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MAPK in Health and Disease

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

Deadline for manuscript submissions: closed (31 January 2023) | Viewed by 19962

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Dr. Francisco Centeno

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Guest Editor

Department of Biochemistry, Molecular Biology and Genetics, Faculty of Sciences, University of Extremadura, 06006 Badajoz, Spain
Interests: cellular signaling; MAPK; ERK; JNK; p38; cell differentiation; cell polarity; respiratory epithelium; neurodegeneration; apoptosis

Special Issue Information

Dear Colleagues,

MAPK (mitogen-activated protein kinase) signaling pathways regulate a variety of biological processes through very different mechanisms. In mammalians, seven subgroups have been identified, i.e., the four conventional MAPK subgroups extracellular-regulated kinase (ERK1/2), C-Jun N-terminal kinase (JNK), p38 MAPK, and ERK5, and three atypical MAPK subgroups, ERK3/4, ERK7/8, and nemo-like kinase (NLK). MAPKs play a pivotal role in converting extracellular stimuli into a wide range of cellular responses, including cell growth, migration, proliferation, differentiation, and apoptosis, among others.

In “MAPK in Health and Disease”, we welcome original research and review articles in the field, with a focus on but not limited to the molecular mechanics for MAPK activation, MAPK genomics and proteomics, new MAPK substrates, MAPK crosstalk, and the physiological role of MAPKs and MAPK-associated pathogenesis.

Sincerely,

Dr. Francisco Centeno
Guest Editor

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Keywords

MAPK
ERK
p38
JNK
SAPK
cell growth
cell migration
cell proliferation
cell differentiation
apoptosis

Published Papers (6 papers)

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Research

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18 pages, 17407 KiB

Open AccessArticle

Sonidegib Suppresses Production of Inflammatory Mediators and Cell Migration in BV2 Microglial Cells and Mice Treated with Lipopolysaccharide via JNK and NF-κB Inhibition

by Ngoc Minh Nguyen, Men Thi Hoai Duong, Bich Phuong Bui, Phuong Linh Nguyen, Xiaozhen Chen, Jungsook Cho and Hee-Chul Ahn

Int. J. Mol. Sci. 2022, 23(18), 10590; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231810590 - 13 Sep 2022

Viewed by 1675

Abstract

Our structure-based virtual screening of the FDA-approved drug library has revealed that sonidegib, a smoothened antagonist clinically used to treat basal cell carcinoma, is a potential c-Jun N-terminal kinase 3 (JNK3) inhibitor. This study investigated the binding of sonidegib to JNK3 via ¹⁹F NMR and its inhibitory effect on JNK phosphorylation in BV2 cells. Pharmacological properties of sonidegib to exert anti-inflammatory and anti-migratory effects were also characterized. We found that sonidegib bound to the ATP binding site of JNK3 and inhibited JNK phosphorylation in BV2 cells, confirming our virtual screening results. Sonidegib also inhibited the phosphorylation of MKK4 and c-Jun, the upstream and downstream signals of JNK, respectively. It reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory factors, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO), and the expression of inducible NO synthase and cyclooxygenase-2. The LPS-induced cell migration was suppressed by sonidegib. Sonidegib inhibited the LPS-induced IκBα phosphorylation, thereby blocking NF-κB nuclear translocation. Consistent with these findings, orally administered sonidegib attenuated IL-6 and TNF-α levels in the brains of LPS-treated mice. Collectively, our results indicate that sonidegib suppresses inflammation and cell migration in LPS-treated BV2 cells and mice by inhibiting JNK and NF-κB signaling. Therefore, sonidegib may be implicated for drug repurposing to alleviate neuroinflammation associated with microglial activation. Full article

(This article belongs to the Special Issue MAPK in Health and Disease)

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15 pages, 2533 KiB

Open AccessArticle

Effect of Extracellular Signal-Regulated Protein Kinase 5 Inhibition in Clear Cell Renal Cell Carcinoma

by Hidenori Kanno, Sei Naito, Yutaro Obara, Hiromi Ito, Osamu Ichiyanagi, Takafumi Narisawa, Tomoyuki Kato, Akira Nagaoka and Norihiko Tsuchiya

Int. J. Mol. Sci. 2022, 23(15), 8448; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158448 - 30 Jul 2022

