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Special Issue "ERK Signaling Pathway in Diseases"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2019).

Special Issue Editor

Prof. Tiziana Crepaldi
E-Mail Website
Guest Editor
Department of Oncology, University of Turin; Candiolo Cancer Institute, FPO-IRCCS, Italy
Interests: Growth Factors; Receptor Tyrosine Kinases (RTKs); Signal transduction pathways; Cancer; Embryonic Development; Tissue Repair

Special Issue Information

Dear Colleagues,

The ERK signaling pathway plays a central role in the control of various cellular processes, such as proliferation, survival, differentiation, and development, as well as apoptosis and stress response. Compartmentalization and dynamic localization of ERK signaling is an important regulatory mechanism of specific biological processes. Consistent with its critical role in key cellular functions, deviation in the normal activities of this pathway has been implicated in the development of many human diseases involving different organs. In particular, mutations hitting the ERK signaling are involved in autosomal-dominant syndromes known as RASopathies. The major complications of these disorders are congenital cardiac defects and development of hypertrophic cardiomyopathy. Furthermore, in the neuronal system ERK has been correlated to different pathological contexts, including stroke, autism and neurodegenerative diseases, such as Multiple Sclerosis, Alzheimer's disease, Parkinson's disease and Amyotrophic Lateral Sclerosis. In the nervous system, ERK pathway regulates various cellular activities including neuron apoptosis through induction of excitotoxicity, neuroinflammation and innate immunity. In addition, ERK has been deeply investigated as anti-cancer target molecule for its important role in tumorigenesis in particular in cancer cell proliferation, migration and invasion. Finally, ERK has been also associated to the development of side effects derived from anti-cancer therapies, such as cardiotoxicity due to chemotherapeutic treatments. Overall, these data suggest that a major comprehension of the pathological mechanisms regulated by the ERK pathway will allow the development of new functional therapies for a great range of diseases with a strong impact on public health.

In this Special Issue of the International Journal of Molecular Sciences the focus will be on the role of the ERK signaling pathway in various pathologies, such as cancer, developmental disorders and diseases affecting the cardiovascular and nervous system.

Prof. Tiziana Crepaldi
Guest Editor

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Keywords

  • ERK signaling pathway
  • Cancer
  • Developmental Disorders
  • Cardiovascular system
  • Nervous System

Published Papers (15 papers)

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Research

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Article
Hypoxia-Induced Epithelial-To-Mesenchymal Transition Mediates Fibroblast Abnormalities via ERK Activation in Cutaneous Wound Healing
Int. J. Mol. Sci. 2019, 20(10), 2546; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102546 - 24 May 2019
Cited by 9 | Viewed by 1942
Abstract
Previous studies described the involvement of extracellular signal-related kinase (ERK) in systemic fibrotic diseases, but the role of ERK in cutaneous scarring is unknown. Although hypoxia drives tissue fibrosis by activating hypoxia-inducible factor-1α (HIF-1α), the specific roles of hypoxia and associated ERK phosphorylation [...] Read more.
Previous studies described the involvement of extracellular signal-related kinase (ERK) in systemic fibrotic diseases, but the role of ERK in cutaneous scarring is unknown. Although hypoxia drives tissue fibrosis by activating hypoxia-inducible factor-1α (HIF-1α), the specific roles of hypoxia and associated ERK phosphorylation in abnormal fibroblast activity during cutaneous scarring are unclear. Here, we investigated whether pathologic myofibroblast-like keloid fibroblast activity is promoted by hypoxia-induced epithelial–mesenchymal transition mediated by ERK activation. ERK phosphorylation was significantly increased in keloid tissue and fibroblasts. Human dermal fibroblasts cultured under hypoxia (1% O2) expressed phosphorylated ERK and exhibited activation of p38 mitogen-activated protein kinase signaling. Hypoxic human dermal fibroblasts showed increased protein and mRNA levels of epithelial–mesenchymal transition markers. Furthermore, administration of an ERK inhibitor (SCH772984) reduced the hypoxia-induced elevation of collagen type I levels in human dermal fibroblasts. Therefore, ERK may be a promising therapeutic target in profibrogenic diseases. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Article
How to Steer and Control ERK and the ERK Signaling Cascade Exemplified by Looking at Cardiac Insufficiency
Int. J. Mol. Sci. 2019, 20(9), 2179; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092179 - 02 May 2019
Cited by 3 | Viewed by 1301
Abstract
Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important [...] Read more.
Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK Thr 188 phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Article
ERK Activity Dynamics during Zebrafish Embryonic Development
Int. J. Mol. Sci. 2019, 20(1), 109; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010109 - 28 Dec 2018
Cited by 11 | Viewed by 2984
Abstract
During vertebrate development, extracellular signal-regulated kinase (ERK) is activated by growth factors such as fibroblast growth factor (FGF), and it regulates the formation of tissues/organs including eyes, brains, somites, limbs, and inner ears. However, an experimental system to monitor ERK activity dynamics in [...] Read more.
During vertebrate development, extracellular signal-regulated kinase (ERK) is activated by growth factors such as fibroblast growth factor (FGF), and it regulates the formation of tissues/organs including eyes, brains, somites, limbs, and inner ears. However, an experimental system to monitor ERK activity dynamics in the entire body of the vertebrate embryo is lacking. We recently studied ERK activity dynamics in the pre-somitic mesoderm of living zebrafish embryos injected with mRNAs encoding a Förster resonance energy transfer (FRET)-based ERK biosensor. In this study, transgenic zebrafish stably and ubiquitously expressing the ERK biosensor were generated to monitor ERK activity dynamics throughout embryonic development. The system allowed the identification of ERK activation domains in embryos from the late blastula to the late segmentation stage, consistent with immunostaining patterns obtained using anti-phosphorylated ERK antibody. A spatiotemporal map of ERK activity in the entire body during zebrafish embryogenesis was generated, and previously unidentified activation dynamics and ERK domains were identified. The proposed system is the first reported method to monitor ERK activity dynamics during vertebrate embryogenesis, providing insight into the role of ERK activity in normal and abnormal development in living vertebrate embryos. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review

