Mechanisms and functions of p38 MAPK signalling

2010 ◽  
Vol 429 (3) ◽  
pp. 403-417 ◽  
Author(s):  
Ana Cuadrado ◽  
Angel R. Nebreda
Keyword(s):  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Biological Effects ◽  
Mitogen Activated Protein Kinase ◽  
Wide Range ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
External Signals ◽  
Protein Kinase Signalling ◽  
Genetic Mouse Models

The p38 MAPK (mitogen-activated protein kinase) signalling pathway allows cells to interpret a wide range of external signals and respond appropriately by generating a plethora of different biological effects. The diversity and specificity in cellular outcomes is achieved with an apparently simple linear architecture of the pathway, consisting of a core of three protein kinases acting sequentially. In the present review, we dissect the molecular mechanisms underlying p38 MAPK functions, with special emphasis on the activation and regulation of the core kinases, the interplay with other signalling pathways and the nature of p38 MAPK substrates as a source of functional diversity. Finally, we discuss how genetic mouse models are facilitating the identification of physiological functions for p38 MAPKs, which may impinge on their eventual use as therapeutic targets.

scholarly journals p38δMAPK: Emerging Roles of a Neglected Isoform

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Carol O’Callaghan ◽  
Liam J. Fanning ◽  
Orla P. Barry
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Biological Processes ◽  
Cellular Processes ◽  
Mapk Activity ◽  
Pathological Conditions ◽  
Mapk Signalling ◽  
Mitogen Activated Protein

p38δmitogen activated protein kinase (MAPK) is a unique stress responsive protein kinase. While the p38 MAPK family as a whole has been implicated in a wide variety of biological processes, a specific role for p38δMAPK in cellular signalling and its contribution to both physiological and pathological conditions are presently lacking. Recent emerging evidence, however, provides some insights into specific p38δMAPK signalling. Importantly, these studies have helped to highlight functional similarities as well as differences between p38δMAPK and the other members of the p38 MAPK family of kinases. In this review we discuss the current understanding of the molecular mechanisms underlying p38δMAPK activity. We outline a role for p38δMAPK in important cellular processes such as differentiation and apoptosis as well as pathological conditions such as neurodegenerative disorders, diabetes, and inflammatory disease. Interestingly, disparate roles for p38δMAPK in tumour development have also recently been reported. Thus, we consider evidence which characterises p38δMAPK as both a tumour promoter and a tumour suppressor. In summary, while our knowledge of p38δMAPK has progressed somewhat since its identification in 1997, our understanding of this particular isoform in many cellular processes still strikingly lags behind that of its counterparts.

scholarly journals The TGFβ-induced phosphorylation and activation of p38 mitogen-activated protein kinase is mediated by MAP3K4 and MAP3K10 but not TAK1

Open Biology ◽  
2013 ◽  
Vol 3 (6) ◽  
pp. 130067 ◽  
Author(s):  
Gopal P. Sapkota
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Phosphorylation ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

The signalling pathways downstream of the transforming growth factor beta (TGFβ) family of cytokines play critical roles in all aspects of cellular homeostasis. The phosphorylation and activation of p38 mitogen-activated protein kinase (MAPK) has been implicated in TGFβ-induced epithelial-to-mesenchymal transition and apoptosis. The precise molecular mechanisms by which TGFβ cytokines induce the phosphorylation and activation of p38 MAPK are unclear. In this study, I demonstrate that TGFβ-activated kinase 1 (TAK1/MAP3K7) does not play a role in the TGFβ-induced phosphorylation and activation of p38 MAPK in MEFs and HaCaT keratinocytes. Instead, RNAi -mediated depletion of MAP3K4 and MAP3K10 results in the inhibition of the TGFβ-induced p38 MAPK phosphorylation. Furthermore, the depletion of MAP3K10 from cells homozygously knocked-in with a catalytically inactive mutant of MAP3K4 completely abolishes the TGFβ-induced phosphorylation of p38 MAPK, implying that among MAP3Ks, MAP3K4 and MAP3K10 are sufficient for mediating the TGFβ-induced activation of p38 MAPK.

scholarly journals The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Sônia A. L. Corrêa ◽  
Katherine L. Eales
Keyword(s):  
Neurodegenerative Diseases ◽  
P38 Mapk ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Mechanisms ◽  
Cellular Localisation ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Normal Ageing ◽  
Actin Remodelling

