Journal of Biological Chemistry
Volume 288, Issue 52, 27 December 2013, Pages 37332-37342
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Signal Transduction
Arrestin-3 Binds c-Jun N-terminal Kinase 1 (JNK1) and JNK2 and Facilitates the Activation of These Ubiquitous JNK Isoforms in Cells via Scaffolding*

https://doi.org/10.1074/jbc.M113.510412Get rights and content
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Non-visual arrestins scaffold mitogen-activated protein kinase (MAPK) cascades. The c-Jun N-terminal kinases (JNKs) are members of MAPK family. Arrestin-3 has been shown to enhance the activation of JNK3, which is expressed mainly in neurons, heart, and testes, in contrast to ubiquitous JNK1 and JNK2. Although all JNKs are activated by MKK4 and MKK7, both of which bind arrestin-3, the ability of arrestin-3 to facilitate the activation of JNK1 and JNK2 has never been reported. Using purified proteins we found that arrestin-3 directly binds JNK1α1 and JNK2α2, interacting with the latter comparably to JNK3α2. Phosphorylation of purified JNK1α1 and JNK2α2 by MKK4 or MKK7 is increased by arrestin-3. Endogenous arrestin-3 interacted with endogenous JNK1/2 in different cell types. Arrestin-3 also enhanced phosphorylation of endogenous JNK1/2 in intact cells upon expression of upstream kinases ASK1, MKK4, or MKK7. We observed a biphasic effect of arrestin-3 concentrations on phosphorylation of JNK1α1 and JNK2α2 both in vitro and in vivo. Thus, arrestin-3 acts as a scaffold, facilitating JNK1α1 and JNK2α2 phosphorylation by MKK4 and MKK7 via bringing JNKs and their activators together. The data suggest that arrestin-3 modulates the activity of ubiquitous JNK1 and JNK2 in non-neuronal cells, impacting the signaling pathway that regulates their proliferation and survival.

Arrestin
Jun N-terminal Kinase (JNK)
MAP Kinases (MAPKs)
Protein Phosphorylation
Scaffold Proteins
Signal Transduction

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*

This work was supported, in whole or in part, by National Institutes of Health Grants NS065868 and DA030103 (to E. V. G.), GM077561, GM081756, and EY011500 (to V. V. G.), and GM059802 (to K. N. D.). This work was also supported by the Welch Foundation (F-1390) (to K. N. D.).

1

Supported by a postdoctoral trainee fellowship from Cancer Prevention Research Institute of Texas (CPRIT).