b-Arrestins: Modulators of Small GTPase Activation and Function - Progress in Molecular Biology and Translational Science - page 151

proliferate upon lysophosphatidic acid (LPA) treatment. 49 These observa-
tions provide evidence that misregulation of the b -arrestin/Ral pathway
might contribute to the pathogenesis of diverse conditions.
Still other roles for the b -arrestin/RalGDS/Ral pathway have been
reported. For example, this signaling axis was shown to regulate exocytosis
of Weibel-Palade bodies (WPB) in endothelial cells. These intracellular
granules contain a number of proteins and cofactors, ready to be released
in the extracellular environment. Their fusion with the plasma membrane
is tightly regulated and requires a -synuclein ( a -Syn). Overexpression of
a -Syn inhibited the activity of RalA through a mechanism involving poten-
tiation of the b -arrestin/RalGDS interaction in human umbilical vein endo-
thelial cells. Interestingly, a -Syn can interact with both b -arrestin and
RalGDS. Together, these data suggest that this interaction might serve to
restrict Ral activation and may function as a negative regulator of WPB exo-
cytosis. In endothelial cells, the physiological function of this pathway
remains to be defined. However, the release of WPB components such as
von Willebrand factor is likely to impact vascular homeostasis. 19
The other closely related Ras family GTPases are the Rap proteins.
Although these small G proteins are known to be activated by 7TM recep-
tors and mediate cellular proliferation through the MAPK pathway, 50,51
there is no evidence so far to suggest that their function is regulated by
b -arrestins. Rather, reports have suggested that 7TM receptor activation
of Raps occurs through heterotrimeric G proteins. 50,52
3. RHO FAMILY GTPases
Members of the Rho family of small GTPases are primarily involved
in cytoskeletal rearrangement, and they are broadly expressed in eukaryotes.
Although the function of the three major members is interconnected in the
regulation of cell migration and polarity, each GTPase has been associated
with a particular function. RhoA is important for actin polymerization lead-
ing to stress fiber formation, Rac regulates formation of the branching actin
chains of the lamellipodia, and Cdc42 controls filopodia formation.
As signaling molecules, Rho GTPases activate a broad variety of down-
stream effectors that impact the function of various proteins. For example,
Rac is well known for its role on NADPH oxidase and the production of
superoxide. Increased Rho, Rac, and Cdc42 activity can be observed upon
agonist stimulation of receptors. As described below, b -arrestins have been