A significant amount of evidence suggests that the p38-mitogen-activated protein kinase (MAPK) signalling cascade plays a crucial role in synaptic plasticity and in neurodegenerative diseases. In this review we will discuss the cellular localisation and activation of p38 MAPK and the recent advances on the molecular and cellular mechanisms of its substrates: MAPKAPK 2 (MK2) and tau protein. In particular we will focus our attention on the understanding of the p38 MAPK-MK2 and p38 MAPK-tau activation axis in controlling neuroinflammation, actin remodelling and tau hyperphosphorylation, processes that are thought to be involved in normal ageing as well as in neurodegenerative diseases. We will also give some insight into how elucidating the precise role of p38 MAPK-MK2 and p38 MAPK-tau signalling cascades may help to identify novel therapeutic targets to slow down the symptoms observed in neurodegenerative diseases such as Alzheimer's and Parkinson's disease.

scholarly journals Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Hayato Nakagawa ◽  
Shin Maeda
Keyword(s):  
Liver Injury ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Effects ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.

The JIP family of MAPK scaffold proteins

2006 ◽  
Vol 34 (5) ◽  
pp. 828-832 ◽  
Author(s):  
A.J. Whitmarsh
Keyword(s):  
Cell Function ◽  
Biochemical Properties ◽  
Scaffold Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Signal Integration ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Β Cell Function ◽  
Insulin Responses ◽  
Protein Kinase Signalling

The components of MAPK (mitogen-activated protein kinase) signalling pathways can assemble into complexes that are co-ordinated by regulatory proteins including scaffold proteins. There is increasing evidence that scaffold proteins (i) maintain signalling specificity and facilitate the activation of pathway components, (ii) localize pathway components to particular subcellular sites or to specific targets, and (iii) serve as a point of signal integration to allow regulation of MAPK pathways by other signalling events in the cell. One family of scaffold proteins that regulate signalling by stress-activated MAPKs are the JIPs [JNK (c-Jun N-terminal kinase)-interacting proteins]. JIP proteins have been demonstrated to form complexes with specific JNK and p38 MAPK signalling modules and to play important roles in brain development, neuronal trafficking, apoptosis, β-cell function and insulin responses. Here, I briefly review our current understanding of the biochemical properties and physiological roles of JIP proteins.

scholarly journals Acanthus ilicifolius L. Treatment for Oral Candidiasis with Immunosuppressive Conditions Subjected to p38 MAPK Enhancement

2021 ◽  
Vol 16 (Supp. 1) ◽  
pp. 17-24
Author(s):  
Dwi Andriani ◽  
Agni Febrina Pargaputri ◽  
Kristanti Parisihni ◽  
Syamsulina Revianti
Keyword(s):  
P38 Mapk ◽  
Potent Inhibitor ◽  
Methanolic Extract ◽  
Oral Candidiasis ◽  
Mitogen Activated Protein Kinase ◽  
Immunohistochemical Examination ◽  
Acanthus Ilicifolius ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
One Way Anova

Methanolic extract from the leaves of Acanthus ilicifolius L. (A. ilicifolius L.) is a potent inhibitor of Candida albicans (C. albicans) growth and anti-inflammatory. C. albicans causes oral candidiasis in immunosuppressive condition. Mitogen-activated protein kinase (MAPK) signalling via p38 appears to discriminate between yeast and hyphal cells of C. albicans. Activation of p38 MAPK by hyphae results in the upregulation of proinflammatory cytokines. The p38 MAPK activation is known to impair corticosteroid action. The research was conducted to investigate the effect of methanolic extract A. ilicifolius L. treatment of oral candidiasis with the immunosuppressive condition through enhancement of p38 MAPK expression in the epithelial cells. Immunosuppressed conditions were obtained when 16 healthy male Rattus norvergicus (Wistar) was given oral administration of dexamethasone and tetracycline for 14 days and induced with C. albicans (ATCC-10231) 1 McFarland. The subjects were divided into four groups (n = 4/group): immunosuppression (IS), immunosuppression with oral candidiasis without treatment (ISC), immunosuppression with oral candidiasis and nystatin treatment (ISC+N), and immunosuppression with oral candidiasis and A. ilicifolius L. treatment (ISC+AI), and were treated for 14 days. Later, the rats were euthanised, and their tongue were biopsied. The p38 MAPK expression was subjected to immunohistochemical examination, observed under a microscope (400× magnification) and statistically analysed (one-way ANOVA, LSD-test, p < 0.05). The p38 MAPK expression of ISC+AI (36.05 ± 1.54) was higher than IS (26 ± 2.32), ISC (26.4 ± 3.71), IS+N (34.2 ± 0.99). Significant differences existed between ISC+AI and ISC+N to IS and ISC (p < 0.05). No significant differences were present between IS and ISC; ISC+AI and ISC+N (p > 0.05). Therefore, this treatment could enhance p38 MAPK expression in oral candidiasis with the immunosuppressed condition.

