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c-Jun N-terminal kinases: New Insights for Old Cell Signaling Pathways

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 26010

Special Issue Editors

Leeds Institute of Medical Research at St. James’s, Faculty of Medicine and Health, University of Leeds, Leeds, UK
Interests: apoptosis; cancer; injury and repair; regeneration; kinase; signal transduction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The c‐Jun N‐terminal kinase (JNK) signaling pathway is a family of protein kinases that regulates many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is well established that mammals express three JNK proteins (JNK1, JNK2 and JNK3) that are encoded by three separate genes jnk1 (Mapk8), jnk2 (Mapk9) and jnk3 (Mapk10), which are alternatively spliced to create at least 10 variants of 46 and 55 kDa. Depending on distinct stimuli, each JNK is activated by specific MAPKKs, which in turns can be activated by more than one MAPKKK, increasing the complexity and diversity of JNK signaling. Importantly, deregulated activation of JNK signaling pathways are becoming the focus of screening strategies probing for new therapeutic approaches to treat human diseases such as diabetes, neurodegenerative conditions, cardiovascular abnormalities, cancer, inflammation and liver disease.

Although these signaling pathways have been a subject of intensive research for more than two decades, only recent research focuses have greatly contributed to understand the biological activities and functions of each JNK protein in human diseases. This special issue aims to collect state-of-the-art primary research studies and review articles from diverse leading groups in the field to update our current understanding of the contributions of JNK to the development and control of specific human conditions. Written by international experts, this special issue may include research articles describing the regulatory mechanisms as well as the contribution of each JNK protein to gene transcription and expression, metabolism, cell cycle regulation, immune responses and tumorigenesis therapeutic perspectives.

Dr. Salvatore Papa
Dr. Concetta Bubici
Guest Editors

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Keywords

  • JNK
  • ERK
  • p38
  • inflammatory responses
  • morphogenesis
  • cell proliferation
  • cell differentiation
  • cell survival
  • cell death
  • tissue regeneration
  • cancer
  • injury and repair
  • gene functions and genetics
  • gene transcription and expression
  • signaling networks and system biology
  • drugs and inhibitors
  • metabolism

Published Papers (5 papers)

