b -arrestins can interact
with GEFs and GTPases to promote their activation. This simple snap shot
of the signaling axis remains incomplete considering the numerous events
occurring during agonist stimulation, including heterotrimeric G protein
activation, plasma membrane lipid transformation, and posttranslational
modification of proteins through enzymes, as well as cytoskeletal remo-
deling. Whether and how b -arrestin controls these biological events to
impact small GTPase activation need to be addressed.
Studies aiming at identifying the binding site between b -arrestins, small
GTPases, and their GEFs and GAPs might be useful to create new tools to
study the relevance of a specific interaction. Instead of knocking down the
expression of the b -arrestin to assess its role in the activation of a specific
GTPase, one could express a mutant protein in a null background to only

A

GDP

GTP

GTPase

GEF

GTPase

β -arrestin

Biological effect

Figure 6.2 General mechanism of GTPase activation by 7TM receptors. Agonist stimu-
lation of a receptor classically leads to conformational changes within the receptor that
not only activates heterotrimeric G proteins but also promotes the recruitment of
b-arrestin proteins. b-Arrestins have been shown to interact with several GEFs and small
GTPases. In many cases, their presence is necessary for activation of the small G protein
(loading of GTP) and its related downstream signaling events.