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Function and Mechanisms of JNK Pathway
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Function and Mechanisms of JNK Pathway

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 (30 June 2021) | Viewed by 37527

Special Issue Editors

Dr. Carme Auladell

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Guest Editor
Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, University of Barcelona, E-08028 Barcelona, Spain
Interests: JNK in genome expression/gene transcription; JNK in tumorogenesis and regeneration; JNK in metabolism; JNK in immunity; JNK in oxidative stress; JNK in apoptotic cell death mechanisms; JNK in inflammatory processes; JNK in adult brain physiological process; JNK in CNS development (embryonic and postnatal stages); JNK and neuroplasticity; JNK in brain diseases; JNK as a therapeutic target for various biological diseases
Dr. Ester Verdaguer

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Guest Editor
Department of Cell Biology, Physiology and Immunology, Institute of Neurosciences, University of Barcelona, E-08028 Barcelona, Spain

Special Issue Information

Dear Colleagues,

JNKs are members of a large group of serine/threonine-directed kinases known as mitogen-activated protein kinases (MAPKs). JNKs are important transducing enzymes that are involved in many biological activities, including cell death and cell survival, inflammatory responses, morphogenesis, cytoskeletal changes, cell proliferation, differentiation, as well as gene expression. Different stress conditions might activate JNK signaling pathway, along with inflammatory signals, growth factors, changes in levels of reactive oxygen species, protein synthesis inhibitors, between other stimuli. In the central nervous system (CNS), JNK activity may be important in developmental stages and in adulthood in situations of absence of stress. Thus in CNS, JNKs are key regulators of brain morphogenesis and developmental death, neuronal migration and pathfinding, axodendritic architecture and synaptic plasticity, with a central role in cognitive function. Different approaches have considered specific proteins of the JNK pathway as a potential therapeutic targets/biomarker to treat human diseases such as diabetes, neurodegenerative conditions, cancer and diseases related with inflammation.

In mammals, there are three genes, namely jnk1 (MAPK8), jnk2 (MAPK9), and jnk3 (MAPK10), that encode for 10 different JNK splice variants. The JNKs activation occurs, after stimulation, through sequentially phosphorylation cascade of three kinases family (MAPK kinase kinase which phosphorylate and activate members of the MAPK kinase family that activate by phosphorylation MAPK proteins). This sequential phosphorylation cascade is facilitated by scaffold JNK-interacting proteins (JIP). The post-translation mechanisms such as acetylation and ubiquitination of members of the MAPK cascade can also affect MAPK activation. The inactivation of this pathway is regulated by MAPK phosphatases (MKPs). More than 50 proteins, located in the cytoplasm and in the nucleus, have been classified as substrates, explaining the elevate range of JNK biological functions.

Dr. Carme Auladell
Dr. Ester Verdaguer
Guest Editors

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Keywords

  • c-Jun N-terminal kinase (JNK)
  • cell death
  • inflammation
  • survival
  • insulin resistance
  • brain development
  • gene transcription
  • tumorigenesis

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Published Papers (8 papers)

