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Cells
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Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases
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Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (1 July 2020) | Viewed by 74439

Special Issue Editor

Prof. Tiziana Borsello

E-Mail Website
Guest Editor
1. Neuronal Death and Neuroprotection lab, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Via Balzaretti 9 - 20133 Milano, Italy
2. Neuroscience Department, IRCCS-Istituto Di Ricerche Farmacologiche, "Mario Negri", Via la Masa 19, 20156 Milano, Italy
Interests: synaptic dysfunction; stress signaling pathway; JNK; neuroprotection; neuronal death; acute and chronic brain diseases

Special Issue Information

Dear Colleagues,

The c-Jun N-terminal kinase (JNK) is a MAP kinase, part of a family of serine/threonine protein kinases playing important roles in cellular responses to external stress signals. Since their identification, about 20 years ago, much has been learned of the activation and regulation of the JNK pathway. Three distinct genes, jnk1, jnk2, and jnk3, have been identified, encoding for three JNK isoforms (JNK1, JNK2, and JNK3). JNK1 and JNK2 have broad tissue distribution, while JNK3 is predominantly found in the central nervous system. JNK regulates many biological activities, including inflammatory responses, morphogenesis, cytoskeletal changes, cell proliferation, differentiation, survival and death, as well as gene expression. Importantly, deregulated JNK signaling pathway activation is becoming the focus of screening strategies for new therapeutic approaches to treat human diseases such as diabetes, neurodegenerative conditions, cardiovascular abnormalities, cancer, inflammation, liver disease, and renal fibrosis. JNK acts on a plethora of substrates and regulates a complicated network with diverse biological functions that results in physiological and pathological effects. In recent years, the approaches targeting JNKs as a potential therapeutic target/biomarker are many, and it is clear that it will be important to consider both tissue- and isoform-specific differences.

This Special Issue aims to present the state-of-the-art as well as new ideas and novel findings around the JNK role in different fields:

  • JNK in brain diseases;
  • JNK in CNS development;
  • JNK in genome expression/gene transcription;
  • JNK in cancer;
  • JNK in diabetes;
  • JNK in immunity;
  • JNK as a therapeutic target.

We invite the community to submit original articles or reviews in the abovementioned fields. We look forward to your contributions.

Prof. Tiziana Borsello
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • c-Jun N-terminal kinase (JNK)
  • brain diseases
  • gene transcription
  • tumorigenesis
  • insulin resistant
  • immunity
  • inflammation
  • survival
  • growth
  • death
  • therapeutic targets

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Published Papers (10 papers)

