ERK1/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth

Gilbert, Christopher J.; Longenecker, Jacob Z.; Accornero, Federica

doi:10.3390/biology10040346

Cited by 20 publications

(20 citation statements)

References 161 publications

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“…The blocking of activation of this signaling pathway mainly relies on the negative regulation of chromosome 10 phosphatase and tensin homolog (PTEN) deletion, which dephosphorylates PIP3 to PIP2 [ 13 , 14 ]. In addition, there are some signal transduction pathways that also play a key role in cell proliferation, transformation, and apoptosis, such as the extracellular signal-regulated kinase (ERK1/2) pathway [ 15 ]. The protective effect of ERK phosphorylation in the heart has also been reported, but whether ghrelin can trigger this protective effect is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The PI3K/Akt and ERK signaling pathways are important central signal transduction pathways. Their mechanism of action is to improve the survival rate of cardiomyocytes and maintain the normal physiological functions of the myocardium by regulating the levels of cell proliferation and apoptosis and regulating protein synthesis and metabolic integration [ 12 , 15 ]. In this study, we demonstrated the upregulation of ghrelin on PTEN.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Ghrelin Intervention on the Ras/ERK Pathway in the Regulation of Heart Failure by PTEN

Zhao

Sun

et al. 2022

Computational and Mathematical Methods in Medicine

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Objective. To study the possible mechanism of ghrelin in heart failure and how it works. Method. In vitro results demonstrated that ghrelin alleviates cardiac function and reduces myocardial fibrosis in rats with heart failure. Moreover, ghrelin intervention increased PTEN expression level and reduced ERK, c-jun, and c-Fos expression level; in vivo experiments demonstrated that ghrelin intervention reduces mast memory expression and increases cardiomyocyte surface area, PTEN expression level, ERK, c-jun, c-Fos expression level, and cell surface area, while ERK blockade suppresses mast gene expression and reduces cell surface area. Results. In vitro experimental results prove that we have successfully constructed a rat model related to heart failure, and ghrelin can alleviate the heart function of heart failure rats and reduce myocardial fibrosis. In addition, ghrelin is closely related to the decrease of the expression levels of ERK, c-jun, and c-Fos, but it can also increase the expression of PTEN in the rat model; in vivo experiments proved that we successfully constructed an in vitro cardiac hypertrophy model, and the intervention of ghrelin would reduce the expression of hypertrophic memory and increase the surface area of cardiomyocytes, increase the expression level of PTEN, and reduce the expression levels of ERK, c-jun, and c-Fos, while the blockade of PTEN will increase the expression of hypertrophy genes and increase the cell surface area, while the blockade of ERK will increase the expression of hypertrophic genes, which in turn will make the cell surface area reducing. Conclusion. Ghrelin inhibits the phosphorylation and nuclear entry of ERK by activating PTEN, thereby controlling the transcription of hypertrophic genes, improving myocardial hypertrophy, and enhancing cardiac function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Effect of Ghrelin Intervention on the Ras/ERK Pathway in the Regulation of Heart Failure by PTEN

Zhao

Sun

et al. 2022

Computational and Mathematical Methods in Medicine

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“…ERK1/2 are activated by various extracellular triggers such as GPCRs, integrins, and receptor tyrosine kinases, and are responsible for the induction of cellular responses such as proliferation, differentiation, and cell survival. The cascade is involved in the development and progression of many diseases including cancer, heart failure, developmental diseases, and autoimmune diseases, but are also vital for many physiological effects such as protection from cell death [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ]. Despite the many triggers that activate this central signaling cascade, it is unclear how ERK1/2 can transmit specific and controlled cellular responses.…”

Section: Erk1/2mentioning

confidence: 99%

“…The activation of these substrates may vary depending on the type of extracellular stimuli, the availability of the scaffold proteins, and on their subcellular localization. Substrates of ERK1/2 have been identified, for example, in the cytoplasm, mitochondria, endoplasmatic reticulum, and particularly in the nucleus [ 35 , 38 , 42 ]. Thus, a tight control and understanding of the activating and modifying signals is central to direct the effects of ERK1/2 to the desired cellular outcome.…”

Section: Erk1/2mentioning

confidence: 99%

“…As noted above, the role of the Raf/MEK/ERK1/2 cascade in the heart is a double-edged sword. ERK1/2 signaling is involved in adverse remodeling but is also responsible for cardiomyocyte survival and protection from stress-induced cardiomyocyte death [ 34 , 35 , 51 , 52 ]. Several lines of evidence demonstrate that the inhibition of Raf/MEK/ERK1/2 signaling can render the heart more vulnerable to injury [ 52 , 53 , 54 ].…”

Section: Erk1/2mentioning

confidence: 99%

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Harnessing RKIP to Combat Heart Disease and Cancer

Lorenz

Rosner

2022

Cancers

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Cancer and heart disease are leading causes of morbidity and mortality worldwide. These diseases have common risk factors, common molecular signaling pathways that are central to their pathogenesis, and even some disease phenotypes that are interdependent. Thus, a detailed understanding of common regulators is critical for the development of new and synergistic therapeutic strategies. The Raf kinase inhibitory protein (RKIP) is a regulator of the cellular kinome that functions to maintain cellular robustness and prevent the progression of diseases including heart disease and cancer. Two of the key signaling pathways controlled by RKIP are the β-adrenergic receptor (βAR) signaling to protein kinase A (PKA), particularly in the heart, and the MAP kinase cascade Raf/MEK/ERK1/2 that regulates multiple diseases. The goal of this review is to discuss how we can leverage RKIP to suppress cancer without incurring deleterious effects on the heart. Specifically, we discuss: (1) How RKIP functions to either suppress or activate βAR (PKA) and ERK1/2 signaling; (2) How we can prevent cancer-promoting kinase signaling while at the same time avoiding cardiotoxicity.

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mAKAPβ signalosome: A potential target for cardiac hypertrophy

Golatkar,

Bhatt

2023

Drug Development Research

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Pathological cardiac hypertrophy is the result of a prolonged increase in the workload of the heart that activates various signaling pathways such as MAPK pathway, PKA‐dependent cAMP signaling, and CaN‐NFAT signaling pathway which further activates genes for cardiac remodeling. Various signalosomes are present in the heart that regulates the signaling of physiological and pathological cardiac hypertrophy. mAKAPβ is one such scaffold protein that regulates signaling pathways involved in promoting cardiac hypertrophy. It is present in the outer nuclear envelope of the cardiomyocytes, which provides specificity of the target toward the heart. In addition, nuclear translocation of signaling components and transcription factors such as MEF2D, NFATc, and HIF‐1α is facilitated due to the localization of mAKAPβ near the nuclear envelope. These factors are required for activation of genes promoting cardiac remodeling. Downregulation of mAKAPβ improves cardiac function and attenuates cardiac hypertrophy which in turn prevents the development of heart failure. Unlike earlier therapies for heart failure, knockout or silencing of mAKAPβ is not associated with side effects because of its high specificity in the striated myocytes. Downregulating expression of mAKAPβ is a favorable therapeutic approach toward attenuating cardiac hypertrophy and hence preventing heart failure. This review discusses mAKAPβ signalosome as a potential target for cardiac hypertrophy intervention.

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ERK1/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth

Cited by 20 publications

References 161 publications

Effect of Ghrelin Intervention on the Ras/ERK Pathway in the Regulation of Heart Failure by PTEN

Effect of Ghrelin Intervention on the Ras/ERK Pathway in the Regulation of Heart Failure by PTEN

Harnessing RKIP to Combat Heart Disease and Cancer

mAKAPβ signalosome: A potential target for cardiac hypertrophy

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