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Protein-Protein Interactions as New Drug Targets pp 15–37Cite as

Arrestins as Multi-Functional Signaling Adaptors

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Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 186))

Abstract

Arrestins are versatile regulators of cellular signaling expressed in every cell in the body. Arrestins bind active phosphorylated forms of their cognate G-protein-coupled receptors, shutting down G-protein activation and linking receptors to alternative signaling pathways. Arrestins directly interact with more than 20 surprisingly diverse proteins, such as several Src family kinases, ubiquitin ligases, protein phosphatases, microtubules, etc., and serve as scaffolds facilitating signaling in two MAP kinase cascades, leading to the activation of ERK1/2 and JNK3. A number of arrestin-binding partners are key players in signaling pathways that regulate cell proliferation, survival, and apoptotic death, which make arrestin interactions with these proteins inviting targets for therapeutic intervention. For example, enhancement of pro-survival or pro-apoptotic arrestin-dependent signaling is a promising strategy in treating disorders such as neurodegenerative diseases or cancer, respectively. Recent studies show that in the cell arrestin exists in at least three distinct conformations, free, receptor-bound, and microtubule-bound, with very different signaling capabilities. Precise identification of arrestin elements mediating its interactions with each partner and elucidation of conformational dependence of these interactions will pave the way to the development of molecular tools for targeted enhancement or attenuation of arrestin interactions with individual partners. This structural information is necessary to devise conventional drug-based approaches and to engineer specialized “designer” arrestins that can compensate for defects in receptor regulation associated with congenital disorders and/or redirect arrestin-mediated signaling to desired pathways. Arrestins are at the crossroads of crucial pathways that determine cell fate and behavior. Therefore, targeted manipulation of arrestin-dependent signaling has an enormous therapeutic potential.

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Authors and Affiliations

  1. Department of Pharmacology, Vanderbilt University, Nashville, TN, 37232, USA

    V. V. Gurevich, E. V. Gurevich & W. M. Cleghorn

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  1. V. V. Gurevich
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  2. E. V. Gurevich
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  3. W. M. Cleghorn
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  1. Leibniz-Institut für Molekulare Pharmakologie, Robert-Rössle-Str. 10, 13125, Berlin, Germany

    Enno Klussmann

  2. The Vollum Institute, Oregon Health & Science University, Medical Research Bldg, Rm 322D 3181 SW Sam Jackson Park Road, Portland, OR, 97239-3098, USA

    John Scott Ph.D.

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Gurevich, V.V., Gurevich, E.V., Cleghorn, W.M. (2008). Arrestins as Multi-Functional Signaling Adaptors. In: Klussmann, E., Scott, J. (eds) Protein-Protein Interactions as New Drug Targets. Handbook of Experimental Pharmacology, vol 186. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-72843-6_2

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