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Research

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12 pages, 973 KiB  
Article
Neuroprotective Effects of a Novel Inhibitor of c-Jun N-Terminal Kinase in the Rat Model of Transient Focal Cerebral Ischemia
by Mark B. Plotnikov, Galina A. Chernysheva, Vera I. Smolyakova, Oleg I. Aliev, Eugene S. Trofimova, Eugene Y. Sherstoboev, Anton N. Osipenko, Andrei I. Khlebnikov, Yana J. Anfinogenova, Igor A. Schepetkin and Dmitriy N. Atochin
Cells 2020, 9(8), 1860; https://doi.org/10.3390/cells9081860 - 8 Aug 2020
Cited by 27 | Viewed by 3563
Abstract
A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the [...] Read more.
A novel specific inhibitor of c-Jun N-terminal kinase, 11H-indeno[1,2-b]quinoxalin-11-one oxime sodium salt (IQ-1S), has a high affinity to JNK3 compared to JNK1/JNK2. The aim of this work was to study the mechanisms of neuroprotective activity of IQ-1S in the models of reversible focal cerebral ischemia (FCI) in Wistar rats. The animals were administered with an intraperitoneal injection of IQ-1S (5 and 25 mg/kg) or citicoline (500 mg/kg). Administration of IQ-1S exerted a pronounced dose-dependent neuroprotective effect, not inferior to the effects of citicoline. Administration of IQ-1S at doses of 5 and 25 mg/kg reduced the infarct size by 20% and 50%, respectively, 48 h after FCI, whereas administration of citicoline reduced the infarct size by 34%. The administration of IQ-1S was associated with a faster amelioration of neurological status. Control rats showed a 2.0-fold increase in phospho-c-Jun levels in the hippocampus compared to the corresponding values in sham-operated rats 4 h after FCI. Administration of IQ-1S at a dose of 25 mg/kg reduced JNK-dependent phosphorylation of c-Jun by 20%. Our findings suggest that IQ-1S inhibits JNK enzymatic activity in the hippocampus and protects against stroke injury when administered in the therapeutic and prophylactic regimen in the rat model of FCI. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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16 pages, 3478 KiB  
Article
Impact of JNK and Its Substrates on Dendritic Spine Morphology
by Emilia Komulainen, Artemis Varidaki, Natalia Kulesskaya, Hasan Mohammad, Christel Sourander, Heikki Rauvala and Eleanor T. Coffey
Cells 2020, 9(2), 440; https://doi.org/10.3390/cells9020440 - 14 Feb 2020
Cited by 14 | Viewed by 4437
Abstract
The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and Jnk1-/- mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate [...] Read more.
The protein kinase JNK1 exhibits high activity in the developing brain, where it regulates dendrite morphology through the phosphorylation of cytoskeletal regulatory proteins. JNK1 also phosphorylates dendritic spine proteins, and Jnk1-/- mice display a long-term depression deficit. Whether JNK1 or other JNKs regulate spine morphology is thus of interest. Here, we characterize dendritic spine morphology in hippocampus of mice lacking Jnk1-/- using Lucifer yellow labelling. We find that mushroom spines decrease and thin spines increase in apical dendrites of CA3 pyramidal neurons with no spine changes in basal dendrites or in CA1. Consistent with this spine deficit, Jnk1-/- mice display impaired acquisition learning in the Morris water maze. In hippocampal cultures, we show that cytosolic but not nuclear JNK, regulates spine morphology and expression of phosphomimicry variants of JNK substrates doublecortin (DCX) or myristoylated alanine-rich C kinase substrate-like protein-1 (MARCKSL1), rescue mushroom, thin, and stubby spines differentially. These data suggest that physiologically active JNK controls the equilibrium between mushroom, thin, and stubby spines via phosphorylation of distinct substrates. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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Review