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Review

19 pages, 2217 KiB  
Review
JNK Signaling in Stem Cell Self-Renewal and Differentiation
by Takashi Semba, Rachel Sammons, Xiaoping Wang, Xuemei Xie, Kevin N. Dalby and Naoto T. Ueno
Int. J. Mol. Sci. 2020, 21(7), 2613; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072613 - 09 Apr 2020
Cited by 47 | Viewed by 7323
Abstract
C-JUN N-terminal kinases (JNKs), which belong to the mitogen-activated protein kinase (MAPK) family, are evolutionarily conserved kinases that mediate cell responses to various types of extracellular stress insults. They regulate physiological processes such as embryonic development and tissue regeneration, playing roles in cell [...] Read more.
C-JUN N-terminal kinases (JNKs), which belong to the mitogen-activated protein kinase (MAPK) family, are evolutionarily conserved kinases that mediate cell responses to various types of extracellular stress insults. They regulate physiological processes such as embryonic development and tissue regeneration, playing roles in cell proliferation and programmed cell death. JNK signaling is also involved in tumorigenesis and progression of several types of malignancies. Recent studies have shown that JNK signaling has crucial roles in regulating the traits of cancer stem cells (CSCs). Here we describe the functions of the JNK signaling pathway in self-renewal and differentiation, which are essential features of various types of stem cells, such as embryonic, induced pluripotent, and adult tissue-specific stem cells. We also review current knowledge of JNK signaling in CSCs and discuss its role in maintaining the CSC phenotype. A better understanding of JNK signaling as an essential regulator of stemness may provide a basis for the development of regenerative medicine and new therapeutic strategies against malignant tumors. Full article
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21 pages, 2233 KiB  
Review
JNK Signaling as a Key Modulator of Soft Connective Tissue Physiology, Pathology, and Healing
by Georgia Nikoloudaki, Sarah Brooks, Alexander P. Peidl, Dylan Tinney and Douglas W. Hamilton
Int. J. Mol. Sci. 2020, 21(3), 1015; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21031015 - 04 Feb 2020
Cited by 21 | Viewed by 4855
Abstract
In healthy individuals, the healing of soft tissues such as skin after pathological insult or post injury follows a relatively predictable and defined series of cell and molecular processes to restore tissue architecture and function(s). Healing progresses through the phases of hemostasis, inflammation, [...] Read more.
In healthy individuals, the healing of soft tissues such as skin after pathological insult or post injury follows a relatively predictable and defined series of cell and molecular processes to restore tissue architecture and function(s). Healing progresses through the phases of hemostasis, inflammation, proliferation, remodeling, and concomitant with re-epithelialization restores barrier function. Soft tissue healing is achieved through the spatiotemporal interplay of multiple different cell types including neutrophils, monocytes/macrophages, fibroblasts, endothelial cells/pericytes, and keratinocytes. Expressed in most cell types, c-Jun N-terminal kinases (JNK) are signaling molecules associated with the regulation of several cellular processes involved in soft tissue wound healing and in response to cellular stress. A member of the mitogen-activated protein kinase family (MAPK), JNKs have been implicated in the regulation of inflammatory cell phenotype, as well as fibroblast, stem/progenitor cell, and epithelial cell biology. In this review, we discuss our understanding of JNKs in the regulation of cell behaviors related to tissue injury, pathology, and wound healing of soft tissues. Using models as diverse as Drosophila, mice, rats, as well as human tissues, research is now defining important, but sometimes conflicting roles for JNKs in the regulation of multiple molecular processes in multiple different cell types central to wound healing processes. In this review, we focus specifically on the role of JNKs in the regulation of cell behavior in the healing of skin, cornea, tendon, gingiva, and dental pulp tissues. We conclude that while parallels can be drawn between some JNK activities and the control of cell behavior in healing, the roles of JNK can also be very specific modes of action depending on the tissue and the phase of healing. Full article
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11 pages, 409 KiB  
Review
Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma
by Shahanshah Khan and Hasan Zaki
Int. J. Mol. Sci. 2020, 21(2), 496; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020496 - 13 Jan 2020
Cited by 11 | Viewed by 3068
Abstract
Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is initiated and promoted by chronic inflammation. Inflammatory mediators are transcriptionally regulated by several inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). cJun N-terminal kinase (JNK), a member [...] Read more.
Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is initiated and promoted by chronic inflammation. Inflammatory mediators are transcriptionally regulated by several inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). cJun N-terminal kinase (JNK), a member of the MAPK family, plays a central role in HCC pathogenesis. Pathogen-associated molecular patterns (PAMPs) activate JNK and other MAPK upon recognition by toll-like receptors (TLRs). Apart from TLRs, PAMPs are sensed by several other pattern recognition receptors, including cytosolic NOD-like receptors (NLRs). In a recent study, we demonstrated that the NLR member NLRP12 plays a critical role in suppressing HCC via negative regulation of the JNK pathway. This article briefly reviews the crosstalk between NLRP12 and JNK that occurs during HCC. Full article
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21 pages, 1572 KiB  
Review
Role of c-Jun N-Terminal Kinases (JNKs) in Epilepsy and Metabolic Cognitive Impairment
by Oriol Busquets, Miren Ettcheto, Amanda Cano, Patricia R. Manzine, Elena Sánchez-Lopez, Triana Espinosa-Jiménez, Ester Verdaguer, Rubén Dario Castro-Torres, Carlos Beas-Zarate, Francesc X. Sureda, Jordi Olloquequi, Carme Auladell, Jaume Folch and Antoni Camins
Int. J. Mol. Sci. 2020, 21(1), 255; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21010255 - 30 Dec 2019
Cited by 18 | Viewed by 4326
Abstract
Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it [...] Read more.
Previous studies have reported that the regulatory function of the different c-Jun N-terminal kinases isoforms (JNK1, JNK2, and JNK3) play an essential role in neurological disorders, such as epilepsy and metabolic-cognitive alterations. Accordingly, JNKs have emerged as suitable therapeutic strategies. In fact, it has been demonstrated that some unspecific JNK inhibitors exert antidiabetic and neuroprotective effects, albeit they usually show high toxicity or lack therapeutic value. In this sense, natural specific JNK inhibitors, such as Licochalcone A, are promising candidates. Nonetheless, research on the understanding of the role of each of the JNKs remains mandatory in order to progress on the identification of new selective JNK isoform inhibitors. In the present review, a summary on the current gathered data on the role of JNKs in pathology is presented, as well as a discussion on their potential role in pathologies like epilepsy and metabolic-cognitive injury. Moreover, data on the effects of synthetic small molecule inhibitors that modulate JNK-dependent pathways in the brain and peripheral tissues is reviewed. Full article
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19 pages, 1073 KiB  
Review
Phosphorylation Dynamics of JNK Signaling: Effects of Dual-Specificity Phosphatases (DUSPs) on the JNK Pathway
by Jain Ha, Eunjeong Kang, Jihye Seo and Sayeon Cho
Int. J. Mol. Sci. 2019, 20(24), 6157; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20246157 - 06 Dec 2019
Cited by 37 | Viewed by 5796
Abstract
Protein phosphorylation affects conformational change, interaction, catalytic activity, and subcellular localization of proteins. Because the post-modification of proteins regulates diverse cellular signaling pathways, the precise control of phosphorylation states is essential for maintaining cellular homeostasis. Kinases function as phosphorylating enzymes, and phosphatases dephosphorylate [...] Read more.
Protein phosphorylation affects conformational change, interaction, catalytic activity, and subcellular localization of proteins. Because the post-modification of proteins regulates diverse cellular signaling pathways, the precise control of phosphorylation states is essential for maintaining cellular homeostasis. Kinases function as phosphorylating enzymes, and phosphatases dephosphorylate their target substrates, typically in a much shorter time. The c-Jun N-terminal kinase (JNK) signaling pathway, a mitogen-activated protein kinase pathway, is regulated by a cascade of kinases and in turn regulates other physiological processes, such as cell differentiation, apoptosis, neuronal functions, and embryonic development. However, the activation of the JNK pathway is also implicated in human pathologies such as cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, the proper balance between activation and inactivation of the JNK pathway needs to be tightly regulated. Dual specificity phosphatases (DUSPs) regulate the magnitude and duration of signal transduction of the JNK pathway by dephosphorylating their substrates. In this review, we will discuss the dynamics of phosphorylation/dephosphorylation, the mechanism of JNK pathway regulation by DUSPs, and the new possibilities of targeting DUSPs in JNK-related diseases elucidated in recent studies. Full article
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