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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 July 2020) | Viewed by 55536

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Special Issue Editors

Dr. Ana Cuenda

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Guest Editor

Department of Immunology and Oncology, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
Interests: signaling; p38MAPK; stress kinases; inflammation; cancer; MAPK

Dr. Juan José Sanz Ezquerro

E-Mail Website
Co-Guest Editor

Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología (CSIC), Madrid, Spain
Interests: signaling; p38; inflammation; regeneration; cancer; embryo development; organogenesis

Special Issue Information

Dear Colleagues,

p38 Mitogen activated protein kinases (p38MAPK) are a group of four protein kinases, which are central for cell adaptation to environmental changes as well as for immune response, inflammation, tissue regeneration, and tumor formation. The p38MAPK family is composed of p38α, p38β, p38γ, and p38δ, p38α being the best characterized, whereas the study of the functions of p38β, p38γ and p38δ has been ignored by most publications. The interest in this group of protein kinases has grown continually since their discovery. Recent studies using new genetic and pharmacological tools are providing helpful information on the function of these stress-activated protein kinases and show that they have an acute impact on the development of prevalent pathologies related to inflammation, diabetes, neurodegeneration, and cancer.

In this Special Issue, we wish to offer a platform for high-quality publications on the latest advances on identification of p38MAPK substrates, functions, and regulation; the characterization of p38MAPK signaling networks and crosstalk; mechanisms underlying the role of p38MAPK in malignant transformation; and therapeutic opportunities associated with regulation of p38MAPK activity.

This issue will be of interest to basic researchers working in cell signaling and immunology and also to chemical biologists interested in drug discovery and clinicians.

Dr. Ana Cuenda
Dr. Juan José Sanz Ezquerro
Guest Editor

Manuscript Submission Information

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Keywords

p38
MAPK
Signaling
Inflammation
Cancer
Inhibitor
Drug discovery

Related Special Issue

P38 Signaling Pathway 2.0 in International Journal of Molecular Sciences (14 articles)

Published Papers (11 papers)

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Editorial

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3 pages, 204 KiB

Open AccessEditorial

p38 Signalling Pathway

by Juan José Sanz-Ezquerro and Ana Cuenda

Int. J. Mol. Sci. 2021, 22(3), 1003; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031003 - 20 Jan 2021

Cited by 11 | Viewed by 2091

Abstract

p38 Mitogen activated protein kinases (p38MAPK) are a highly evolutionary conserved group of protein kinases, which are central for cell adaptation to environmental changes as well as for immune response, inflammation, tissue regeneration, and tumour formation [...] Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

Research

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17 pages, 4133 KiB

Open AccessArticle

Transcriptomic Evaluation of Pulmonary Fibrosis-Related Genes: Utilization of Transgenic Mice with Modifying p38 Signal in the Lungs

by Shuichi Matsuda, Jun-Dal Kim, Fumihiro Sugiyama, Yuji Matsuo, Junji Ishida, Kazuya Murata, Kanako Nakamura, Kana Namiki, Tatsuhiko Sudo, Tomoyuki Kuwaki, Masahiko Hatano, Koichiro Tatsumi, Akiyoshi Fukamizu and Yoshitoshi Kasuya

Int. J. Mol. Sci. 2020, 21(18), 6746; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186746 - 14 Sep 2020

Cited by 7 | Viewed by 4067

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing lung disease that is caused by the dysregulation of alveolar epithelial type II cells (AEC II). The mechanisms involved in the progression of IPF remain incompletely understood, although the immune response accompanied by p38 mitogen-activated protein kinase (MAPK) activation may contribute to some of them. This study aimed to examine the association of p38 activity in the lungs with bleomycin (BLM)-induced pulmonary fibrosis and its transcriptomic profiling. Accordingly, we evaluated BLM-induced pulmonary fibrosis during an active fibrosis phase in three genotypes of mice carrying stepwise variations in intrinsic p38 activity in the AEC II and performed RNA sequencing of their lungs. Stepwise elevation of p38 signaling in the lungs of the three genotypes was correlated with increased severity of BLM-induced pulmonary fibrosis exhibiting reduced static compliance and higher collagen content. Transcriptome analysis of these lung samples also showed that the enhanced p38 signaling in the lungs was associated with increased transcription of the genes driving the p38 MAPK pathway and differentially expressed genes elicited by BLM, including those related to fibrosis as well as the immune system. Our findings underscore the significance of p38 MAPK in the progression of pulmonary fibrosis. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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16 pages, 2400 KiB