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17 pages, 739 KiB  
Review
Activation of c-Jun N-Terminal Kinase, a Potential Therapeutic Target in Autoimmune Arthritis
by Benjamin Lai, Chien-Hsiang Wu and Jenn-Haung Lai
Cells 2020, 9(11), 2466; https://doi.org/10.3390/cells9112466 - 12 Nov 2020
Cited by 16 | Viewed by 3273
Abstract
The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in [...] Read more.
The c-Jun-N-terminal kinase (JNK) is a critical mediator involved in various physiological processes, such as immune responses, and the pathogenesis of various diseases, including autoimmune disorders. JNK is one of the crucial downstream signaling molecules of various immune triggers, mainly proinflammatory cytokines, in autoimmune arthritic conditions, mainly including rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. The activation of JNK is regulated in a complex manner by upstream kinases and phosphatases. Noticeably, different subtypes of JNKs behave differentially in immune responses. Furthermore, aside from biologics targeting proinflammatory cytokines, small-molecule inhibitors targeting signaling molecules such as Janus kinases can act as very powerful therapeutics in autoimmune arthritis patients unresponsiveness to conventional synthetic antirheumatic drugs. Nevertheless, despite these encouraging therapies, a population of patients with an inadequate therapeutic response to all currently available medications still remains. These findings identify the critical signaling molecule JNK as an attractive target for investigation of the immunopathogenesis of autoimmune disorders and for consideration as a potential therapeutic target for patients with autoimmune arthritis to achieve better disease control. This review provides a useful overview of the roles of JNK, how JNK is regulated in immunopathogenic responses, and the potential of therapeutically targeting JNK in patients with autoimmune arthritis. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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25 pages, 1808 KiB  
Review
Alarmins and c-Jun N-Terminal Kinase (JNK) Signaling in Neuroinflammation
by Nina D. Anfinogenova, Mark T. Quinn, Igor A. Schepetkin and Dmitriy N. Atochin
Cells 2020, 9(11), 2350; https://doi.org/10.3390/cells9112350 - 24 Oct 2020
Cited by 28 | Viewed by 4919
Abstract
Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of neuroinflammation and in the acute phase of ischemia. Defensins, cathelicidin, high-mobility group [...] Read more.
Neuroinflammation is involved in the progression or secondary injury of multiple brain conditions, including stroke and neurodegenerative diseases. Alarmins, also known as damage-associated molecular patterns, are released in the presence of neuroinflammation and in the acute phase of ischemia. Defensins, cathelicidin, high-mobility group box protein 1, S100 proteins, heat shock proteins, nucleic acids, histones, nucleosomes, and monosodium urate microcrystals are thought to be alarmins. They are released from damaged or dying cells and activate the innate immune system by interacting with pattern recognition receptors. Being principal sterile inflammation triggering agents, alarmins are considered biomarkers and therapeutic targets. They are recognized by host cells and prime the innate immune system toward cell death and distress. In stroke, alarmins act as mediators initiating the inflammatory response after the release from the cellular components of the infarct core and penumbra. Increased c-Jun N-terminal kinase (JNK) phosphorylation may be involved in the mechanism of stress-induced release of alarmins. Putative crosstalk between the alarmin-associated pathways and JNK signaling seems to be inherently interwoven. This review outlines the role of alarmins/JNK-signaling in cerebral neurovascular inflammation and summarizes the complex response of cells to alarmins. Emerging anti-JNK and anti-alarmin drug treatment strategies are discussed. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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22 pages, 1860 KiB  
Review
JNK3 as Therapeutic Target and Biomarker in Neurodegenerative and Neurodevelopmental Brain Diseases
by Clara Alice Musi, Graziella Agrò, Francesco Santarella, Erika Iervasi and Tiziana Borsello
Cells 2020, 9(10), 2190; https://doi.org/10.3390/cells9102190 - 28 Sep 2020
Cited by 38 | Viewed by 5292
Abstract
The c-Jun N-terminal kinase 3 (JNK3) is the JNK isoform mainly expressed in the brain. It is the most responsive to many stress stimuli in the central nervous system from ischemia to Aβ oligomers toxicity. JNK3 activity is spatial and temporal organized [...] Read more.
The c-Jun N-terminal kinase 3 (JNK3) is the JNK isoform mainly expressed in the brain. It is the most responsive to many stress stimuli in the central nervous system from ischemia to Aβ oligomers toxicity. JNK3 activity is spatial and temporal organized by its scaffold protein, in particular JIP-1 and β-arrestin-2, which play a crucial role in regulating different cellular functions in different cellular districts. Extensive evidence has highlighted the possibility of exploiting these adaptors to interfere with JNK3 signaling in order to block its action. JNK plays a key role in the first neurodegenerative event, the perturbation of physiological synapse structure and function, known as synaptic dysfunction. Importantly, this is a common mechanism in many different brain pathologies. Synaptic dysfunction and spine loss have been reported to be pharmacologically reversible, opening new therapeutic directions in brain diseases. Being JNK3-detectable at the peripheral level, it could be used as a disease biomarker with the ultimate aim of allowing an early diagnosis of neurodegenerative and neurodevelopment diseases in a still prodromal phase. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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22 pages, 3028 KiB  
Review
Involvement of JNK1 in Neuronal Polarization During Brain Development
by Rubén Darío Castro-Torres, Oriol Busquets, Antoni Parcerisas, Ester Verdaguer, Jordi Olloquequi, Miren Ettcheto, Carlos Beas-Zarate, Jaume Folch, Antoni Camins and Carme Auladell
Cells 2020, 9(8), 1897; https://doi.org/10.3390/cells9081897 - 13 Aug 2020
