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.

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.

Role of p38 mitogen-activated protein kinase in cardiac myocyte secretion of the inflammatory cytokine TNF-α

2001 ◽  
Vol 280 (5) ◽  
pp. H1970-H1981 ◽  
Author(s):  
Cherry Ballard-Croft ◽  
D. Jean White ◽  
David L. Maass ◽  
Dixie Peters Hybki ◽  
Jureta W. Horton
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Cardiac Myocyte ◽  
Total Body Surface Area ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Assay ◽  
Burn Trauma ◽  
Mapk Activity ◽  
Tnf Α ◽  
Mitogen Activated Protein

This study examined the hypothesis that burn trauma promotes cardiac myocyte secretion of inflammatory cytokines such as tumor necrosis factor (TNF)-α and produces cardiac contractile dysfunction via the p38 mitogen-activated protein kinase (MAPK) pathway. Sprague-Dawley rats were divided into four groups: 1) sham burn rats given anesthesia alone, 2) sham burn rats given the p38 MAPK inhibitor SB203580 (6 mg/kg po, 15 min; 6- and 22-h postburn), 3) rats given third-degree burns over 40% total body surface area and treated with vehicle (1 ml of saline) plus lactated Ringer solution for resuscitation (4 ml · kg−1 · percent burn−1), and 4) burn rats given injury and fluid resuscitation plus SB203580. Rats from each group were killed at several times postburn to examine p38 MAPK activity (by Western blot analysis or in vitro kinase assay); myocardial function and myocyte secretion of TNF-α were examined at 24-h postburn. These studies showed significant activation of p38 MAPK at 1-, 2-, and 4-h postburn compared with time-matched shams. Burn trauma impaired cardiac mechanical performance and promoted myocyte secretion of TNF-α. SB203580 inhibited p38 MAPK activity, reduced myocyte secretion of TNF-α, and prevented burn-mediated cardiac deficits. These data suggest p38 MAPK activation is one aspect of the signaling cascade that culminates in postburn secretion of TNF-α and contributes to postburn cardiac dysfunction.

Differentiation regulates interleukin-1β-induced cyclo-oxygenase-2 in human articular chondrocytes: role of p38 mitogen-activated protein kinase

2002 ◽  
Vol 362 (2) ◽  
pp. 367-373 ◽  
Author(s):  
Béatrice THOMAS ◽  
Sylvie THIRION ◽  
Lydie HUMBERT ◽  
Lujian TAN ◽  
Mary B. GOLDRING ◽  
...  
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Articular Chondrocytes ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Human Articular Chondrocytes ◽  
Osteoarthritic Cartilage ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Cox 2

Chondrocyte dedifferentiation has been noted in osteoarthritic cartilage, but the contribution of this phenomenon is poorly understood. Interleukin (IL)-1β, the major pro-inflammatory cytokine found in osteoarthritic synovial fluid, induces the dedifferentiation of cultured articular chondrocytes, whereas E-series prostaglandins (PGE) are capable of inducing cell differentiation. Since PGE2 synthesis is up-regulated by IL-1β, we addressed the question of whether the state of chondrocyte differentiation may influence the production of IL-1-induced PGE2 by modulating cyclooxygenase (COX)-2 expression. Immortalized human articular chondrocytes, (tsT/AC62) cultured in monolayer after passage through alginate matrix (alg+) produced 5-fold greater amounts of PGE2 than continuous monolayer cultures (alg-) after stimulation with IL-1β. Moreover, IL-1β induced COX-2 expression at 0.01ng/ml in (alg+) cells, whereas a 100-fold higher dose of cytokine was necessary for stimulation in (alg-) cells. SB203580, a selective p38 mitogen-activated protein kinase (MAPK) inhibitor, completely abolished the IL-1β-induced COX-2 mRNA. Overexpression of p38 MAPK induces a COX-2 reporter, whereas overexpression of dominant negative p38 MAPK represses IL-1β-induced promoter expression. Interestingly, IL-1β-induced p38 MAPK activity was greatly enhanced in (alg+) compared with (alg-) cells. Our results suggest that differentiated articular chondrocytes are highly responsive to IL-1β and that p38 MAPK mediates this response by inducing COX-2 gene expression.

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.

scholarly journals Mouse model of testosterone-induced muscle fiber hypertrophy: involvement of p38 mitogen-activated protein kinase-mediated Notch signaling

2009 ◽  
Vol 201 (1) ◽  
pp. 129-139 ◽  
Author(s):  
Danielle Brown ◽  
Amiya P Sinha Hikim ◽  
Ekaterina L Kovacheva ◽  
Indrani Sinha-Hikim
Keyword(s):  
Protein Kinase ◽  
Mouse Model ◽  
Notch Signaling ◽  
P38 Mapk ◽  
Muscle Fiber ◽  
Molecular Mechanisms ◽  
Concomitant Administration ◽  
Mitogen Activated Protein Kinase ◽  
Nuclear Antigen ◽  
Mitogen Activated Protein