Cited by 1 | Viewed by 1424

Abstract

(1) Background: Extracellular signal-regulating kinase 5 (ERK5) has been implicated in many cellular functions, including survival, proliferation, and vascularization. Our objectives were to examine the expression and effect of ERK5 in clear cell renal cell carcinoma (ccRCC). (2) Methods: The expressions of ERK5 and its regulating micro-RNA miR-143 were investigated using immunohistochemistry and quantitative reverse transcriptase PCR in surgical specimens of ccRCC patients. With invitro and in vivo studies, we used pharmacologic ERK5 inhibitor XMD8-92, RNA interference, pre-miR-143 transduction, Western blotting, MTS assay, apoptosis assay, and subcutaneous xenograft model. (3) Results: A strong ERK5 expression in surgical specimen was associated with high-grade (p = 0.01), high-recurrence free rate (p = 0.02), and high cancer-specific survival (p = 0.03). Expression levels of ERK5 and miR-143 expression level were correlated (p = 0.049). Pre-miR-143 transduction into ccRCC cell A498 suppressed ERK5 expression. ERK5 inhibition enhanced cyclin-dependent kinase inhibitor p21 expression and decreased anti-apoptotic molecules BCL2, resulting in decreased cell proliferation and survival both in ccRCC and endothelial cells. In the xenograft model, ERK5 inhibitor XMD8-92 suppressed tumor growth. (4) Conclusions: ERK5 is regulated by miR-143, and ERK5 inhibition is a promising target for ccRCC treatment. Full article

(This article belongs to the Special Issue MAPK in Health and Disease)

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23 pages, 8435 KiB

Open AccessArticle

Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial Cells via a Ca²⁺-Regulated ERK1/2-Activating Pathway

by Jhe-Wei Lin, Yi-Chun Lin, Jui-Ming Liu, Shing-Hwa Liu, Kai-Min Fang, Ren-Jun Hsu, Chun-Fa Huang, Kai-Yao Chang, Kuan-I Lee, Kai-Chih Chang, Chin-Chuan Su and Ya-Wen Chen

Int. J. Mol. Sci. 2022, 23(9), 4666; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094666 - 23 Apr 2022

Cited by 3 | Viewed by 2899

Abstract

Ketamine-associated cystitis is characterized by suburothelial inflammation and urothelial cell death. Norketamine (NK), the main metabolite of ketamine, is abundant in urine following ketamine exposure. NK has been speculated to exert toxic effects in urothelial cells, similarly to ketamine. However, the molecular mechanisms contributing to NK-induced urothelial cytotoxicity are almost unclear. Here, we aimed to investigate the toxic effects of NK and the potential mechanisms underlying NK-induced urothelial cell injury. In this study, NK exposure significantly reduced cell viability and induced apoptosis in human urinary bladder epithelial-derived RT4 cells that NK (0.01–0.5 mM) exhibited greater cytotoxicity than ketamine (0.1–3 mM). Signals of mitochondrial dysfunction, including mitochondrial membrane potential (MMP) loss and cytosolic cytochrome c release, were found to be involved in NK-induced cell apoptosis and death. NK exposure of cells also triggered the expression of endoplasmic reticulum (ER) stress-related proteins including GRP78, CHOP, XBP-1, ATF-4 and -6, caspase-12, PERK, eIF-2α, and IRE-1. Pretreatment with 4-phenylbutyric acid (an ER stress inhibitor) markedly prevented the expression of ER stress-related proteins and apoptotic events in NK-exposed cells. Additionally, NK exposure significantly activated JNK, ERK1/2, and p38 signaling and increased intracellular calcium concentrations ([Ca²⁺]_i). Pretreatment of cells with both PD98059 (an ERK1/2 inhibitor) and BAPTA/AM (a cell-permeable Ca²⁺ chelator), but not SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), effectively suppressed NK-induced mitochondrial dysfunction, ER stress-related signals, and apoptotic events. The elevation of [Ca²⁺]_i in NK-exposed cells could be obviously inhibited by BAPTA/AM, but not PD98059. Taken together, these findings suggest that NK exposure exerts urothelial cytotoxicity via a [Ca²⁺]_i-regulated ERK1/2 activation, which is involved in downstream mediation of the mitochondria-dependent and ER stress-triggered apoptotic pathway, consequently resulting in urothelial cell death. Our findings suggest that regulating [Ca²⁺]_i/ERK signaling pathways may be a promising strategy for treatment of NK-induced urothelial cystitis. Full article

(This article belongs to the Special Issue MAPK in Health and Disease)