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Research

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13 pages, 3879 KiB  
Article
Colocalization and Interaction Study of Neuronal JNK3, JIP1, and β-Arrestin2 Together with PSD95
by Clara Alice Musi, Giacomo Marchini, Arianna Giani, Giovanni Tomaselli, Erica Cecilia Priori, Luca Colnaghi and Tiziana Borsello
Int. J. Mol. Sci. 2022, 23(8), 4113; https://doi.org/10.3390/ijms23084113 - 8 Apr 2022
Cited by 3 | Viewed by 2720
Abstract
c-Jun N-terminal kinases (JNKs) are stress-activated serine/threonine protein kinases belonging to the mitogen-activated protein kinase (MAPK) family. Among them, JNK3 is selectively expressed in the central nervous system, cardiac smooth muscle, and testis. In addition, it is the most responsive JNK isoform to [...] Read more.
c-Jun N-terminal kinases (JNKs) are stress-activated serine/threonine protein kinases belonging to the mitogen-activated protein kinase (MAPK) family. Among them, JNK3 is selectively expressed in the central nervous system, cardiac smooth muscle, and testis. In addition, it is the most responsive JNK isoform to stress stimuli in the brain, and it is involved in synaptic dysfunction, an essential step in neurodegenerative processes. JNK3 pathway is organized in a cascade of amplification in which signal transduction occurs by stepwise, highly controlled phosphorylation. Since different MAPKs share common upstream activators, pathway specificity is guaranteed by scaffold proteins such as JIP1 and β-arrestin2. To better elucidate the physiological mechanisms regulating JNK3 in neurons, and how these interactions may be involved in synaptic (dys)function, we used (i) super-resolution microscopy to demonstrate the colocalization among JNK3–PSD95–JIP1 and JNK3–PSD95–β-arrestin2 in cultured hippocampal neurons, and (ii) co-immunoprecipitation techniques to show that the two scaffold proteins and JNK3 can be found interacting together with PSD95. The protein-protein interactions that govern the formation of these two complexes, JNK3–PSD95–JIP1 and JNK3–PSD95–β-arrestin2, may be used as targets to interfere with their downstream synaptic events. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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23 pages, 4873 KiB  
Article
Dissection of the Regulatory Elements of the Complex Expression Pattern of Puckered, a Dual-Specificity JNK Phosphatase
by Katerina Karkali and Enrique Martin-Blanco
Int. J. Mol. Sci. 2021, 22(22), 12205; https://doi.org/10.3390/ijms222212205 - 11 Nov 2021
Cited by 1 | Viewed by 2456
Abstract
For developmental processes, we know most of the gene networks controlling specific cell responses. We still have to determine how these networks cooperate and how signals become integrated. The JNK pathway is one of the key elements modulating cellular responses during development. Yet, [...] Read more.
For developmental processes, we know most of the gene networks controlling specific cell responses. We still have to determine how these networks cooperate and how signals become integrated. The JNK pathway is one of the key elements modulating cellular responses during development. Yet, we still know little about how the core components of the pathway interact with additional regulators or how this network modulates cellular responses in the whole organism in homeostasis or during tissue morphogenesis. We have performed a promoter analysis, searching for potential regulatory sequences of puckered (puc) and identified different specific enhancers directing gene expression in different tissues and at different developmental times. Remarkably, some of these domains respond to the JNK activity, but not all. Altogether, these analyses show that puc expression regulation is very complex and that JNK activities participate in non-previously known processes during the development of Drosophila. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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18 pages, 27414 KiB  
Article
Dual Mkk4 and Mkk7 Gene Deletion in Adult Mouse Causes an Impairment of Hippocampal Immature Granule Cells
by Rubén Darío Castro-Torres, Jordi Olloquequi, Miren Etchetto, Pablo Caruana, Luke Steele, Kyra-Mae Leighton, Jesús Ureña, Carlos Beas-Zarate, Antoni Camins, Ester Verdaguer and Carme Auladell