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Review
ERK Pathway in Activated, Myofibroblast-Like, Hepatic Stellate Cells: A Critical Signaling Crossroad Sustaining Liver Fibrosis
Int. J. Mol. Sci. 2019, 20(11), 2700; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20112700 - 01 Jun 2019
Cited by 25 | Viewed by 2594
Abstract
Fibrogenic progression of chronic liver disease, whatever the etiology, is characterized by persistent chronic parenchymal injury, chronic activation of inflammatory response, and sustained activation of liver fibrogenesis, and of pathological wound healing response. A critical role in liver fibrogenesis is played by hepatic [...] Read more.
Fibrogenic progression of chronic liver disease, whatever the etiology, is characterized by persistent chronic parenchymal injury, chronic activation of inflammatory response, and sustained activation of liver fibrogenesis, and of pathological wound healing response. A critical role in liver fibrogenesis is played by hepatic myofibroblasts (MFs), a heterogeneous population of α smooth-muscle actin—positive cells that originate from various precursor cells through a process of activation and transdifferentiation. In this review, we focus the attention on the role of extracellular signal-regulated kinase (ERK) signaling pathway as a critical one in modulating selected profibrogenic phenotypic responses operated by liver MFs. We will also analyze major therapeutic antifibrotic strategies developed in the last two decades in preclinical studies, some translated to clinical conditions, designed to interfere directly or indirectly with the Ras/Raf/MEK/ERK signaling pathway in activated hepatic MFs, but that also significantly increased our knowledge on the biology and pathobiology of these fascinating profibrogenic cells. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
Biological Rationale for Targeting MEK/ERK Pathways in Anti-Cancer Therapy and to Potentiate Tumour Responses to Radiation
Int. J. Mol. Sci. 2019, 20(10), 2530; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102530 - 23 May 2019
Cited by 20 | Viewed by 1908
Abstract
ERK1 and ERK2 (ERKs), two extracellular regulated kinases (ERK1/2), are evolutionary-conserved and ubiquitous serine-threonine kinases involved in regulating cell signalling in normal and pathological tissues. The expression levels of these kinases are almost always different, with ERK2 being the more prominent. ERK1/2 activation [...] Read more.
ERK1 and ERK2 (ERKs), two extracellular regulated kinases (ERK1/2), are evolutionary-conserved and ubiquitous serine-threonine kinases involved in regulating cell signalling in normal and pathological tissues. The expression levels of these kinases are almost always different, with ERK2 being the more prominent. ERK1/2 activation is fundamental for the development and progression of cancer. Since their discovery, much research has been dedicated to their role in mitogen-activated protein kinases (MAPK) pathway signalling and in their activation by mitogens and mutated RAF or RAS in cancer cells. In order to gain a better understanding of the role of ERK1/2 in MAPK pathway signalling, many studies have been aimed at characterizing ERK1/2 splicing isoforms, mutants, substrates and partners. In this review, we highlight the differences between ERK1 and ERK2 without completely discarding the hypothesis that ERK1 and ERK2 exhibit functional redundancy. The main goal of this review is to shed light on the role of ERK1/2 in targeted therapy and radiotherapy and highlight the importance of identifying ERK inhibitors that may overcome acquired resistance. This is a highly relevant therapeutic issue that needs to be addressed to combat tumours that rely on constitutively active RAF and RAS mutants and the MAPK pathway. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer
Int. J. Mol. Sci. 2019, 20(10), 2505; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20102505 - 21 May 2019
Cited by 44 | Viewed by 1861
Abstract
The extracellular signal-related kinases (ERKs) act as pleiotropic molecules in tumors, where they activate pro-survival pathways leading to cell proliferation and migration, as well as modulate apoptosis, differentiation, and senescence. Given its central role as sensor of extracellular signals, ERK transduction system is [...] Read more.
The extracellular signal-related kinases (ERKs) act as pleiotropic molecules in tumors, where they activate pro-survival pathways leading to cell proliferation and migration, as well as modulate apoptosis, differentiation, and senescence. Given its central role as sensor of extracellular signals, ERK transduction system is widely exploited by cancer cells subjected to environmental stresses, such as chemotherapy and anti-tumor activity of the host immune system. Aggressive tumors have a tremendous ability to adapt and survive in stressing and unfavorable conditions. The simultaneous resistance to chemotherapy and immune system responses is common, and ERK signaling plays a key role in both types of resistance. In this review, we dissect the main ERK-dependent mechanisms and feedback circuitries that simultaneously determine chemoresistance and immune-resistance/immune-escape in cancer cells. We discuss the pros and cons of targeting ERK signaling to induce chemo-immune-sensitization in refractory tumors. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation
