b-Arrestins: Modulators of Small GTPase Activation and Function - Progress in Molecular Biology and Translational Science - page 158

4.2. Modulation of Rab function through interaction
The question of interest for this chapter is whether b -arrestins directly mod-
ulate GTP loading of Rabs. Unlike many other GTPases, no evidence in the
literature clearly demonstrates that they do. Rabs function to control traf-
ficking of a vesicle from one organelle to another. They are highly special-
ized, and although they are key players dictating the route a 7TM receptor
will utilize, their activation does not appear to depend on any extracellular
stimuli. Like other small G proteins, activation is possible via GEFs and inac-
tivation facilitated by GAPs. The molecular mechanisms triggering activa-
tion of Rab regulatory factors remains to be fully elucidated. It is,
however, becoming more and more evident that b -arrestins and Rabs act
in concert to dictate intracellular trafficking. For example, Rab5 and
b -arrestin binding to the carboxyl-terminal tail of the AT 1 R is an event
important for retention of this receptor in early endosomes. 90 Whether as
scaffold proteins, b -arrestins bind to Rabs or their regulatory proteins to
modulate their activity remains to be explored.
5. ARF FAMILY GTPases
The ARFs were first identified as a cellular activity required for ADP-
ribosylation of G a s by cholera toxin, a process by which it exerts its toxic
effect. 91,92 ARFs are part of a larger family of small Ras-related
G proteins that include Sar and Arl (ARF-like), identified mainly by genome
sequencing. The focus here will, however, be on ARFs since evidence
shows that their activity is regulated by receptor stimulation. Although they
are typically called small GTPases, ARFs have actually no intrinsic GTPase
activity and require GAPs for GTP hydrolysis. The numerous roles of ARFs
in cells are not related to ADP-ribosylation. Rather, these small G proteins
are best known to participate in the formation of coated vesicles responsible
for membrane traffic, lipid transformation, and reorganization of the actin
cytoskeleton. Six isoforms of ARFs have been identified (ARF1-6), and
they are ubiquitously expressed with the exception of ARF2 that is not pre-
sent in humans. The best-characterized ARFs are ARF1 and ARF6. ARF1
is known for orchestrating the coating of budding vesicles at the Golgi. 93
However, some evidence suggests that this ARF isoform can localize to
plasma membranes to mediate receptor-dependent events. 94-97 No data
suggesting cross talk with b -arrestins have been reported in the literature.
ARF6 is the small G protein classically present at the cell periphery, and