Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2

Perander, Maria; Al-Mahdi, Rania; Jensen, Thomas Clemens; Nunn, Jennifer L.; Kildalsen, Hanne; Johansen, Bjarne; Gabrielsen, Mads; Keyse, Stephen M.; Seternes, Ole Morten

doi:10.1038/srep43471

Cited by 31 publications

(23 citation statements)

References 36 publications

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“…Analogous to classical MAP kinases, ERK3 is activated by phosphorylation of the activation loop, which stimulates its intrinsic catalytic activity and affinity for the substrate MK5 (7). Activation loop phosphorylation is mediated by Group I p21-activated kinases (8, 9), and is reversed by the action of the MAP kinase phosphatase DUSP2 (10). Of note, it has been previously proposed that ERK3 enzymatic activity is dispensable for MK5 activation and that ERK3 may exert a scaffolding function (11).…”

Section: Introductionmentioning

confidence: 99%

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Soulez¹,

Saba-El-Leil²,

Turgeon

et al. 2018

Preprint

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38The physiological functions of the atypical MAP kinase ERK3 remain poorly characterized. 39Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus 40 (Mapk6 lacZ ) showed that inactivation of ERK3 in Mapk6 lacZ mice leads to perinatal lethality 41 associated with intrauterine growth restriction, defective lung maturation, and neuromuscular 42 anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel 43 mouse models expressing a catalytically-inactive (Mapk6 KD ) or conditional (Mapk6  ) allele of 44 ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive 45 the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant 46 mice reached adulthood, were fertile and showed no apparent health problem. However, analysis 47 56 57 Extracellular signal-regulated kinase 3 (ERK3) and ERK4 are atypical members of the mitogen-58 activated protein (MAP) kinase family (1). Despite their identification more than 25 years ago, 59 very little is known about their physiological functions. The ERK3 gene (MAPK6 in human) is 60 expressed ubiquitously in adult mammalian tissues, while ERK4 gene (MAPK4) shows a 61 restricted expression profile being detected mainly in brain tissue (2-4) 62 (www.gtexportal.org/home). During mouse embryogenesis, ERK3 mRNA and protein levels 63 peak around embryonic day 11, after the onset of organogenesis, and then decline thereafter (5). 64Expression of ERK3 is also up-regulated during in vitro differentiation of cell line models along 65 the neuronal or muscle lineage (2, 6). These early observations have suggested a potential role 66 for ERK3 signaling in cell differentiation and tissue development. 67 68 Analogous to classical MAP kinases, ERK3 is activated by phosphorylation of the activation 69 loop, which stimulates its intrinsic catalytic activity and affinity for the substrate MK5 (7). 70Activation loop phosphorylation is mediated by Group I p21-activated kinases (8, 9), and is 71 reversed by the action of the MAP kinase phosphatase DUSP2 (10). Of note, it has been 72 previously proposed that ERK3 enzymatic activity is dispensable for MK5 activation and that 73 ERK3 may exert a scaffolding function (11). However, other experiments using coupled in vitro 74 kinase assays did not suppport this hypothesis (7). A more recent study reported that 75 overexpression of ERK3 induces rounding of MDA-MB-231 breast cancer cells by an unknown 76 mechanism independent of its kinase activity (12). The physiological importance of catalytic and 77 non-catalytic functions of ERK3 remains an open question. 78 * Mixed C57Bl/6J-129/Sv genetic background

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Section: Introductionmentioning

confidence: 99%

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Soulez¹,

Saba-El-Leil²,

Turgeon

et al. 2018

Preprint

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“…DUSP2 (9). Of note, it has been previously proposed that ERK3 enzymatic activity is dispensable for MK5 activation and that ERK3 exerts a scaffolding function (10).…”