Int. J. Mol. Sci. 2019, 20(9), 2243; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092243 - 07 May 2019
Cited by 24 | Viewed by 2428
Abstract
Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15–20% of children a facial PWS involving the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), a neurocutaneous disorder with vascular malformations in the cerebral cortex [...] Read more.
Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15–20% of children a facial PWS involving the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), a neurocutaneous disorder with vascular malformations in the cerebral cortex on the same side of the facial PWS lesions. Recently, evidence has surfaced that advanced our understanding of the pathogenesis of PWS/SWS, including discoveries of somatic genetic mutations (GNAQ, PI3K), MAPK and PI3K aberrant activations, and molecular phenotypes of PWS endothelial cells. In this review, we summarize current knowledge on the etiology and pathology of PWS/SWS based on evidence that the activation of MAPK and/or PI3K contributes to the malformations, as well as potential futuristic treatment approaches targeting these aberrantly dysregulated signaling pathways. Current data support that: (1) PWS is a multifactorial malformation involving the entire physiological structure of human skin; (2) PWS should be pathoanatomically re-defined as “a malformation resulting from differentiation-impaired endothelial cells with a progressive dilatation of immature venule-like vasculatures”; (3) dysregulation of vascular MAPK and/or PI3K signaling during human embryonic development plays a part in the pathogenesis and progression of PWS/SWS; and (4) sporadic low frequency somatic mutations, such as GNAQ, PI3K, work as team players but not as a lone wolf, contributing to the development of vascular phenotypes. We also address many crucial questions yet to be answered in the future research investigations. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
ERK: A Key Player in the Pathophysiology of Cardiac Hypertrophy
Int. J. Mol. Sci. 2019, 20(9), 2164; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20092164 - 01 May 2019
Cited by 53 | Viewed by 3298
Abstract
Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity [...] Read more.
Cardiac hypertrophy is an adaptive and compensatory mechanism preserving cardiac output during detrimental stimuli. Nevertheless, long-term stimuli incite chronic hypertrophy and may lead to heart failure. In this review, we analyze the recent literature regarding the role of ERK (extracellular signal-regulated kinase) activity in cardiac hypertrophy. ERK signaling produces beneficial effects during the early phase of chronic pressure overload in response to G protein-coupled receptors (GPCRs) and integrin stimulation. These functions comprise (i) adaptive concentric hypertrophy and (ii) cell death prevention. On the other hand, ERK participates in maladaptive hypertrophy during hypertension and chemotherapy-mediated cardiac side effects. Specific ERK-associated scaffold proteins are implicated in either cardioprotective or detrimental hypertrophic functions. Interestingly, ERK phosphorylated at threonine 188 and activated ERK5 (the big MAPK 1) are associated with pathological forms of hypertrophy. Finally, we examine the connection between ERK activation and hypertrophy in (i) transgenic mice overexpressing constitutively activated RTKs (receptor tyrosine kinases), (ii) animal models with mutated sarcomeric proteins characteristic of inherited hypertrophic cardiomyopathies (HCMs), and (iii) mice reproducing syndromic genetic RASopathies. Overall, the scientific literature suggests that during cardiac hypertrophy, ERK could be a “good” player to be stimulated or a “bad” actor to be mitigated, depending on the pathophysiological context. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
MAPK/ERK Signaling in Regulation of Renal Differentiation
Int. J. Mol. Sci. 2019, 20(7), 1779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20071779 - 10 Apr 2019
Cited by 20 | Viewed by 3283
Abstract
Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects derived from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. [...] Read more.