272. Signalling pathways involved in mouse GDF9 and BMP15 stimulated thymidine uptake by rat granulosa cells

2008 ◽  
Vol 20 (9) ◽  
pp. 72
Author(s):  
K. L. Reader ◽  
C. J. McIntosh ◽  
J. L. Juengel
Keyword(s):  
P38 Mapk ◽  
Granulosa Cells ◽  
Molecular Mechanisms ◽  
Thymidine Incorporation ◽  
Fold Increase ◽  
Fertility Control ◽  
Mitogen Activated Protein Kinase ◽  
Thymidine Uptake ◽  
Cooperative Effects ◽  
Mitogen Activated Protein

The oocyte-secreted factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are essential for ovarian follicular growth and development. Understanding the molecular mechanisms of these factors could assist with the development of future products for fertility control. Thymidine uptake by rat granulosa cells is stimulated cooperatively by GDF9 and BMP15. Inhibitors of the activin receptor-like kinase (ALK) 4,5,7 and the nuclear factor kappaB (NFKB) second messenger pathways block ovine GDF9 and BMP15 stimulated thymidine incorporation. The ALK 4,5,7 receptor pathway is known to be essential for the cooperative effects of mouse (m)GDF9 and mBMP15 on thymidine incorporation but the role of other pathways has yet to be determined, which was the focus of this study. Inhibitors of NFKB (Sn50; 10µg/mL), ALK 2,3,6 receptor (Dorsomorphin; 1µM), p38 mitogen-activated protein kinase (p38 MAPK; SB239063; 5 µM) and c-Jun-N-terminal kinase (JNK; TAT-TI-JIP153–163; 5 µM) pathways were each cultured with recombinant mGDF9 (25 ng/mL) and mBMP15 (6 ng/mL) in a rat granulosa cell [3H]-thymidine bioassay. The p38 MAPK inhibitor caused partial inhibition of thymidine uptake but this appeared to be non-specific as a similar level of suppression was observed in the control cultures. Neither the ALK 2,3,6 receptor nor the NFKB pathway inhibitors had any effect on mGDF9 and mBMP15 stimulated thymidine uptake. The JNK inhibitor showed a 1.7-fold increase in stimulation above the mGDF9 and mBMP15 effect (P < 0.01) but a similar stimulation was also observed in some controls. This differs from the results observed with ovine GDF9 and BMP15 where thymidine uptake was completely blocked by the NFKB inhibitor and the JNK inhibitor had no effect. In conclusion, the molecular mechanisms of GDF9 and BMP15 function are dependent on the species of origin of the growth factor and therefore caution is needed when extrapolating findings from one species to another.

scholarly journals New targets of urocortin-mediated cardioprotection

2010 ◽  
Vol 45 (2) ◽  
pp. 69-85 ◽  
Author(s):  
Seán P Barry ◽  
Kevin M Lawrence ◽  
James McCormick ◽  
Surinder M Soond ◽  
Mike Hubank ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Nuclear Factor ◽  
Free Radical Damage ◽  
Apoptosis Protein ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Crh Receptors