Cited by 9 | Viewed by 4712
Abstract
The c-Jun N-terminal Kinases (JNKs) are a group of regulatory elements responsible for the control of a wide array of functions within the cell. In the central nervous system (CNS), JNKs are involved in neuronal polarization, starting from the cell division of neural [...] Read more.
The c-Jun N-terminal Kinases (JNKs) are a group of regulatory elements responsible for the control of a wide array of functions within the cell. In the central nervous system (CNS), JNKs are involved in neuronal polarization, starting from the cell division of neural stem cells and ending with their final positioning when migrating and maturing. This review will focus mostly on isoform JNK1, the foremost contributor of total JNK activity in the CNS. Throughout the text, research from multiple groups will be summarized and discussed in order to describe the involvement of the JNKs in the different steps of neuronal polarization. The data presented support the idea that isoform JNK1 is highly relevant to the regulation of many of the processes that occur in neuronal development in the CNS. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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19 pages, 350 KiB  
Review
Biological Properties of JNK3 and Its Function in Neurons, Astrocytes, Pancreatic β-Cells and Cardiovascular Cells
by Rei Nakano, Tomohiro Nakayama and Hiroshi Sugiya
Cells 2020, 9(8), 1802; https://doi.org/10.3390/cells9081802 - 29 Jul 2020
Cited by 25 | Viewed by 4093
Abstract
JNK is a protein kinase, which induces transactivation of c-jun. The three isoforms of JNK, JNK1, JNK2, and JNK3, are encoded by three distinct genes. JNK1 and JNK2 are expressed ubiquitously throughout the body. By contrast, the expression of JNK3 is limited and [...] Read more.
JNK is a protein kinase, which induces transactivation of c-jun. The three isoforms of JNK, JNK1, JNK2, and JNK3, are encoded by three distinct genes. JNK1 and JNK2 are expressed ubiquitously throughout the body. By contrast, the expression of JNK3 is limited and observed mainly in the brain, heart, and testes. Concerning the biological properties of JNKs, the contribution of upstream regulators and scaffold proteins plays an important role in the activation of JNKs. Since JNK signaling has been described as a form of stress-response signaling, the contribution of JNK3 to pathophysiological events, such as stress response or cell death including apoptosis, has been well studied. However, JNK3 also regulates the physiological functions of neurons and non-neuronal cells, such as development, regeneration, and differentiation/reprogramming. In this review, we shed light on the physiological functions of JNK3. In addition, we summarize recent advances in the knowledge regarding interactions between JNK3 and cellular reprogramming. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
22 pages, 2119 KiB  
Review
The JNK Signaling Pathway in Inflammatory Skin Disorders and Cancer
by Manel B. Hammouda, Amy E. Ford, Yuan Liu and Jennifer Y. Zhang
Cells 2020, 9(4), 857; https://doi.org/10.3390/cells9040857 - 2 Apr 2020
Cited by 168 | Viewed by 20806
Abstract
The c-Jun N-terminal kinases (JNKs), with its members JNK1, JNK2, and JNK3, is a subfamily of (MAPK) mitogen-activated protein kinases. JNK signaling regulates a wide range of cellular processes, including cell proliferation, differentiation, survival, apoptosis, and inflammation. Dysregulation of JNK pathway is associated [...] Read more.
The c-Jun N-terminal kinases (JNKs), with its members JNK1, JNK2, and JNK3, is a subfamily of (MAPK) mitogen-activated protein kinases. JNK signaling regulates a wide range of cellular processes, including cell proliferation, differentiation, survival, apoptosis, and inflammation. Dysregulation of JNK pathway is associated with a wide range of immune disorders and cancer. Our objective is to provide a review of JNK proteins and their upstream regulators and downstream effector molecules in common skin disorders, including psoriasis, dermal fibrosis, scleroderma, basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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31 pages, 1088 KiB  
Review
Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes
by Justin Hou Ming Yung and Adria Giacca
Cells 2020, 9(3), 706; https://doi.org/10.3390/cells9030706 - 13 Mar 2020
Cited by 147 | Viewed by 10877
Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines [...] Read more.
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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24 pages, 2047 KiB  
Review
JNK Signaling Pathway Involvement in Spinal Cord Neuron Development and Death
by Roberta Schellino, Marina Boido and Alessandro Vercelli
Cells 2019, 8(12), 1576; https://doi.org/10.3390/cells8121576 - 5 Dec 2019
Cited by 43 | Viewed by 9240
Abstract
The c-Jun NH2-terminal protein kinase (JNK) is a Janus-faced kinase, which, in the nervous system, plays important roles in a broad range of physiological and pathological processes. Three genes, encoding for 10 JNK isoforms, have been identified: jnk1, jnk2, and jnk3 [...] Read more.
The c-Jun NH2-terminal protein kinase (JNK) is a Janus-faced kinase, which, in the nervous system, plays important roles in a broad range of physiological and pathological processes. Three genes, encoding for 10 JNK isoforms, have been identified: jnk1, jnk2, and jnk3. In the developing spinal cord, JNK proteins control neuronal polarity, axon growth/pathfinding, and programmed cell death; in adulthood they can drive degeneration and regeneration, after pathological insults. Indeed, recent studies have highlighted a role for JNK in motor neuron (MN) diseases, such as amyotrophic lateral sclerosis and spinal muscular atrophy. In this review we discuss how JNK-dependent signaling regulates apparently contradictory functions in the spinal cord, in both the developmental and adult stages. In addition, we examine the evidence that the specific targeting of JNK signaling pathway may represent a promising therapeutic strategy for the treatment of MN diseases. Full article
(This article belongs to the Special Issue Role of c-Jun N-terminal Kinase (JNK) Signaling in Biological Diseases)
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