Congenital anomalies of the kidney and urinary tract (CAKUT) are common birth defects derived from abnormalities in renal differentiation during embryogenesis. CAKUT is the major cause of end-stage renal disease and chronic kidney diseases in children, but its genetic causes remain largely unresolved. Here we discuss advances in the understanding of how mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity contributes to the regulation of ureteric bud branching morphogenesis, which dictates the final size, shape, and nephron number of the kidney. Recent studies also demonstrate that the MAPK/ERK pathway is directly involved in nephrogenesis, regulating both the maintenance and differentiation of the nephrogenic mesenchyme. Interestingly, aberrant MAPK/ERK signaling is linked to many cancers, and recent studies suggest it also plays a role in the most common pediatric renal cancer, Wilms’ tumor. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
Targeting the ERK Signaling Pathway in Melanoma
Int. J. Mol. Sci. 2019, 20(6), 1483; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061483 - 25 Mar 2019
Cited by 49 | Viewed by 3248
Abstract
The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by [...] Read more.
The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
Review
Impact of ERK5 on the Hallmarks of Cancer
Int. J. Mol. Sci. 2019, 20(6), 1426; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061426 - 21 Mar 2019
Cited by 26 | Viewed by 4358
Abstract
Extracellular signal-regulated kinase 5 (ERK5) belongs to the mitogen-activated protein kinase (MAPK) family that consists of highly conserved enzymes expressed in all eukaryotic cells and elicits several biological responses, including cell survival, proliferation, migration, and differentiation. In recent years, accumulating lines of evidence [...] Read more.
Extracellular signal-regulated kinase 5 (ERK5) belongs to the mitogen-activated protein kinase (MAPK) family that consists of highly conserved enzymes expressed in all eukaryotic cells and elicits several biological responses, including cell survival, proliferation, migration, and differentiation. In recent years, accumulating lines of evidence point to a relevant role of ERK5 in the onset and progression of several types of cancer. In particular, it has been reported that ERK5 is a key signaling molecule involved in almost all the biological features of cancer cells so that its targeting is emerging as a promising strategy to suppress tumor growth and spreading. Based on that, in this review, we pinpoint the hallmark-specific role of ERK5 in cancer in order to identify biological features that will potentially benefit from ERK5 targeting. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
Roles of Cyclic AMP Response Element Binding Activation in the ERK1/2 and p38 MAPK Signalling Pathway in Central Nervous System, Cardiovascular System, Osteoclast Differentiation and Mucin and Cytokine Production
Int. J. Mol. Sci. 2019, 20(6), 1346; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20061346 - 17 Mar 2019
Cited by 36 | Viewed by 2760
Abstract
There are many downstream targets of mitogen-activated protein kinase (MAPK) signalling that are involved in neuronal development, cellular differentiation, cell migration, cancer, cardiovascular dysfunction and inflammation via their functions in promoting apoptosis and cell motility and regulating various cytokines. It has been reported [...] Read more.
There are many downstream targets of mitogen-activated protein kinase (MAPK) signalling that are involved in neuronal development, cellular differentiation, cell migration, cancer, cardiovascular dysfunction and inflammation via their functions in promoting apoptosis and cell motility and regulating various cytokines. It has been reported that cyclic AMP response element-binding protein (CREB) is phosphorylated and activated by cyclic AMP signalling and calcium/calmodulin kinase. Recent evidence also points to CREB phosphorylation by the MAPK signalling pathway. However, the specific roles of CREB phosphorylation in MAPK signalling have not yet been reviewed in detail. Here, we describe the recent advances in the study of this MAPK-CREB signalling axis in human diseases. Overall, the crosstalk between extracellular signal-related kinase (ERK) 1/2 and p38 MAPK signalling has been shown to regulate various physiological functions, including central nervous system, cardiac fibrosis, alcoholic cardiac fibrosis, osteoclast differentiation, mucin production in the airway, vascular smooth muscle cell migration, steroidogenesis and asthmatic inflammation. In this review, we focus on ERK1/2 and/or p38 MAPK-dependent CREB activation associated with various diseases to provide insights for basic and clinical researchers. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer
Int. J. Mol. Sci. 2019, 20(5), 1194; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20051194 - 08 Mar 2019
Cited by 47 | Viewed by 3441
Abstract
The extracellular signal-regulated kinases 1/2 (ERK) are central signaling components that regulate stimulated cellular processes such as proliferation and differentiation. When dysregulated, these kinases participate in the induction and maintenance of various pathologies, primarily cancer. While ERK is localized in the cytoplasm of [...] Read more.
