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Arrestin-Dependent Activation of ERK and Src Family Kinases

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Arrestins - Pharmacology and Therapeutic Potential

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 219))

Abstract

The four members of the mammalian arrestin family, two visual and two nonvisual, share the property of stimulus-dependent docking to G protein-coupled receptors. This conformational selectivity permits them to function in receptor desensitization, as arrestin binding sterically inhibits G protein coupling. The two nonvisual arrestins further act as adapter proteins, linking receptors to the clathrin-dependent endocytic machinery and regulating receptor sequestration, intracellular trafficking, recycling, and degradation. Arrestins also function as ligand-regulated scaffolds, recruiting catalytically active proteins into receptor-based multiprotein “signalsome” complexes. Arrestin binding thus marks the transition from a transient G protein-coupled state on the plasma membrane to a persistent arrestin-coupled state that continues to signal as the receptor internalizes. Two of the earliest discovered and most studied arrestin-dependent signaling pathways involve regulation of Src family nonreceptor tyrosine kinases and the ERK1/2 mitogen-activated kinase cascade. In each case, arrestin scaffolding imposes constraints on kinase activity that dictate signal duration and substrate specificity. Evidence suggests that arrestin-bound ERK1/2 and Src not only play regulatory roles in receptor desensitization and trafficking but also mediate longer term effects on cell growth, migration, proliferation, and survival.

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Abbreviations

BRET:

Bioluminescence resonance energy transfer

EGF:

Epidermal growth factor

ERK1/2:

Extracellular signal-regulated kinases 1 and 2

GPCR:

G protein-coupled receptor

GRK:

GPCR kinase

JNK/SAPK:

c-Jun N-terminal kinase/stress-activated protein kinase

LPA:

Lysophosphatidic acid

MAPK:

Mitogen-activated protein kinase

MEF:

Murine embryo fibroblast

PAR:

Protease-activated receptor

PK:

Protein kinase

PLC:

Phospholipase C

PTH:

Parathyroid hormone

SH:

Src homology

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Acknowledgments

Work conducted in the authors’ laboratory is supported by National Institutes of Health Grant R01 DK055524 and the Research Service of the Charleston, SC Veterans Affairs Medical Center. The contents of this article do not represent the views of the Department of Veterans Affairs or the United States Government.

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Authors and Affiliations

  1. Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA

    Erik G. Strungs & Louis M. Luttrell

  2. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Louis M. Luttrell

  3. Research Service of the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, USA

    Louis M. Luttrell

  4. Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 816-CSB, MSC624, Charleston, SC, 29425, USA

    Louis M. Luttrell

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  1. Erik G. Strungs
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Correspondence to Louis M. Luttrell .

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Editors and Affiliations

  1. Professor of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA

    Vsevolod V. Gurevich

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Strungs, E.G., Luttrell, L.M. (2014). Arrestin-Dependent Activation of ERK and Src Family Kinases. In: Gurevich, V. (eds) Arrestins - Pharmacology and Therapeutic Potential. Handbook of Experimental Pharmacology, vol 219. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-41199-1_12

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