The urocortin (UCN) hormones UCN1 and UCN2 have been shown previously to confer significant protection against myocardial ischaemia/reperfusion (I/R) injury; however, the molecular mechanisms underlying their action are poorly understood. To further define the transcriptional effect of UCNs that underpins their cardioprotective activity, a microarray analysis was carried out using an in vivo rat coronary occlusion model of I/R injury. Infusion of UCN1 or UCN2 before the onset of reperfusion resulted in the differential regulation of 66 and 141 genes respectively, the majority of which have not been described previously. Functional analysis demonstrated that UCN-regulated genes are involved in a wide range of biological responses, including cell death (e.g. X-linked inhibitor of apoptosis protein), oxidative stress (e.g. nuclear factor erythroid derived 2-related factor 1/nuclear factor erythroid derived 2-like 1) and metabolism (e.g. Prkaa2/AMPK). In addition, both UCN1 and UCN2 were found to modulate the expression of a host of genes involved in G-protein-coupled receptor (GPCR) signalling including Rac2, Gnb1, Dab2ip (AIP1), Ralgds, Rnd3, Rap1a and PKA, thereby revealing previously unrecognised signalling intermediates downstream of CRH receptors. Moreover, several of these GPCR-related genes have been shown previously to be involved in mitogen-activated protein kinase (MAPK) activation, suggesting a link between CRH receptors and induction of MAPKs. In addition, we have shown that both UCN1 and UCN2 significantly reduce free radical damage following myocardial infarction, and comparison of the UCN gene signatures with that of the anti-oxidant tempol revealed a significant overlap. These data uncover novel gene expression changes induced by UCNs, which will serve as a platform to further understand their mechanism of action in normal physiology and cardioprotection.

scholarly journals Mechanisms of MAPK signalling specificity

2006 ◽  
Vol 34 (5) ◽  
pp. 837-841 ◽  
Author(s):  
L. Bardwell
Keyword(s):  
Cellular Response ◽  
Short Review ◽  
Feedback Loops ◽  
Scaffold Proteins ◽  
Mitogen Activated Protein Kinase ◽  
Signalling Pathways ◽  
Regulatory Circuits ◽  
Mapk Signalling ◽  
Mitogen Activated Protein ◽  
Protein Kinase Signalling

MAPK (mitogen-activated protein kinase) signalling pathways contribute to the regulation of diverse responses, including normal and pathological aspects of cell growth, division, differentiation and death. Their ubiquity and versatility raise the issue of how they achieve specific coupling of signal with cellular response. How do the kinases in the cascade distinguish their correct substrates from the vast excess of incorrect substrates? Furthermore, how do different signals elicit distinct responses when they are transmitted by the same components? This short review highlights several mechanisms that can promote specificity in MAPK signalling, including tethering interactions between MAPKs and their substrates and regulators mediated by docking sites, feedback loops and cross-pathway regulatory circuits, and the selective activation of scaffold proteins.

scholarly journals Nemo-Like Kinase, an Essential Effector of Anterior Formation, Functions Downstream of p38 Mitogen-Activated Protein Kinase

2009 ◽  
Vol 30 (3) ◽  
pp. 675-683 ◽  
Author(s):  
Eriko Ohnishi ◽  
Toshiyasu Goto ◽  
Atsushi Sato ◽  
Mi-sun Kim ◽  
Shun-ichiro Iemura ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Molecular Mechanisms ◽  
Phosphorylation Site ◽  
Mitogen Activated Protein Kinase ◽  
Marker Genes ◽  
Head Formation ◽  
Mitogen Activated Protein ◽  
Upstream Kinase ◽  
Morpholino Oligonucleotides

ABSTRACT Nemo-like kinase (NLK) is known to function as a mitogen-activated protein kinase (MAPK)-like kinase. However, the upstream molecules and molecular mechanisms that regulate NLK activity remain unclear. In the present study, we identified p38 MAPK as an upstream kinase and activator of NLK. p38 regulates the function of NLK via phosphorylation, and this modification can be abrogated by depletion of endogenous p38. In Xenopus laevis embryos, depletion of either p38β or NLK by antisense morpholino oligonucleotides results in a severe defect in anterior development and impaired expression of endogenous anterior markers. It is notable that morphants of Xenopus p38α, another isoform of the p38 MAPK family, exhibited no obvious defects in anterior development. Defects in head formation or in the expression of anterior marker genes caused by suppression of endogenous p38β expression could be rescued by expression of wild-type NLK but not by expression of mutant NLK lacking the p38β phosphorylation site. In contrast, defects in head formation or in the expression of anterior marker genes caused by suppression of endogenous NLK expression could not be rescued by expression of p38. These results provide the first evidence that p38 specifically regulates NLK function, which is required for anterior formation in Xenopus development.

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