b-Arrestins: Modulators of Small GTPase Activation and Function - Progress in Molecular Biology and Translational Science - page 144

whether they act to control small GTPase activity remains a subject of great interest.
Over the years, considerable evidence has suggested that b-arrestins and GTPases
might be effectors of the same signaling pathways. One example is the roles of
both b-arrestin and Ras, the prototypical GTPase, in coordinating activation of
mitogen-activated protein kinase. Recently developed tools effective in suppressing
the expression of b-arrestins will help define whether they are essential for small
G protein activation. Furthermore, novel approaches to identify protein complexes will
greatly advance our understanding of the possible cross talk between b-arrestin and
small GTPases.
1. INTRODUCTION
Initially identified as key proteins regulating desensitization, internal-
ization, and recycling of seven-transmembrane (7TM) receptors, b -arrestin
proteins are now considered multifunctional scaffolds and central regulators
of signal transduction events. 1,2 Through their ability to interact with
numerous partners, they coordinate signaling from 7TM receptors and small
GTP-binding proteins. The latter are characterized as molecular switches
regulating a wide range of cellular responses. In this chapter, we review
the evidence suggesting that b -arrestins are key regulators of GTPase activity
and our current understanding of the mechanisms whereby b -arrestins
regulate the function of monomeric G proteins and the pathways they acti-
vate. We focus on how b -arrestins modulate the regulation of GTPase
activity to affect cellular processes like receptor trafficking and cytoskeletal
rearrangement.
1.1. The family of GTPases
Small GTPases are single-chain polypeptides of 20-40 kDa. These proteins
are considered molecular switches that determine the temporal aspects of a
broad variety of signaling events involved in numerous cellular processes and
responses. The G domain responsible for guanine nucleotide binding is
highly conserved between the different families of GTPases. When bound
to guanosine diphosphate (GDP), small GTPases are inactive. Some families
are maintained inactive through binding guanosine nucleotide dissociation
inhibitors (GDIs). These accessory proteins not only prevent nucleotide
exchange but also restrict relocalization of GTPases to membranes. Loading
of guanosine triphosphate (GTP) results in the stabilization of a new 3D
conformation that enables them to interact with and modulate the activity