Extracellular signal-regulated kinase (ERK) activation preserves cardiac function in pressure overload induced hypertrophy

Mutlak, Michael; Schlesinger-Laufer, Michal; Haas, Tali; Shofti, Rona; Ballan, Nimer; Lewis, Yair E.; Zuler, Mor; Zohar, Yaniv; Caspi, Lilac; Kehat, Izhak

doi:10.1016/j.ijcard.2018.05.068

Cited by 33 publications

(26 citation statements)

References 47 publications

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“…In view that evidence of non-redundancy is apparent from isoform-specific ERK targeted mice, overexpression of intrinsically active ERK1 and ERK2 in the heart were generated to further test the effects of ERK1/2. A recent study reported transgenic mice expressing activated ERK1 under the transcriptional control of the α-MHC promoterwhich, similar to the observations in hypertrophy, is phosphorylated on both the TEY and the Thr207 motifs and is overexpressed at pathophysiological levelsdeveloped a modest adaptive hypertrophy with increased contractile function and without fibrosis [43]. Nevertheless, another recent study demonstrated that volume overload-induced eccentric hypertrophy is associated with reduced cardiac ERK1/2 activation while phosphorylation of other MAPKs was unaffected in vivo.…”

Section: Targeting Erk1/2supporting

confidence: 53%

Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy

Yan

Zeng

et al. 2021

Cardiol J.

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Cardiac hypertrophy is the result of increased myocardial cell size responding to an increased workload and developmental signals. These extrinsic and intrinsic stimuli as key drivers of cardiac hypertrophy have spurred efforts to target their associated signaling pathways. The extracellular signal-regulated kinases 1/2(ERK1/2), as an essential member of mitogen-activated protein kinases (MAPKs), has been widely recognized for promoting cardiac growth. Several modified transgenic mouse models have been generated through either affecting the upstream kinase to change ERK1/2 activity, manipulating the direct role of ERK1/2 in the heart, or targeting phosphatases or MAPK scaffold proteins to alter total ERK1/2 activity in response to an increased workload. Using these models, both regulation of the upstream events and modulation of each isoform and indirect effector could provide important insights into how ERK1/2 modulates cardiomyocyte biology. Furthermore, a plethora of compounds, inhibitors, and regulators have emerged in consideration of ERK, or its MAPKKs, are possible therapeutic targets against cardiac hypertrophic diseases. Herein, is a review of the available evidence regarding the exact role of ERK1/2 in regulating cardiac hypertrophy and a discussion of pharmacological strategy for treatment of cardiac hypertrophy.

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Section: Targeting Erk1/2supporting

confidence: 53%

Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy

Yan

Zeng

et al. 2021

Cardiol J.

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“…Another mutation, R84H in Erk1, occurred at the same residue in which the only oncogenic mutation identified so far in Erks, R84S, also occurred [82]. As Erk1 R84S was shown to be intrinsically catalytically active and spontaneously active when expressed in culture cells and in transgenic mice [82,108], it could be that Erk1 R84H also acquired similar properties and is independent of upstream activation, making it resistant to Raf and MEK inhibitors. Indeed, kinase assays using the various mutants, expressed in and immunoprecipitated from A375 cells, showed that the mutants maintained activity in the presence of either VRT-11E or SCH772984, another Erk inhibitor [96].…”

Section: A Large Number Of Mutations Can Render Erks Resistant To Phamentioning

confidence: 94%

“…Six Mpk1 mutants were isolated, but only the R68S mutation was found relevant to Erks of higher eukaryotes, including of Drosophila and mammals [73]. Drosophila and mammalian Erks carrying the equivalent mutation (R80S in Drosophila's ERK/Rolled; R84S in mammalian Erk1; R65S in mammalian Erk2) displayed high spontaneous intrinsic catalytic activity (>30% of the activity of Mek-activated Erk), independent of Mek activation in in vitro assays [73,82], in cell cultures [82] and in vivo, in transgenic mice and flies [83,108]. Furthermore, Erk1 R84S and Rolled R80S were shown to function as oncogenes, capable of transforming NIH3T3 cells and to give rise to tumors in the fly, respectively [82,83].…”

Section: Only a Few Of The Mutations Identified Via Genetic Screens Imentioning

confidence: 99%

“…Furthermore, Erk1 R84S and Rolled R80S were shown to function as oncogenes, capable of transforming NIH3T3 cells and to give rise to tumors in the fly, respectively [82,83]. Erk1 R84S was also shown to cause mild cardiac hypertrophy, when expressed as a transgene in the heart of mice [108]. The basic mechanism of action of the R80S/R84S/R65S mutation is similar to that of the other intrinsically active variants described above, namely, it bestowed upon the Rolled and Erk proteins an efficient autophosphorylation capability [73,82,83].…”

