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

Kook, Seunghyi; Zhan, Xiaoli; Kaoud, Tamer S.; Dalby, Kevin N.; Gurevich, Vsevolod V.; Gurevich, Eugenia V.

doi:10.1074/jbc.m113.510412

Cited by 60 publications

(70 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Prior studies have demonstrated that JNK can be activated by an arrestin scaffold [19, 20]. To assess the role of arrestin in opioid-induced JNK activation, we measured the effect of GRK3 gene deletion (GRK3 −/− ) on phospho-JNK-IR in vivo .…”

Section: Resultsmentioning

confidence: 99%

“…Additional kinases have been implicated in opioid receptor mediated JNK activation upstream of the MAPKKs, including PKC and Src [1, 15–17]. In some instances, arrestin has been shown to act as a scaffold for JNK activation recruiting MKK4 and MKK7, in addition to ASK1, in close proximity with JNK [18–20]. It has also been demonstrated that arrestin can regulate the cellular localization of extracellular signal-regulated kinases (ERK) and other signaling molecules [21–23].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms

Kuhar

Bedini

Melief

et al. 2015

Cellular Signalling

View full text Add to dashboard Cite

G protein-coupled receptor desensitization is typically mediated by receptor phosphorylation by G protein receptor kinase (GRK) and subsequent arrestin binding; morphine, however, was previously found to activate a c-Jun N-Terminal Kinase (JNK)-dependent, GRK/arrestin-independent pathway to produce mu opioid receptor (MOR) inactivation in spinally-mediated, acute anti-nociceptive responses Melief, et. al., 2010 [1]. In the current study, we determined that JNK2 was also required for centrally-mediated analgesic tolerance to morphine using the hotplate assay. We compared JNK activation by morphine and fentanyl in JNK1−/−, JNK2−/−, JNK3−/−, and GRK3−/− mice and found that both compounds specifically activate JNK2 in vivo; however, fentanyl activation of JNK2 was GRK3-dependent, whereas morphine activation of JNK2 was GRK3-independent. In MOR-GFP expressing HEK293 cells, treatment with either arrestin siRNA, the Src family kinase inhibitor PP2, or the protein kinase C (PKC) inhibitor Gö6976 indicated that morphine activated JNK2 through an arrestin-independent Src- and PKC-dependent mechanism, whereas fentanyl activated JNK2 through a Src- GRK3/arrestin2-dependent and PKC-independent mechanism. This study resolves distinct ligand-directed mechanisms of JNK activation by mu opioid agonists and understanding ligand-directed signaling at MOR may improve opioid therapeutics.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms

Kuhar

Bedini

Melief

et al. 2015

Cellular Signalling

View full text Add to dashboard Cite

show abstract

“…Seclusion of phosphorylated ERK1/2 in the cytosol precludes ERK-mediated transcription and prolongs ERK signaling. Similarly, ␤arr2 scaffolds JNK1/2 with its upstream kinases MKK4 and MKK7, which phosphorylate different residues in its activation loop (13). Activation of p38 signaling cascades is also ␤arr-dependent, although a direct scaffolding complex of ␤arr and p38 has not been elucidated (51,52).…”

Section: Signalingmentioning

confidence: 99%

“…␤arr1 and ␤arr2 scaffold to different signaling pathways; however, this is often cell type-and receptor-specific. ␤arr2, but not ␤arr1, is known to be necessary for creating a signaling that activates JNKs (13). ␤arr1 and ␤arr2 can "reciprocally regulate" signaling at certain receptors; that is, one isoform increases pathway-specific signaling, whereas the other isoform inhibits signaling.…”

