The Role of Arrestins in Development - Progress in Molecular Biology and Translational Science - page 218

1. INTRODUCTION

arrs) are scaffolding proteins, which assemble signaling
complexes and thereby orchestrate a large number of signaling cascades
(reviewed in Ref. 1 ). By doing so, they are fundamental regulators of mul-
tiple physiological as well as pathological processes in our bodies. Due to
their rather ubiquitous expression 2-5

b -Arrestins ( b

b

and the normal fertility of arr1 or

arr2 knockout (KO) mice, 4,5 it has long been assumed that b arrs play no

significant role during embryogenesis. However, there is growing evidence
in animal models other than mice demonstrating that

b

arrs implement their
role in cellular signaling already during embryonic development. This chap-
ter gives an overview of the different functions of

b

b arrs in development that

have been uncovered up to date.
In the adult, arrs facilitate a large variety of signaling cascades. Besides

their traditional role in G protein-coupled receptor (GPCR) desensitization
and internalization,

b

arrs enable G protein-independent signal transduction
by the assembly of signaling complexes. 6 Furthermore, they have been
found to be central regulators of the so-called atypical GPCRs (i.e. Smooth-
ened (Smo) or Frizzled proteins) as well as molecules with structures
completely different from seven-transmembrane receptors. 7 Considering
their impact upon such a large repertoire of pathways, it is surprising that
mice lacking one or the other

b

arr1
KOmice are viable and fertile. They show normal cardiac parameters but are
hypersensitive to adrenergic stimulation. 5 Continuous treatment of

b arr would develop normally. In fact, b

b arr1

KO mice with the -adrenergic receptor agonist isoproterenol results in

DNA damage through suppression of p53. 8 Similarly, mice lacking

b

arr2
appear to be normal. However, they display prolonged analgesic effects
when treated with the opioid agonist morphine. 4
b arr1 and 2 are highly conserved proteins, which can be found through-
out vertebrate as well as invertebrate species ( Fig. 9.1 ). They share great
homology with each other, which is likely to be the reason why single
KOs for either

b

b arr are viable. The combined loss of both b arrs, however,

is incompatible with life. Newborn arr1/2 double KO mice are smaller

than their wild-type littermates and die soon after birth from respiratory fail-
ure as they do not develop fully mature lungs. 9 When looking more thor-
oughly, it appears that their lungs arrest in differentiation, which manifests in
reduced proliferation, abnormal accumulation of glycogen, and disturbed
production of surfactant proteins. In addition, this phenotype is associated

b