title: 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.
abstract: 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.
authors.affiliation: From the Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232.
authors.forename: Seunghyi
authors.initials: S
authors.lastname: Kook
authors.forename: Xuanzhi
authors.initials: X
authors.lastname: Zhan
authors.forename: Tamer S
authors.initials: TS
authors.lastname: Kaoud
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Dalby
authors.forename: Vsevolod V
authors.initials: VV
authors.lastname: Gurevich
authors.forename: Eugenia V
authors.initials: EV
authors.lastname: Gurevich
mesh_terms: D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D002522:Chlorocebus aethiops; D004789:Enzyme Activation / Q000502:physiology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology
chemical_list: D019390:Arrestins; D007527:Isoenzymes; C082333:arrestin3; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse
keywords: Arrestin; Jun N-terminal Kinase (JNK); MAP Kinases (MAPKs); Protein Phosphorylation; Scaffold Proteins; Signal Transduction