Differential regulation of M3/6 (DUSP8) signaling complexes in response to arsenite-induced oxidative stress

Oehrl, Wolf; Cotsiki, Marina; Panayotou, George

doi:10.1016/j.cellsig.2012.11.010

Cited by 23 publications

(23 citation statements)

References 52 publications

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“…For example, proteins with the 6b exon have similar Michaelis constants (K M ) for their common substrate ATF2, but these constants are consistently higher than those containing the 6a exon (161). The catalytic efficacy of phosphatases toward JNK can also be different for the different splice isoforms: DUSP8 preferentially inactivates exon 6a-containing JNKs, at least in vitro (162). Taken together, these observations suggest that the individual JNK isoforms will likely show different enzyme activities and activation/ deactivation kinetics in vivo.…”

Section: Activities and Modifications Of Individual Jnk Isoformsmentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

387

350

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SUMMARYThe c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.

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Section: Activities and Modifications Of Individual Jnk Isoformsmentioning

confidence: 99%

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

Zeke

Misheva

Reményi

et al. 2016

Microbiol Mol Biol Rev

387

350

View full text Add to dashboard Cite

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“…Whilst it has been shown to be important for regulating embryonic aspects of stem cell pluripotency and differentiation [49, 50] and has been shown to be common in the early mouse embryo [51] and in the zebrafish [52], there are few, if any, reports where specific splice variants have been shown to play a discrete mechanistic role during embryogenesis that is unique to that transcript and not shared with other related transcripts. There is tantalising circumstantial evidence in the literature to support the idea that individual transcripts may be specifically activated by different gene networks, for example the phosphatase DUSP8 preferentially inactivates exon 6a-containing (equivalent of Ex7 in zebrafish) JNK1 peptides [53]. In this study we have comprehensively shown developmental and organ specific splicing changes within the duplicated and highly conserved gene jnk1 .…”

Section: Discussionmentioning

confidence: 62%

An alternatively spliced zebrafishjnk1atranscript has an essential and non-redundant role in development of the first heart field derived proximal ventricular chamber

Santos-Ledo¹,

Washer²,

Dhanaseelan³

et al. 2019

Preprint

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“…16 Our finding that oxidative stress negatively regulates the association between ataxin-1 and DUSP8 suggests a similar possibility of DUSP8 modification. In fact, we also observed that the presence of ataxin-1 and oxidative stress reduced the relative amount of GST-DUSP8 substantially ( Fig.…”

Section: Notesmentioning

confidence: 71%

Interaction Between DUSP8 and the Polyglutamine Protein Ataxin-1

Lee¹,

Cho

2013

Bulletin of the Korean Chemical Society

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Polyglutamine (polyQ) diseases are a group of inherited neurodegenerative disorders caused by the expansion of polyQ repeats in the disease proteins. Expansion of polyQ repeats presumably leads to misfolding and aggregation of polyQ proteins.1 Although details of the molecular mechanisms are still elusive, transcriptional dysfunction and oxidative damage are suggested as underlying events responsible for polyQ pathogenesis.2 Misfolded polyQ proteins are frequently concentrated into intranuclear inclusions, which increase generation of reactive oxygen species (ROS) and activate stress signaling pathways. In cultured cells expressing expanded polyQ proteins, mitogen-activated protein kinases (MAPK), e.g., p38 and JNK, are activated and the cytotoxicity induced by polyQ proteins, partially through sustained activation of MAP kinases, can be reduced by administration of a p38 inhibitor.3-6 MAPK are activated by MAPK kinase (MEK)-mediated phosphorylation of threonine and tyrosine residues located in the signature sequence (TxY) and MEK is in turn activated by MAPK kinase kinase (MEKK).7 Since MAPK are involved in a wide variety of cellular processes including cell survival and apoptosis, cells must tightly regulate the magnitude and duration of MAPK activation. The negative regulation of MAPK is often achieved by phosphatase-mediated dephosphorylation of MAPK. A group of protein phosphatases referred as type I cysteinebased protein tyrosine phosphatases including DUSPs (dualspecificity phosphatases) dephosphorylate both tyrosine and serine/threonine residues within the same substrate and as a result counteract MAPK. 8Involvement of protein tyrosine phosphatases (PTPs) in polyQ-induced cell death has been reported in previous studies. Several PTP proteins including MKP-1 are up-regulated by over-expression of cytotoxic polyQ-expanded huntingtin (Htt) fragment.9 Moreover, polyQ-expanded Htt fragment activates JNK pathway by reducing solubility of JNK phosphatase M3/6 (also known as hVH5 or DUSP8). 4A recent study demonstrated that a DUSP protein laforin can suppress the cytotoxicity caused by misfolded proteins and hinted that phosphatases can be potential targets for pharmacological intervention of neurodegenerative disorders.10 The polyQ protein ataxin-1 is a soluble protein of about 816 amino acids, which varies depending on the length of polyQ repeats, and located both in the cytoplasm and nucleus. Although the exact functions are not completely understood, ataxin-1 is apparently involved in transcription regulation through its ability to interact with several transcription factors as well as RNA.11 While it is generally assumed that expansion of polyQ repeats causes misfolding of ataxin-1 and leads to neuronal death in spinocerebellar ataxia 1 (SCA1), contribution of other domains to pathogenesis also becomes increasingly clear. Besides N-terminal polyQ region, AXH domain (570-689; for interaction with transcription factors and RNA), endogenous phosphorylation site (776) and nuclear localization signal (795-798) a...

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Differential regulation of M3/6 (DUSP8) signaling complexes in response to arsenite-induced oxidative stress

Cited by 23 publications

References 52 publications

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships

An alternatively spliced zebrafishjnk1atranscript has an essential and non-redundant role in development of the first heart field derived proximal ventricular chamber

Interaction Between DUSP8 and the Polyglutamine Protein Ataxin-1

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