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confidence: 99%

Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models

Soulez

Saba-El-Leil

Turgeon

et al. 2019

Molecular and Cellular Biology

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The physiological functions of the atypical mitogen-activated protein kinase extracellular signal-regulated kinase 3 (ERK3) remain poorly characterized. Previous analysis of mice with a targeted insertion of the lacZ reporter in the Mapk6 locus (Mapk6 lacZ ) showed that inactivation of ERK3 in Mapk6 lacZ mice leads to perinatal lethality associated with intrauterine growth restriction, defective lung maturation, and neuromuscular anomalies. To further explore the role of ERK3 in physiology and disease, we generated novel mouse models expressing a catalytically inactive (Mapk6 KD ) or conditional (Mapk6 ⌬ ) allele of ERK3. Surprisingly, we found that mice devoid of ERK3 kinase activity or expression survive the perinatal period without any observable lung or neuromuscular phenotype. ERK3 mutant mice reached adulthood, were fertile, and showed no apparent health problem. However, analysis of growth curves revealed that ERK3 kinase activity is necessary for optimal postnatal growth. To gain insight into the genetic basis underlying the discrepancy in phenotypes of different Mapk6 mutant mouse models, we analyzed the regulation of genes flanking the Mapk6 locus by quantitative PCR. We found that the expression of several Mapk6 neighboring genes is deregulated in Mapk6 lacZ mice but not in Mapk6 KD or Mapk6 ⌬ mutant mice. Our genetic analysis suggests that off-target effects of the targeting construct on local gene expression are responsible for the perinatal lethality phenotype of Mapk6 lacZ mutant mice.

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“…Consistent with this nding, we also noticed that, in present study, the level of p-MK5 signi cantly decreased in the condition of MAPK4 de ciency. Interestingly, Perander et al reported that the expression of DUSP2 could inhibit ERK3 and ERK4 mediated activation of its downstream substrate MK5 [38]. Therefore, further study on the roles of other couple molecules of MAPK4, which did not be screened in current study, is much valuable for investigation on the exact connections among MAPK4/MK5, AKT and other signaling pathways in the pathology of ALI.…”

Section: Discussionmentioning

confidence: 84%

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

Mao

Zhou

Chen

et al. 2020

Preprint

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Background: Acute lung injury (ALI) is a serious disease with highly morbidity and mortality that causes serious health problems worldwide. Atypical mitogen activated protein kinases (MAPKs) play critical roles in the development of tissues and have been proposed as promising therapeutic targets for various diseases. However, the potential role of atypical MAPKs in ALI remains elusive. In this study, we investigated the role of atypical MAPKs family member MAPK4 in ALI using LPS-induced murine ALI model. Results: We found that MAPK4 deficiency mice exhibited prolonged survival time after LPS challenge, accompanied by alleviated pathology in lung tissues, decreased levels of pro-inflammatory cytokines and altered composition of immune cells in BALF. Furthermore, the transduction of related signaling pathways, including MK5, AKT, JNK, and p38 MAPK pathways, was reduced obviously in LPS-treated MAPK4-/- mice. Notably, the expression of MAPK4 was up-regulated in lung tissues of ALI model, which was not related with MAPK4 promoter methylation, but negatively orchestrated by transcriptional factors NFKB1 and NR3C1. Further studies have shown that the expression of MAPK4 was also increased in LPS-treated macrophages. Meanwhile, MAPK4 deficiency reduced the expression of related pro-inflammatory cytokines in macrophage in response to LPS treatment. Finally, MAPK4 inhibition using shRNA pre-treatment could ameliorate the pathology of lung tissues and prolong the survival time of mice after LPS challenge. Conclusions: Collectively, these findings reveal an important biological function of atypical MAPK in mediating the pathology of ALI, indicating that MAPK4 might be a novel potential therapeutic target for ALI treatment.

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Regulation of atypical MAP kinases ERK3 and ERK4 by the phosphatase DUSP2

Cited by 31 publications

References 36 publications

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Reevaluation of the Role of ERK3 in Perinatal Survival and Post-Natal Growth Using New Genetically-Engineered Mouse Models

Reevaluation of the Role of Extracellular Signal-Regulated Kinase 3 in Perinatal Survival and Postnatal Growth Using New Genetically Engineered Mouse Models

Identification of Atypical Mitogen-Activated Protein Kinase MAPK4 as A Novel Regulator in Acute Lung Injury

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