Int. J. Mol. Sci. 2021, 22(17), 9545; https://doi.org/10.3390/ijms22179545 - 2 Sep 2021
Cited by 4 | Viewed by 3150
Abstract
(1) Background: The c-Jun-NH2-terminal protein kinase (JNK) is a mitogen-activated protein kinase involved in regulating physiological processes in the central nervous system. However, the dual genetic deletion of Mkk4 and Mkk7 (upstream activators of JNK) in adult mice is not reported. The aim [...] Read more.
(1) Background: The c-Jun-NH2-terminal protein kinase (JNK) is a mitogen-activated protein kinase involved in regulating physiological processes in the central nervous system. However, the dual genetic deletion of Mkk4 and Mkk7 (upstream activators of JNK) in adult mice is not reported. The aim of this study was to induce the genetic deletion of Mkk4/Mkk7 in adult mice and analyze their effect in hippocampal neurogenesis. (2) Methods: To achieve this goal, Actin-CreERT2 (Cre+/−), Mkk4flox/flox, Mkk7flox/flox mice were created. The administration of tamoxifen in these 2-month-old mice induced the gene deletion (Actin-CreERT2 (Cre+/−), Mkk4∆/∆, Mkk7∆/∆ genotype), which was verified by PCR, Western blot, and immunohistochemistry techniques. (3) Results: The levels of MKK4/MKK7 at 7 and 14 days after tamoxifen administration were not eliminated totally in CNS, unlike what happens in the liver and heart. These data could be correlated with the high levels of these proteins in CNS. In the hippocampus, the deletion of Mkk4/Mkk7 induced a misalignment position of immature hippocampal neurons together with alterations in their dendritic architecture pattern and maturation process jointly to the diminution of JNK phosphorylation. (4) Conclusion: All these data supported that the MKK4/MKK7–JNK pathway has a role in adult neurogenic activity. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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18 pages, 4122 KiB  
Article
Suppression of LPS-Induced Inflammation and Cell Migration by Azelastine through Inhibition of JNK/NF-κB Pathway in BV2 Microglial Cells
by Phuong Linh Nguyen, Bich Phuong Bui, Men Thi Hoai Duong, Kyeong Lee, Hee-Chul Ahn and Jungsook Cho
Int. J. Mol. Sci. 2021, 22(16), 9061; https://doi.org/10.3390/ijms22169061 - 23 Aug 2021
Cited by 23 | Viewed by 4599
Abstract
The c-Jun N-terminal kinases (JNKs) are implicated in many neuropathological conditions, including neurodegenerative diseases. To explore potential JNK3 inhibitors from the U.S. Food and Drug Administration-approved drug library, we performed structure-based virtual screening and identified azelastine (Aze) as one of the candidates. NMR [...] Read more.
The c-Jun N-terminal kinases (JNKs) are implicated in many neuropathological conditions, including neurodegenerative diseases. To explore potential JNK3 inhibitors from the U.S. Food and Drug Administration-approved drug library, we performed structure-based virtual screening and identified azelastine (Aze) as one of the candidates. NMR spectroscopy indicated its direct binding to the ATP-binding site of JNK3, validating our observations. Although the antihistamine effect of Aze is well documented, the involvement of the JNK pathway in its action remains to be elucidated. This study investigated the effects of Aze on lipopolysaccharide (LPS)-induced JNK phosphorylation, pro-inflammatory mediators, and cell migration in BV2 microglial cells. Aze was found to inhibit the LPS-induced phosphorylation of JNK and c-Jun. It also inhibited the LPS-induced production of pro-inflammatory mediators, including interleukin-6, tumor necrosis factor-α, and nitric oxide. Wound healing and transwell migration assays indicated that Aze attenuated LPS-induced BV2 cell migration. Furthermore, Aze inhibited LPS-induced IκB phosphorylation, thereby suppressing nuclear translocation of NF-κB. Collectively, our data demonstrate that Aze exerts anti-inflammatory and anti-migratory effects through inhibition of the JNK/NF-κB pathway in BV2 cells. Based on our findings, Aze may be a potential candidate for drug repurposing to mitigate neuroinflammation in various neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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Review