Open AccessArticle

P38 Regulates Kainic Acid-Induced Seizure and Neuronal Firing via Kv4.2 Phosphorylation

by Jia-hua Hu, Cole Malloy and Dax A. Hoffman

Int. J. Mol. Sci. 2020, 21(16), 5921; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165921 - 18 Aug 2020

Cited by 7 | Viewed by 3029

Abstract

The subthreshold, transient A-type K⁺ current is a vital regulator of the excitability of neurons throughout the brain. In mammalian hippocampal pyramidal neurons, this current is carried primarily by ion channels comprising Kv4.2 α-subunits. These channels occupy the somatodendritic domains of these principle excitatory neurons and thus regulate membrane voltage relevant to the input–output efficacy of these cells. Owing to their robust control of membrane excitability and ubiquitous expression in the hippocampus, their dysfunction can alter network stability in a manner that manifests in recurrent seizures. Indeed, growing evidence implicates these channels in intractable epilepsies of the temporal lobe, which underscores the importance of determining the molecular mechanisms underlying their regulation and contribution to pathologies. Here, we describe the role of p38 kinase phosphorylation of a C-terminal motif in Kv4.2 in modulating hippocampal neuronal excitability and behavioral seizure strength. Using a combination of biochemical, single-cell electrophysiology, and in vivo seizure techniques, we show that kainic acid-induced seizure induces p38-mediated phosphorylation of Thr607 in Kv4.2 in a time-dependent manner. The pharmacological and genetic disruption of this process reduces neuronal excitability and dampens seizure intensity, illuminating a cellular cascade that may be targeted for therapeutic intervention to mitigate seizure intensity and progression. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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21 pages, 4322 KiB

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The MKK-Dependent Phosphorylation of p38α Is Augmented by Arginine Methylation on Arg49/Arg149 during Erythroid Differentiation

by Mei-Yin Liu, Wei-Kai Hua, Chi-Ju Chen and Wey-Jinq Lin

Int. J. Mol. Sci. 2020, 21(10), 3546; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103546 - 17 May 2020

Cited by 11 | Viewed by 2316

Abstract

The activation of p38 mitogen-activated protein kinases (MAPKs) through a phosphorylation cascade is the canonical mode of regulation. Here, we report a novel activation mechanism for p38α. We show that Arg49 and Arg149 of p38α are methylated by protein arginine methyltransferase 1 (PRMT1). The non-methylation mutations of Lys49/Lys149 abolish the promotive effect of p38α on erythroid differentiation. MAPK kinase 3 (MKK3) is identified as the major p38α upstream kinase and MKK3-mediated activation of the R49/149K mutant p38α is greatly reduced. This is due to a profound reduction in the interaction of p38α and MKK3. PRMT1 can enhance both the methylation level of p38α and its interaction with MKK3. However, the phosphorylation of p38α by MKK3 is not a prerequisite for methylation. MAPK-activated protein kinase 2 (MAPKAPK2) is identified as a p38α downstream effector in the PRMT1-mediated promotion of erythroid differentiation. The interaction of MAPKAPK2 with p38α is also significantly reduced in the R49/149K mutant. Together, this study unveils a novel regulatory mechanism of p38α activation via protein arginine methylation on R49/R149 by PRMT1, which impacts partner interaction and thus promotes erythroid differentiation. This study provides a new insight into the complexity of the regulation of the versatile p38α signaling and suggests new directions in intervening p38α signaling. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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Review