Section: Only a Few Of The Mutations Identified Via Genetic Screens Imentioning

confidence: 99%

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Mutations That Confer Drug-Resistance, Oncogenicity and Intrinsic Activity on the ERK MAP Kinases—Current State of the Art

Smorodinsky-Atias

Soudah

Engelberg

2020

Cells

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Unique characteristics distinguish extracellular signal-regulated kinases (Erks) from other eukaryotic protein kinases (ePKs). Unlike most ePKs, Erks do not autoactivate and they manifest no basal activity; they become catalysts only when dually phosphorylated on neighboring Thr and Tyr residues and they possess unique structural motifs. Erks function as the sole targets of the receptor tyrosine kinases (RTKs)-Ras-Raf-MEK signaling cascade, which controls numerous physiological processes and is mutated in most cancers. Erks are therefore the executers of the pathway’s biology and pathology. As oncogenic mutations have not been identified in Erks themselves, combined with the tight regulation of their activity, Erks have been considered immune against mutations that would render them intrinsically active. Nevertheless, several such mutations have been generated on the basis of structure-function analysis, understanding of ePK evolution and, mostly, via genetic screens in lower eukaryotes. One of the mutations conferred oncogenic properties on Erk1. The number of interesting mutations in Erks has dramatically increased following the development of Erk-specific pharmacological inhibitors and identification of mutations that cause resistance to these compounds. Several mutations have been recently identified in cancer patients. Here we summarize the mutations identified in Erks so far, describe their properties and discuss their possible mechanism of action.

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“…In addition, increased and decreased expression of atrial ERK1/2 and BCL2, respectively, were reported in AF patients [34,35]. ERK signaling is involved in cardiac hypertrophy, in which ERK1 and ERK2 have redundant functions [36], and it was reported that the ERK pathway acts to promote a compensated hypertrophic response and reduced fibrosis in the heart in a mice model overexpressing ERK1 in cardiomyocyte [37]. BCL2 is an anti-apoptotic protein for heart fibroblast [38] and is reported to be potentially associated with myocardial fibrosis phenotype in patients with dilated cardiomyopathy (DCM) [39].…”

Section: Possible Target Genes Strongly Regulated By 11 Mirnasmentioning

confidence: 99%

Exploratory Analysis of Circulating miRNA Signatures in Atrial Fibrillation Patients Determining Potential Biomarkers to Support Decision-Making in Anticoagulation and Catheter Ablation

Kiyosawa

Watanabe

Morishima

et al. 2020

IJMS

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Novel biomarkers are desired to improve risk management for patients with atrial fibrillation (AF). We measured 179 plasma miRNAs in 83 AF patients using multiplex qRT-PCR. Plasma levels of eight (i.e., hsa-miR-22-3p, hsa-miR-128-3p, hsa-miR-130a-3p, hsa-miR-140-5p, hsa-miR-143-3p, hsa-miR-148b-3p, hsa-miR-497-5p, hsa-miR-652-3p) and three (i.e., hsa-miR-144-5p, hsa-miR-192-5p, hsa-miR-194-5p) miRNAs showed positive and negative correlations with CHA2DS2-VASc scores, respectively, which also showed negative and positive correlations with catheter ablation (CA) procedure, respectively, within the follow-up observation period up to 6-month after enrollment. These 11 miRNAs were functionally associated with TGF-β signaling and androgen signaling based on pathway enrichment analysis. Seven of possible target genes of these miRNAs, namely TGFBR1, PDGFRA, ZEB1, IGFR1, BCL2, MAPK1 and DICER1 were found to be modulated by more than four miRNAs of the eleven. Of them, TGFBR1, PDGFRA, ZEB1 and BCL2 are reported to exert pro-fibrotic functions, suggesting that dysregulations of these eleven miRNAs may reflect pro-fibrotic condition in the high-risk patients. Although highly speculative, these miRNAs may potentially serve as potential biomarkers, providing mechanistic and quantitative information for pathophysiology in daily clinical practice with AF such as possible pro-fibrotic state in left atrium, which would enhance the risk of stroke and reduce the preference for performing CA.

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Extracellular signal-regulated kinase (ERK) activation preserves cardiac function in pressure overload induced hypertrophy

Cited by 33 publications

References 47 publications

Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy

Role of extracellular signal-regulated kinase 1/2 signaling underlying cardiac hypertrophy

Mutations That Confer Drug-Resistance, Oncogenicity and Intrinsic Activity on the ERK MAP Kinases—Current State of the Art

Exploratory Analysis of Circulating miRNA Signatures in Atrial Fibrillation Patients Determining Potential Biomarkers to Support Decision-Making in Anticoagulation and Catheter Ablation

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