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15 pages, 2202 KiB  
Review
JNK Signaling in Drosophila Aging and Longevity
by Tian Gan, Lixia Fan, Long Zhao, Mala Misra, Min Liu, Min Zhang and Ying Su
Int. J. Mol. Sci. 2021, 22(17), 9649; https://doi.org/10.3390/ijms22179649 - 6 Sep 2021
Cited by 10 | Viewed by 5968
Abstract
The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global [...] Read more.
The evolutionarily conserved c-Jun N-terminal kinase (JNK) signaling pathway is a critical genetic determinant in the control of longevity. In response to extrinsic and intrinsic stresses, JNK signaling is activated to protect cells from stress damage and promote survival. In Drosophila, global JNK upregulation can delay aging and extend lifespan, whereas tissue/organ-specific manipulation of JNK signaling impacts lifespan in a context-dependent manner. In this review, focusing on several tissues/organs that are highly associated with age-related diseases—including metabolic organs (intestine and fat body), neurons, and muscles—we summarize the distinct effects of tissue/organ-specific JNK signaling on aging and lifespan. We also highlight recent progress in elucidating the molecular mechanisms underlying the tissue-specific effects of JNK activity. Together, these studies highlight an important and comprehensive role for JNK signaling in the regulation of longevity in Drosophila. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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25 pages, 2366 KiB  
Review
Cytoskeleton and Associated Proteins: Pleiotropic JNK Substrates and Regulators
by Béatrice Benoit, Anita Baillet and Christian Poüs
Int. J. Mol. Sci. 2021, 22(16), 8375; https://doi.org/10.3390/ijms22168375 - 4 Aug 2021
Cited by 23 | Viewed by 5290
Abstract
This review extensively reports data from the literature concerning the complex relationships between the stress-induced c-Jun N-terminal kinases (JNKs) and the four main cytoskeleton elements, which are actin filaments, microtubules, intermediate filaments, and septins. To a lesser extent, we also focused on the [...] Read more.
This review extensively reports data from the literature concerning the complex relationships between the stress-induced c-Jun N-terminal kinases (JNKs) and the four main cytoskeleton elements, which are actin filaments, microtubules, intermediate filaments, and septins. To a lesser extent, we also focused on the two membrane-associated cytoskeletons spectrin and ESCRT-III. We gather the mechanisms controlling cytoskeleton-associated JNK activation and the known cytoskeleton-related substrates directly phosphorylated by JNK. We also point out specific locations of the JNK upstream regulators at cytoskeletal components. We finally compile available techniques and tools that could allow a better characterization of the interplay between the different types of cytoskeleton filaments upon JNK-mediated stress and during development. This overview may bring new important information for applied medical research. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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12 pages, 1397 KiB  
Review
The Emerging Roles of JNK Signaling in Drosophila Stem Cell Homeostasis
by Salvador C. Herrera and Erika A. Bach
Int. J. Mol. Sci. 2021, 22(11), 5519; https://doi.org/10.3390/ijms22115519 - 24 May 2021
Cited by 20 | Viewed by 6280
Abstract
The Jun N-terminal kinase (JNK) pathway is an evolutionary conserved kinase cascade best known for its roles during stress-induced apoptosis and tumor progression. Recent findings, however, have identified new roles for this pleiotropic pathway in stem cells during regenerative responses and in cellular [...] Read more.
The Jun N-terminal kinase (JNK) pathway is an evolutionary conserved kinase cascade best known for its roles during stress-induced apoptosis and tumor progression. Recent findings, however, have identified new roles for this pleiotropic pathway in stem cells during regenerative responses and in cellular plasticity. Here, we provide an overview of recent findings about the new roles of JNK signaling in stem cell biology using two well-established Drosophila models: the testis and the intestine. We highlight the pathway’s roles in processes such as proliferation, death, self-renewal and reprogramming, and discuss the known parallels between flies and mammals. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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12 pages, 813 KiB  
Review
JNK Pathway in CNS Pathologies
by Teresa de los Reyes Corrales, María Losada-Pérez and Sergio Casas-Tintó
Int. J. Mol. Sci. 2021, 22(8), 3883; https://doi.org/10.3390/ijms22083883 - 9 Apr 2021
Cited by 40 | Viewed by 5196
Abstract
The c-Jun N-terminal kinase (JNK) signalling pathway is a conserved response to a wide range of internal and external cellular stress signals. Beside the stress response, the JNK pathway is involved in a series of vital regulatory mechanisms during development and adulthood that [...] Read more.
The c-Jun N-terminal kinase (JNK) signalling pathway is a conserved response to a wide range of internal and external cellular stress signals. Beside the stress response, the JNK pathway is involved in a series of vital regulatory mechanisms during development and adulthood that are critical to maintain tissue homeostasis. These mechanisms include the regulation of apoptosis, growth, proliferation, differentiation, migration and invasion. The JNK pathway has a diverse functionality and cell-tissue specificity, and has emerged as a key player in regeneration, tumorigenesis and other pathologies. The JNK pathway is highly active in the central nervous system (CNS), and plays a central role when cells need to cope with pathophysiological insults during development and adulthood. Here, we review the implications of the JNK pathway in pathologies of the CNS. More specifically, we discuss some newly identified examples and mechanisms of JNK-driven tumor progression in glioblastoma, regeneration/repair after an injury, neurodegeneration and neuronal cell death. All these new discoveries support the central role of JNK in CNS pathologies and reinforce the idea of JNK as potential target to reduce their detrimental effects. Full article
(This article belongs to the Special Issue Function and Mechanisms of JNK Pathway)
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