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14 pages, 1004 KiB

Open AccessReview

p38β and Cancer: The Beginning of the Road

by Olga Roche, Diego M. Fernández-Aroca, Elena Arconada-Luque, Natalia García-Flores, Liliana F. Mellor, María José Ruiz-Hidalgo and Ricardo Sánchez-Prieto

Int. J. Mol. Sci. 2020, 21(20), 7524; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21207524 - 12 Oct 2020

Cited by 13 | Viewed by 2656

Abstract

The p38 mitogen-activated protein kinase (MAPK) signaling pathway is implicated in cancer biology and has been widely studied over the past two decades as a potential therapeutic target. Most of the biological and pathological implications of p38MAPK signaling are often associated with p38α (MAPK14). Recently, several members of the p38 family, including p38γ and p38δ, have been shown to play a crucial role in several pathologies including cancer. However, the specific role of p38β (MAPK11) in cancer is still elusive, and further investigation is needed. Here, we summarize what is currently known about the role of p38β in different types of tumors and its putative implication in cancer therapy. All evidence suggests that p38β might be a key player in cancer development, and could be an important therapeutic target in several pathologies, including cancer. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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19 pages, 2167 KiB

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p38 MAPK Pathway in the Heart: New Insights in Health and Disease

by Rafael Romero-Becerra, Ayelén M. Santamans, Cintia Folgueira and Guadalupe Sabio

Int. J. Mol. Sci. 2020, 21(19), 7412; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197412 - 08 Oct 2020

Cited by 69 | Viewed by 6921

Abstract

The p38 mitogen-activated kinase (MAPK) family controls cell adaptation to stress stimuli. p38 function has been studied in depth in relation to cardiac development and function. The first isoform demonstrated to play an important role in cardiac development was p38α; however, all p38 family members are now known to collaborate in different aspects of cardiomyocyte differentiation and growth. p38 family members have been proposed to have protective and deleterious actions in the stressed myocardium, with the outcome of their action in part dependent on the model system under study and the identity of the activated p38 family member. Most studies to date have been performed with inhibitors that are not isoform-specific, and, consequently, knowledge remains very limited about how the different p38s control cardiac physiology and respond to cardiac stress. In this review, we summarize the current understanding of the role of the p38 pathway in cardiac physiology and discuss recent advances in the field. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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17 pages, 614 KiB

Open AccessReview

p38 MAPK in Glucose Metabolism of Skeletal Muscle: Beneficial or Harmful?

by Eyal Bengal, Sharon Aviram and Tony Hayek

Int. J. Mol. Sci. 2020, 21(18), 6480; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186480 - 04 Sep 2020

Cited by 39 | Viewed by 9366

Abstract

Skeletal muscles respond to environmental and physiological changes by varying their size, fiber type, and metabolic properties. P38 mitogen-activated protein kinase (MAPK) is one of several signaling pathways that drive the metabolic adaptation of skeletal muscle to exercise. p38 MAPK also participates in the development of pathological traits resulting from excessive caloric intake and obesity that cause metabolic syndrome and type 2 diabetes (T2D). Whereas p38 MAPK increases insulin-independent glucose uptake and oxidative metabolism in muscles during exercise, it contrastingly mediates insulin resistance and glucose intolerance during metabolic syndrome development. This article provides an overview of the apparent contradicting roles of p38 MAPK in the adaptation of skeletal muscles to exercise and to pathological conditions leading to glucose intolerance and T2D. Here, we focus on the involvement of p38 MAPK in glucose metabolism of skeletal muscle, and discuss the possibility of targeting this pathway to prevent the development of T2D. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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23 pages, 1407 KiB

Open AccessReview

Nuclear P38: Roles in Physiological and Pathological Processes and Regulation of Nuclear Translocation

by Galia Maik-Rachline, Lucia Lifshits and Rony Seger

Int. J. Mol. Sci. 2020, 21(17), 6102; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21176102 - 24 Aug 2020

