Arrestins as Regulators of Kinases and Phosphatases - Progress in Molecular Biology and Translational Science - page 110

CHAPTER FIVE

Arrestins as Regulators of Kinases
and Phosphatases

‡ , William E. Miller }
* Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA
† Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston,
South Carolina, USA
‡

, † ,

Louis M. Luttrell *

The Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston,
South Carolina, USA
} Department of Molecular Genetics, Biochemistry & Microbiology, University of Cincinnati College of
Medicine, Cincinnati, Ohio, USA

Contents
1. Introduction 116

2. Arrestins as GPCR Effectors 118

2.1 Adaptors or scaffolds? 118

2.2 Mechanism of arrestin-signaling scaffolds 121

2.3 Spatial and temporal control of kinase activity 122

2.4 The arrestin-regulated kinome 123

3. Positive and Negative Regulation of Kinase Pathways 124

3.1 Negative regulation of second messenger-dependent protein kinases 124

3.2 Positive and negative regulation of arrestin-associated kinases 125

4. Arrestin-Regulated Kinase and Phosphatase Pathways 126

4.1 Tyrosine protein kinases 126

4.2 Mitogen-activated protein kinases 130

4.3 Other SER/THR kinases 135

4.4 Protein phosphatases 136

4.5 Lipid kinases 139

5. Conclusions 140

Acknowledgments 141

References 141

Abstract
The discovery that, in addition to mediating G protein-coupled receptor (GPCR) desensiti-
zation and endocytosis, arrestins bind to diverse catalytically active nonreceptor proteins
and act as ligand-regulated signaling scaffolds led to a paradigm shift in the study of
GPCR signal transduction. Research over the past decade has solidified the concept that
arrestins confer novel GPCR-signaling capacity by recruiting protein and lipid kinase, phos-
phatase, phosphodiesterase, and ubiquitin ligase activity into receptor-basedmultiprotein
“ signalsome ” complexes. Signalsomes regulate downstream pathways controlled by Src