The extracellular signal-regulated kinases 1/2 (ERK) are central signaling components that regulate stimulated cellular processes such as proliferation and differentiation. When dysregulated, these kinases participate in the induction and maintenance of various pathologies, primarily cancer. While ERK is localized in the cytoplasm of resting cells, many of its substrates are nuclear, and indeed, extracellular stimulation induces a rapid and robust nuclear translocation of ERK. Similarly to other signaling components that shuttle to the nucleus upon stimulation, ERK does not use the canonical importinα/β mechanism of nuclear translocation. Rather, it has its own unique nuclear translocation signal (NTS) that interacts with importin7 to allow stimulated shuttling via the nuclear pores. Prevention of the nuclear translocation inhibits proliferation of B-Raf- and N/K-Ras-transformed cancers. This effect is distinct from the one achieved by catalytic Raf and MEK inhibitors used clinically, as cells treated with the translocation inhibitors develop resistance much more slowly. In this review, we describe the mechanism of ERK translocation, present all its nuclear substrates, discuss its role in cancer and compare its translocation to the translocation of other signaling components. We also present proof of principle data for the use of nuclear ERK translocation as an anti-cancer target. It is likely that the prevention of nuclear ERK translocation will eventually serve as a way to combat Ras and Raf transformed cancers with less side-effects than the currently used drugs. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
Role of p90RSK in Kidney and Other Diseases
Int. J. Mol. Sci. 2019, 20(4), 972; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20040972 - 23 Feb 2019
Cited by 9 | Viewed by 2021
Abstract
The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK. p90RSK plays an important role in the Ras-mitogen-activated protein kinase (MAPK) signalling cascade and is the [...] Read more.
The 90 kDa ribosomal s6 kinases (RSKs) are a group of serine/threonine kinases consisting of 4 RSK isoforms (RSK1-4), of which RSK1 is also designated as p90RSK. p90RSK plays an important role in the Ras-mitogen-activated protein kinase (MAPK) signalling cascade and is the direct downstream effector of Ras-extracellular signal-regulated kinase (ERK1/2) signalling. ERK1/2 activation directly phosphorylates and activates p90RSK, which, in turn, activates various signalling events through selection of different phosphorylation substrates. Upregulation of p90RSK has been reported in numerous human diseases. p90RSK plays an important role in the regulation of diverse cellular processes. Thus, aberrant activation of p90RSK plays a critical role in the pathogenesis of organ dysfunction and damage. In this review, we focus on the current understanding of p90RSK functions and roles in the development and progression of kidney diseases. Roles of p90RSK, as well as other RSKs, in cardiovascular disorders and cancers are also discussed. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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Review
ERK Activity Imaging During Migration of Living Cells In Vitro and In Vivo
Int. J. Mol. Sci. 2019, 20(3), 679; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20030679 - 05 Feb 2019
Cited by 5 | Viewed by 2137
Abstract
Extracellular signal-regulated kinase (ERK) is a major downstream factor of the EGFR-RAS-RAF signalling pathway, and thus the role of ERK in cell growth has been widely examined. The development of biosensors based on fluorescent proteins has enabled us to measure ERK activities in [...] Read more.
Extracellular signal-regulated kinase (ERK) is a major downstream factor of the EGFR-RAS-RAF signalling pathway, and thus the role of ERK in cell growth has been widely examined. The development of biosensors based on fluorescent proteins has enabled us to measure ERK activities in living cells, both after growth factor stimulation and in its absence. Long-term imaging unexpectedly revealed the oscillative activation of ERK in an epithelial sheet or a cyst in vitro. Studies using transgenic mice expressing the ERK biosensor have revealed inhomogeneous ERK activities among various cell species. In vivo Förster (or fluorescence) resonance energy transfer (FRET) imaging shed light on a novel role of ERK in cell migration. Neutrophils and epithelial cells in various organs such as intestine, skin, lung and bladder showed spatio-temporally different cell dynamics and ERK activities. Experiments using inhibitors confirmed that ERK activities are required for various pathological responses, including epithelial repair after injuries, inflammation, and niche formation of cancer metastasis. In conclusion, biosensors for ERK will be powerful and valuable tools to investigate the roles of ERK in situ. Full article
(This article belongs to the Special Issue ERK Signaling Pathway in Diseases)
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