Section: Distinct and Overlapping Roles For The ␤Arrsmentioning

confidence: 99%

The β-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors

Smith¹,

Rajagopal

2016

Journal of Biological Chemistry

252

222

View full text Add to dashboard Cite

The ␤-arrestins (␤arrs) are versatile, multifunctional adapter proteins that are best known for their ability to desensitize G protein-coupled receptors (GPCRs), but also regulate a diverse array of cellular functions. To signal in such a complex fashion, ␤arrs adopt multiple conformations and are regulated at multiple levels to differentially activate downstream pathways. Recent structural studies have demonstrated that ␤arrs have a conserved structure and activation mechanism, with plasticity of their structural fold, allowing them to adopt a wide array of conformations. Novel roles for ␤arrs continue to be identified, demonstrating the importance of these dynamic regulators of cellular signaling. ␤-Arrestins (␤arrs)2 are ubiquitously expressed proteins that were first described for their role in desensitizing G proteincoupled receptors (GPCRs) (1). We now appreciate that these proteins are multifunctional adapter proteins that regulate a vast array of cellular functions. ␤arrs were identified through their sequence homology to visual arrestin (arrestin-1), so named because of its ability to "arrest" rhodopsin signaling in the retina (2). There are two ␤arr isoforms, ␤-arrestin1 and ␤-arrestin2 (also denoted as arrestin-2 and arrestin-3, respectively). Both are expressed ubiquitously and share 78% sequence homology (3). ␤arrs are highly conserved across species, with ϳ50% sequence homology between vertebrates and invertebrates. The other arrestins are expressed in the eye: arrestin-1 (visual arrestin) and arrestin-4 (cone arrestin) (4). There are other proteins, termed ␣-arrestins or arrestin domain-containing proteins, that share the arrestin structural fold and are involved in receptor endocytosis, although the full breadth of their functions is still emerging (5). Similar to arrestin's function in the visual system, ␤arrs were first identified for their capacity to desensitize ␤2 adrenergic receptor (␤2AR) G protein signaling following agonist stimulation (1). Through a number of investigations, it became apparent that the two ␤arr isoforms shared the capability to interact with activated GPCRs, but that they differed in terms of their expression patterns, their specificity for different GPCRs, and their functional effects (6). We now appreciate that the ␤arrs regulate a diverse array of cellular processes including MAPK signaling, receptor transactivation, receptor trafficking, and transcriptional regulation in addition to the canonical roles of GPCR desensitization and internalization (7,8). These studies have revealed the current spectrum of ␤arr-mediated cell processes downstream of GPCRs (Fig. 1). Distinct and Overlapping Roles for the ␤arrs␤arr1 and ␤arr2 knockouts are phenotypically normal and produce viable progeny, but these mice display abnormal responses to physiologic stresses (9, 10). This suggests a compensatory ability for each isoform. Nevertheless, important differences between ␤arr isoforms are present (11). Although both accumulate in the cytoplasm following overexpression, ␤arr1, but not...

show abstract

“…The C-terminus of arrestin-2 expressed alone, which makes it fully accessible, inhibited GPCR internalization via competition with the arrestin-receptors complexes for clathrin and AP2 (Krupnick et al, 1997b). Ubiquitously expressed arrestin-2 and -3 were shown to interact with at least 21 different protein kinases (DeWire et al, 2007; Gurevich and Gurevich, 2006a; Kook et al, 2013), i.e., ~3.5% of ~600 protein kinases present in mammalian genome. The first studies of arrestin-mediated activation of protein kinases c-Src, JNK3, and ERK1/2 reported that arrestin-mediated signaling in these pathways was triggered by GPCR activation, i.e., by receptor-bound arrestins (Luttrell et al, 1999; Luttrell et al, 2001; McDonald et al, 2000).…”

Section: The Functional Cycle Of Arrestinsmentioning

confidence: 99%

Overview of Different Mechanisms of Arrestin‐Mediated Signaling

Gurevich

2014

CP Pharmacology

Self Cite

View full text Add to dashboard Cite

Arrestins were discovered based on their ability to selectively bind active phosphorylated GPCRs and suppress (arrest) receptor coupling to G proteins. Subsequently non-visual arrestins were shown to be signaling proteins in their own right, activating a variety of cellular pathways. Arrestins are highly flexible proteins that can assume several distinct conformations. In receptor-bound conformation, arrestins have higher affinity for a subset of partners. This explains how receptor activation regulates certain branches of arrestin-dependent signaling via arrestin recruitment to GPCRs. However, free arrestins are also active molecular entities that act in other pathways and localize signaling proteins to particular subcellular compartments, such as cytoskeleton. These functions are regulated by the enhancement or reduction of arrestin affinity for target proteins by other binding partners and by proteolytic cleavage. Recent findings suggest that the two visual arrestins expressed in photoreceptor cells do not regulate signaling solely via binding to photopigments, but also interact with a variety of non-receptor partners, critically affecting the health and survival of photoreceptor cells. This overview describes GPCR-dependent and –independent modes of arrestin-mediated regulation of cellular signaling pathways.

show abstract

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

Cited by 60 publications

References 70 publications

Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms

Mu opioid receptor stimulation activates c-Jun N-terminal kinase 2 by distinct arrestin-dependent and independent mechanisms

The β-Arrestins: Multifunctional Regulators of G Protein-coupled Receptors

Overview of Different Mechanisms of Arrestin‐Mediated Signaling

Contact Info

Product

Resources

About