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The activity of all mitogen-activated protein kinases (MAPKs) is stimulated via phosphorylation by upstream MAPK kinases (MAPKK), which are in their turn activated via phosphorylation by MAPKK kinases (MAPKKKs). The cells ensure the specificity of signaling in these cascades by employing a variety of scaffolding proteins that bind matching MAPKKKs, MAPKKs, and MAPKs. All four vertebrate arrestin subtypes bind JNK3, but only arrestin-3 serves as a scaffold, promoting JNK3 activation in intact cells. Arrestin-3-mediated JNK3 activation does not depend on arrestin-3 interaction with G protein-coupled receptors (GPCRs), as demonstrated by the ability of some arrestin mutants that cannot bind receptors to activate JNK3, whereas certain mutants with enhanced GPCR binding fail to promote JNK3 activation. Recent findings suggest that arrestin-3 directly binds both MAPKKs necessary for JNK activation and facilitates JNK3 phosphorylation at both Thr (by MKK4) and Tyr (by MKK7). JNK3 is expressed in a limited set of cell types, whereas JNK1 and JNK2 isoforms are as ubiquitous as arrestin-3. Recent study showed that arrestin-3 facilitates the activation of JNK1 and JNK2, scaffolding MKK4/7-JNK1/2/3 signaling complexes. In all cases, arrestin-3 acts by bringing the kinases together: JNK phosphorylation shows biphasic dependence on arrestin-3, being enhanced at lower and suppressed at supraoptimal concentrations. Thus, arrestin-3 regulates the activity of multiple JNK isoforms, suggesting that it might play a role in survival and apoptosis of all cell types.