Identification of Arrestin-3-specific Residues Necessary for JNK3 Kinase Activation

Arrestins bind active phosphorylated G protein-coupled receptors, blocking G protein activation and channeling the signaling to G protein-independent pathways. Free arrestin-3 and receptor-bound arrestin-3 scaffold the ASK1-MKK4-JNK3 module, promoting JNK3 phosphorylation, whereas highly homologous...

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Bibliographic Details
Published in:The Journal of biological chemistry 2011-08, Vol.286 (32), p.27894-27901
Main Authors: Seo, Jungwon, Tsakem, Elviche L., Breitman, Maya, Gurevich, Vsevolod V.
Format: Article
Language:English
Subjects:
Animals
Arrestin
Arrestins - genetics
Arrestins - metabolism
Cattle
Chlorocebus aethiops
COS Cells
Enzyme Activation - physiology
G Protein-coupled Receptors (GPCRs)
Jun N-terminal kinase (JNK)
MAP Kinase Kinase Kinase 5 - genetics
MAP Kinase Kinase Kinase 5 - metabolism
MAP Kinases (MAPKs)
Mitogen-Activated Protein Kinase 10 - genetics
Mitogen-Activated Protein Kinase 10 - metabolism
Phosphorylation - physiology
Protein Structure, Secondary
Protein Structure, Tertiary
Protein-Protein Interactions
Signal Transduction
Site-directed Mutagenesis
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Summary:Arrestins bind active phosphorylated G protein-coupled receptors, blocking G protein activation and channeling the signaling to G protein-independent pathways. Free arrestin-3 and receptor-bound arrestin-3 scaffold the ASK1-MKK4-JNK3 module, promoting JNK3 phosphorylation, whereas highly homologous arrestin-2 does not. Here, we used arrestin-2/3 chimeras and mutants to identify key residues of arrestin-3 responsible for its ability to facilitate JNK3 activation. Our data demonstrate that both arrestin domains are involved in JNK3 activation, with the C-terminal domain being more important than the N-terminal domain. We found that Val-343 is the key contributor to this function, whereas Leu-278, Ser-280, His-350, Asp-351, His-352, and Ile-353 play supporting roles. We also show that the arrestin-3-specific difference in the arrangement of the β-strands in the C-terminal domain that underlies its lower selectivity for active phosphoreceptors does not play an appreciable role in its ability to enhance JNK3 activation. Importantly, the strength of the binding of ASK1 or JNK3, as revealed by the efficiency of co-immunoprecipitation, does not correlate with the ability of arrestin proteins to promote ASK1-dependent JNK3 phosphorylation. Thus, multiple residues on the non-receptor-binding side of arrestin-3 are crucial for JNK3 activation, and this function and the receptor-binding characteristics of arrestin can be manipulated independently by targeted mutagenesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M111.260448