Cited by 32 | Viewed by 4034

Abstract

The p38 mitogen-activated protein kinase (p38MAPK, termed here p38) cascade is a central signaling pathway that transmits stress and other signals to various intracellular targets in the cytoplasm and nucleus. More than 150 substrates of p38α/β have been identified, and this number is likely to increase. The phosphorylation of these substrates initiates or regulates a large number of cellular processes including transcription, translation, RNA processing and cell cycle progression, as well as degradation and the nuclear translocation of various proteins. Being such a central signaling cascade, its dysregulation is associated with many pathologies, particularly inflammation and cancer. One of the hallmarks of p38α/β signaling is its stimulated nuclear translocation, which occurs shortly after extracellular stimulation. Although p38α/β do not contain nuclear localization or nuclear export signals, they rapidly and robustly translocate to the nucleus, and they are exported back to the cytoplasm within minutes to hours. Here, we describe the physiological and pathological roles of p38α/β phosphorylation, concentrating mainly on the ill-reviewed regulation of p38α/β substrate degradation and nuclear translocation. In addition, we provide information on the p38α/β ′s substrates, concentrating mainly on the nuclear targets and their role in p38α/b functions. Finally, we also provide information on the mechanisms of nuclear p38α/b translocation and its use as a therapeutic target for p38α/β-dependent diseases. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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14 pages, 1223 KiB

Open AccessReview

Involvement of p38 MAPK in Synaptic Function and Dysfunction

by Chiara Falcicchia, Francesca Tozzi, Ottavio Arancio, Daniel Martin Watterson and Nicola Origlia

Int. J. Mol. Sci. 2020, 21(16), 5624; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21165624 - 06 Aug 2020

Cited by 95 | Viewed by 8687

Abstract

Many studies have revealed a central role of p38 MAPK in neuronal plasticity and the regulation of long-term changes in synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). However, p38 MAPK is classically known as a responsive element to stress stimuli, including neuroinflammation. Specific to the pathophysiology of Alzheimer’s disease (AD), several studies have shown that the p38 MAPK cascade is activated either in response to the Aβ peptide or in the presence of tauopathies. Here, we describe the role of p38 MAPK in the regulation of synaptic plasticity and its implication in an animal model of neurodegeneration. In particular, recent evidence suggests the p38 MAPK α isoform as a potential neurotherapeutic target, and specific inhibitors have been developed and have proven to be effective in ameliorating synaptic and memory deficits in AD mouse models. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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19 pages, 844 KiB

Open AccessReview

P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

by Ursula A. Germann and John J. Alam

Int. J. Mol. Sci. 2020, 21(15), 5485; https://doi.org/10.3390/ijms21155485 - 31 Jul 2020

Cited by 23 | Viewed by 4926

Abstract

Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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14 pages, 1496 KiB

Open AccessReview

Is p38 MAPK Associated to Drugs of Abuse-Induced Abnormal Behaviors?

by Rana El Rawas, Inês M. Amaral and Alex Hofer

Int. J. Mol. Sci. 2020, 21(14), 4833; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21144833 - 08 Jul 2020

Cited by 19 | Viewed by 6741

Abstract

The family members of the mitogen-activated protein kinases (MAPK) mediate a wide variety of cellular behaviors in response to extracellular stimuli. p38 MAPKs are key signaling molecules in cellular responses to external stresses and regulation of pro-inflammatory cytokines. Some studies have suggested that p38 MAPK in the region of the nucleus accumbens is involved in abnormal behavioral responses induced by drugs of abuse. In this review, we discuss the role of the p38 MAPK in the rewarding effects of drugs of abuse. We also summarize the implication of p38 MAPK in stress, anxiety, and depression. We opine that p38 MAPK activation is more closely associated to stress-induced aversive responses rather than drug effects per se, in particular cocaine. p38 MAPK is only involved in cocaine reward, predominantly when promoted by stress. Downstream substrates of p38 that may contribute to the p38 MAPK associated-behavioral responses are proposed. Finally, we suggest p38 MAPK inhibitors as possible therapeutic interventions against stress-related disorders by potentially increasing resilience against stress and addiction relapse induced by adverse experiences. Full article

(This article belongs to the Special Issue P38 Signaling Pathway)

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