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Scaffolding c-Jun N-Terminal Kinase Cascades: Mechanistic Insights from the Reconstituted Arrestin-JNK Cascades

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The Structural Basis of Arrestin Functions

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Abstract

Although other subtypes appear to interact at least with some kinases in the ASK1-MKK4/7-JNK1/2/3 cascades, only arrestin-3 facilitates JNK activation in cells. While cell-based assays are suggestive, only the experiments with purified proteins can definitively show which protein-protein interactions are direct. Pure arrestin-3 was shown to facilitate the phosphorylation of JNK3 and other isoforms by MKK4 and MKK7. Biphasic dependence of the effect on arrestin-3 concentration showed that arrestin acts as a simple scaffold, bringing the kinases (MKKs ) and their substrates (JNKs ) into close proximity, rather than by activating MKKs or their substrate JNKs. Dissections of arrestin-3 elements involved allowed the identification of a surprisingly small 25-residue peptide that binds all relevant kinases and promotes JNK3 activation in cells.

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Notes

  1. 1.

    Here we use the systematic names of arrestin proteins: arrestin-1 (historic names S-antigen, 48 kDa protein, visual or rod arrestin), arrestin-2 (β-arrestin or β-arrestin1), arrestin-3 (β-arrestin2 or hTHY-ARRX), and arrestin-4 (cone or X-arrestin; for unclear reasons its gene is called “arrestin 3” in the HUGO database).

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Authors and Affiliations

  1. Department of Chemistry, Tennessee Technological University, Cookeville, TN, 38505, USA

    Xuanzhi Zhan

  2. Department of Pharmacology, Vanderbilt University, Nashville, TN, 46795, USA

    Vsevolod V. Gurevich & Eugenia V. Gurevich

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  1. Xuanzhi Zhan
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  2. Vsevolod V. Gurevich
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Correspondence to Vsevolod V. Gurevich .

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  1. Department of Pharmacology, Vanderbilt University, Nashville, Tennessee, USA

    Vsevolod V. Gurevich

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Zhan, X., Gurevich, V.V., Gurevich, E.V. (2017). Scaffolding c-Jun N-Terminal Kinase Cascades: Mechanistic Insights from the Reconstituted Arrestin-JNK Cascades. In: Gurevich, V. (eds) The Structural Basis of Arrestin Functions. Springer, Cham. https://doi.org/10.1007/978-3-319-57553-7_14

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