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associated with the regulation of nucleocytoplasmic transport during the cell
cycle (interphase) and the organization of the spindle apparatus during mito-
sis. Evidence in the literature suggests a role of
b
-arrestin 1 in the nucleus.
102
Although no studies have tested whether
b
-arrestin 1 can modulate the
activity of Ran, the possibility that it does remains to be examined.
7. PERSPECTIVES AND FUTURE DIRECTIONS
Although it is clear that 7TM receptors can activate small GTPases and
that GTPases can in turn participate in defining the cellular response medi-
ated by agonist stimulation, both at the levels of receptor trafficking and sig-
naling, numerous questions remain unanswered. The studies described in
this chapter provide a framework for future experimental work that will
clarify the role of
b
-arrestins as modulators of small GTPase activity and
function. For some small G proteins, great progress has been made, and
we are now able to provide a model. However, for others, little is known.
A comprehensive study of GTPase activation, in conditions of
b
-arrestin
knockdown, could represent an initial step toward delineating possible
involvement of these ubiquitous scaffold proteins.
7.1. Defining the role of
-arrestin 2
Very few studies have addressed the roles of both
b
-arrestin isoforms in
modulating small GTPase activity. Although the contribution of one iso-
form versus the other might depend upon the stimulus, the nature of recep-
tor, and the cellular context, few studies have systematically reported the role
of
b
-arrestin 1 and
b
-arrestin 2 simultaneously. Now that reagents such as
si- and shRNAs are in common use, these experiments could easily be
revisited. Although
b
-arrestins might have redundant effects, it is generally
appreciated that they often play specific, as well as complementary, roles.
A significant amount of evidence suggests that
b
-arrestin 1 is a key interme-
diate in Ral, Rho, and ARF6 activation.
8,14,18
However, some studies have
proposed that both
b
-arrestins might contribute.
13
Differentially studying
complex formation between the
b
-arrestins and the GTPase, and the con-
sequence of one isoform versus the other in the activation process of a given
small G, should give us better insight into the function of each isoform in
mediating receptor activation of small GTPase-dependent cellular responses.
This aspect has been well defined in the endocytic paradigm.
-arrestin 1 and
b
b
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