As a prerequisite for studies using mutant mice, we established a mouse model for investigating the molecular mechanisms by which testosterone (T) promotes muscle growth. Groups of six adult male mice (C57BL/6) received one of the following treatments: 1) vehicle (sterile distilled water; normal control) and 2) GnRH antagonist with empty (sham control) or 2 cm T- filled implant. Mice were killed 2, 6, and 8 weeks after treatment. T treatment for 8 weeks resulted in a significant (P<0.001) increase in fiber area of gastrocnemius muscles. T-induced fiber-hypertrophy was accompanied by up-regulation of the Notch ligand Delta 1 and activation of Notch signaling, as evidenced by increase in activated forms of Notch 1 and Notch 2. Consistent with this, we also observed an increase in the number of proliferating cell nuclear antigen (PCNA)-positive nuclei in muscles of T-treated mice, indicating that activation of Notch signaling enhanced cell proliferation. T supplementation not only triggered p38 mitogen-activated protein kinase (MAPK) activation but also concurrently inhibited c-Jun NH2-terminal kinase (JNK) activation within 2 weeks of treatment. Concomitant administration of SB203580, a p38 MAPK inhibitor, effectively blocked T-induced activation of Notch signaling and significantly (P<0.001) suppressed PCNA levels. Together, our results indicate that T induces muscle fiber hypertrophy through activation of Notch signaling and the inactivation of JNK together with the activation of p38 MAPK may be critical for T-induced activation of Notch signaling and, as a consequence, muscle fiber hypertrophy.

Roles of p38 MAPKs in invasion and metastasis

2012 ◽  
Vol 40 (1) ◽  
pp. 79-84 ◽  
Author(s):  
Ivan del Barco Barrantes ◽  
Angel R. Nebreda
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Recent Progress ◽  
Mitogen Activated Protein Kinase ◽  
Surrounding Tissue ◽  
Activity Levels ◽  
Invasion And Metastasis ◽  
Mapk Activity ◽  
Mitogen Activated Protein ◽  
Protein Kinase Signalling

Cells from primary tumours need to go through several steps to become fully metastatic. During this process, cancer cells acquire the ability to invade, migrate across the surrounding tissue, enter into the circulation and colonize distant organs. In the present paper, we review recent progress in understanding how the p38 MAPK (mitogen-activated protein kinase) signalling pathway participates in the different steps of metastasis. Experimental evidence suggests that tumour cells need to modulate p38 MAPK activity levels to successfully metastasize.

scholarly journals The Proto-oncoprotein Brx Activates Estrogen Receptor β by a p38 Mitogen-activated Protein Kinase Pathway

2001 ◽  
Vol 276 (50) ◽  
pp. 46792-46797 ◽  
Author(s):  
Paul H. Driggers ◽  
James H. Segars ◽  
Domenica M. Rubino
Keyword(s):  
Protein Kinase ◽  
P38 Mapk ◽  
Active Form ◽  
Mitogen Activated Protein Kinase ◽  
The Novel ◽  
Mapk Activity ◽  
Dependent Activity ◽  
Mitogen Activated Protein ◽  
P38 Mapk Inhibitor ◽  
Mapk Inhibitor

The estrogen receptors (ERs) are ligand-inducible transcription factors that play key roles in the control of growth and differentiation in reproductive tissues. We showed that the novel Dbl family proto-oncoprotein Brx enhances ligand-dependent activity of ERα via a Cdc42-dependent pathway. Brx also significantly enhances ligand-dependent activity of ERβ. This enhancement is not affected by inhibition of p44/42 mitogen-activated protein kinase (MAPK) activation by PD98059. However, addition of the p38 MAPK inhibitor SB202190 abrogates the enhancement of ERβ activity by Brx, showing that p38 MAPK activity is required for the enhancement of ERβ function by Brx. In COS-7 cells, transfection of Brx leads to activation of endogenous p38 MAPK activity. Co-expression of the β2 isoform of human p38 MAPK and a constitutively active form of the p38 MAPK kinase MKK6 (MKK6-EE) synergistically augments ligand-dependent activity of ERβ. Our findings suggest that p38 MAPKs may be important regulators of ERβ activity.

Thymocyte development past the CD4+CD8+stage requires an active p38 mitogen-activated protein kinase

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1356-1361 ◽  
Author(s):  
Edgar Fernández
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Cell Line ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Cell Functions ◽  
Mapk Activity ◽  
Mitogen Activated Protein

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway is important for some T-cell functions, but its role in intrathymic development is unclear. To investigate the function of p38 MAPK during the late stages of thymocyte differentiation, pharmacologic and genetic manipulations were used to inhibit p38 MAPK activity in developing thymocytes. Ligation of the T-cell antigen receptor (TCR) on either thymocytes or a thymocyte cell line resulted in p38 MAPK activation. Selective pharmacologic inhibition of p38 MAPK activity with the pyridinyl imidazole drug SB203580 severely impaired the development of mature CD4+ and CD8+ single positive (SP) thymocytes from their CD4+CD8+ double positive (DP) precursors in fetal thymic organ culture (FTOC). Further, pharmacologic or genetic suppression of p38 MAPK activity, the latter achieved by overexpressing a catalytically inactive p38 MAPK, resulted in a blockade of the DP-to-SP transition of a thymocyte cell line in a novel in vitro differentiation assay. Taken together, these data constitute the first demonstration that p38 MAPK plays a critical role in the DP-to-SP differentiation of thymocytes during late intrathymic development.

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