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22 pages, 2935 KiB

Open AccessArticle

Systematic Discovery of FBXW7-Binding Phosphodegrons Highlights Mitogen-Activated Protein Kinases as Important Regulators of Intracellular Protein Levels

by Neha Singh, András Zeke and Attila Reményi

Int. J. Mol. Sci. 2022, 23(6), 3320; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23063320 - 19 Mar 2022

Cited by 5 | Viewed by 3138

Abstract

A FBXW7 is an F-box E3 ubiquitin-ligase affecting cell growth by controlling protein degradation. Mechanistically, its effect on its substrates depends on the phosphorylation of degron motifs, but the abundance of these phosphodegrons has not been systematically explored. We used a ratiometric protein degradation assay geared towards the identification of FBXW7-binding degron motifs phosphorylated by mitogen-activated protein kinases (MAPKs). Most of the known FBXW7 targets are localized in the nucleus and function as transcription factors. Here, in addition to more transcription affecting factors (ETV5, KLF4, SP5, JAZF1, and ZMIZ1 CAMTA2), we identified phosphodegrons located in proteins involved in chromatin regulation (ARID4B, KMT2E, KMT2D, and KAT6B) or cytoskeletal regulation (MAP2, Myozenin-2, SMTL2, and AKAP11), and some other proteins with miscellaneous functions (EIF4G3, CDT1, and CCAR2). We show that the protein level of full-length ARID4B, ETV5, JAZF1, and ZMIZ1 are affected by different MAPKs since their FBXW7-mediated degradation was diminished in the presence of MAPK-specific inhibitors. Our results suggest that MAPK and FBXW7 partnership plays an important cellular role by directly affecting the level of key regulatory proteins. The data also suggest that the p38α-controlled phosphodegron in JAZF1 may be responsible for the pathological regulation of the cancer-related JAZF1-SUZ12 fusion construct implicated in endometrial stromal sarcoma. Full article

(This article belongs to the Special Issue MAPK in Health and Disease)

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17 pages, 2840 KiB

Open AccessArticle

ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke

by Constanze Schanbacher, Michael Bieber, Yvonne Reinders, Deya Cherpokova, Christina Teichert, Bernhard Nieswandt, Albert Sickmann, Christoph Kleinschnitz, Friederike Langhauser and Kristina Lorenz

Int. J. Mol. Sci. 2022, 23(2), 706; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23020706 - 09 Jan 2022

Cited by 4 | Viewed by 2173

Abstract

Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2^wt) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIP^wt) and its phosphorylation-deficient mutant RKIP^S153A, known inhibitors of the ERK1/2 signaling cascade. RKIP^wt and RKIP^S153A attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke. Full article

(This article belongs to the Special Issue MAPK in Health and Disease)

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Review

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21 pages, 1403 KiB

Open AccessReview

MAPK/ERK Pathway as a Central Regulator in Vertebrate Organ Regeneration

by Xiaomin Wen, Lindi Jiao and Hong Tan

Int. J. Mol. Sci. 2022, 23(3), 1464; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23031464 - 27 Jan 2022

Cited by 39 | Viewed by 7518

Abstract

Damage to organs by trauma, infection, diseases, congenital defects, aging, and other injuries causes organ malfunction and is life-threatening under serious conditions. Some of the lower order vertebrates such as zebrafish, salamanders, and chicks possess superior organ regenerative capacity over mammals. The extracellular signal-regulated kinases 1 and 2 (ERK1/2), as key members of the mitogen-activated protein kinase (MAPK) family, are serine/threonine protein kinases that are phylogenetically conserved among vertebrate taxa. MAPK/ERK signaling is an irreplaceable player participating in diverse biological activities through phosphorylating a broad variety of substrates in the cytoplasm as well as inside the nucleus. Current evidence supports a central role of the MAPK/ERK pathway during organ regeneration processes. MAPK/ERK signaling is rapidly excited in response to injury stimuli and coordinates essential pro-regenerative cellular events including cell survival, cell fate turnover, migration, proliferation, growth, and transcriptional and translational activities. In this literature review, we recapitulated the multifaceted MAPK/ERK signaling regulations, its dynamic spatio-temporal activities, and the profound roles during multiple organ regeneration, including appendages, heart, liver, eye, and peripheral/central nervous system, illuminating the possibility of MAPK/ERK signaling as a critical mechanism underlying the vastly differential regenerative capacities among vertebrate species, as well as its potential applications in tissue engineering and regenerative medicine. Full article

(This article belongs to the Special Issue MAPK in Health and Disease)

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