Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pro-inflammatory activity of Tumor necrosis factor-alpha (TNF-alpha) together with tissue hypoxia determine the clinical outcome in sepsis and septic shock. p38 MAPKinase is the primary intracellular signaling pathway that regulates lipopolysaccharide (LPS)-induced TNF-alpha biosynthesis, however, the effect of hypoxia on LPS mediated activation of p38 is not known. Here we report that SB203580, a specific p38 MAPK inhibitor, which completely abolished LPS-induced TNF-alpha expression by the mouse macrophage cell RAW264.7 in normoxic conditions, lost the inhibitory effect in hypoxic conditions. Hypoxia did not modulate expression of p38 MAPK, but increased that of p-MK2, a downstream target of p38 MAPK. In LPS induced endotoxemia mice model SB203580 had no inhibitory effect on the serum levels of TNF-alpha. Furthermore, hypoxia inducible factor-1alpha (HIF-1alpha) was detected in vivo after LPS administration but its expression was not affected by SB203580. Our data indicate that LPS induced p38 MAPK activation was enhanced by hypoxia and consequently increased TNF-alpha secretion. Furthermore, the induction of HIF-1alpha in mice with endotoxemia suggested a synergistic effect on p38 mediated TNF-alpha expression. These findings provide new insights on the pathophysiological effects of hypoxia in sepsis and septic shock.
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PMID:Hypoxia modulates lipopolysaccharide induced TNF-alpha expression in murine macrophages. 1825 61

G protein-coupled receptor kinases (GRKs) are serine/threonine kinases first discovered by its role in receptor desensitization. Phosphorylation of the C-terminal tail of GPCRs by GRKs triggers the docking of beta-arrestins and the functional uncoupling of G proteins and receptors. In addition, we and others have uncovered new direct ways by which GRKs could impinge into intracellular signalling pathways independently of receptor phosphorylation. In particular, we have characterized that elevated GRK2 levels can reduce CCR2-mediated activation of the ERK MAPK route in a manner that is independent of kinase activity and also of G proteins. This inhibition of ERK occurred in the absence of any reduction on MEK phosphorylation, what implicates that GRK2 is acting at the level of MEK or at the MEK-ERK interface to achieve a downregulation of ERK phosphorylation. In fact, we describe here that a direct association between GRK2 and MEK proteins can be detected in vitro. p38 MAPK pathway also appears to be regulated directly by GRK2 in a receptor-independent manner. p38 can be phosphorylated by GRK2 in threonine 123, a residue sitting at the entrance of a docking groove by which this MAPK associates to substrates and upstream activators. The T123phospho-mimetic mutant of p38 shows a reduced ability to bind to MKK6, concomitant with an impaired p38 activation, and a decreased phosphorylation of downstream substrates such as MEF2, MK2 and ATF2. Elevated levels of GRK2 downregulate p38-dependent cellular responses, such as differentiation of preadipocytic cells, while LPS-induced cytokine release is enhanced in macrophages from GRK2 (+/-) mice. In sum, we describe in this article different ways by which GRK2 directly regulates MAPK-mediated cellular events. This regulation of the MAPK modules by GRK2 could be relevant in pathological situations where the levels of this kinase are altered, such as during inflammatory diseases or cardiovascular pathologies.
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PMID:GRK2-dependent desensitization downstream of G proteins. 1843 30

The 27-kDa heat shock protein (Hps27) is phosphorylated in a way that appears to regulate antioxidant defenses by mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2), a component of the p38(MAPK) pathway. To investigate the role of Hsp27 in cellular resistance to oxidant stress, lung cells (A549) were incubated with MAPK inhibitors to investigate the pathway's role in antioxidant defense. Cells were harvested for measurement of reduced gluthathione and glutathione disulfide (GSH and GSSH); or, exposed to 2,3-dimethoxy-1,4-napthoquinone (DMNQ). Inhibition of MAPK with SB203580 decreased total cellular glutathione (mean +/- SE): Vehicle, 150 +/- 20 mu M; SB203580, 57 +/- 10* (*P < .01). Inhibition of MAPK tripled [GSSG]/[GSH]: Vehicle, 0.29 +/- 0.09; SB203580, 1.06 +/- 0.43* (*P > .05; n = 6 per group). Hsp27 protein content did not change significantly after MAPK inhibition: Vehicle 2.20 +/- 0.24 ng/mg protein; SB203580, 2.03 +/- 0.34 (P > .05). Transfection of epithelial cells with wild-type (pcDNA-HA-Hsp27) or phosphomimic (pcDNA-HA-Hsp27-S3D) vector increased Hsp27 protein, which significantly protected cells from oxidant stress. Inhibition of the MAPK system, including p38(MAPK), results in cellular oxidant stress. Hsp27, which is phosphorylated by MK2 in the MAPK pathway, protects epithelial cells from oxidant stress.
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PMID:Kinase activity, heat shock protein 27 phosphorylation, and lung epithelial cell glutathione. 1846 3

TTP (tristetraprolin) is an RNA-binding protein that suppresses inflammation by accelerating the degradation of cytokine mRNAs. TTP binds to an AU-rich element in the 3'-untranslated region of its target mRNAs. In macrophages, the induction of cytokine expression requires activation of the p38-MAPK (mitogen-activated protein kinase)-MK2 [MAPKAP (MAPK-activated protein) kinase-2] kinase cascade. MK2 directly phosphorylates TTP and thereby contributes to transient stabilization of cytokine mRNAs. In the present review, we address the target specificity of TTP, summarize TTP-interacting proteins and discuss how phosphorylation regulates the activity, localization and stability of TTP.
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PMID:Control of mRNA decay by phosphorylation of tristetraprolin. 1848 87

MAP kinase-activated protein kinase 5 (MK5) was originally described as a protein kinase activated downstream of the p38 MAP kinase and is also named p38-regulated/activated protein kinase (PRAK). However, while MK5 is most similar in sequence to the two p38 regulated MAPKAP kinases MK2 and MK3, recent data has shown that in contrast to these enzymes MK5 is not activated in response to either cellular stress or pro-inflammatory cytokines. This lack of response to stimuli which cause robust activation of p38 MAP kinase in vivo is supported by data obtained using transgenic mice lacking MK5. Unlike animals lacking MK2 and MK3, MK5 null mice respond normally to endotoxic shock and display an unchanged pattern of cytokine expression in response to LPS. Clues as to the physiological function of MK5 have come from the recent observation that MK5 is uniquely regulated and activated following complex formation with the atypical MAP kinases ERK3 and ERK4. Thus, it is possible that MK5 is unique amongst the MAPKAP kinases in being regulated downstream of signaling pathways other than the classical MAP kinases p38 and ERK1/2.
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PMID:Does MK5 reconcile classical and atypical MAP kinases? 1850 33

The MAPK-activated protein kinases MK2 and MK3 form a pair of structurally and functionally closely related enzymes present in mammals and birds. Both protein kinases can bind to p38alpha MAPK and are activated by p38alpha via multiple proline-directed phosphorylations in a stress-dependent manner. Although the expression level and activity of MK2 is always significantly higher than that of MK3, the substrate spectrum of both enzymes is indistinguishable and covers proteins involved in cytokines production, endocytosis, reorganization of the cytoskeleton, cell migration, cell cycle control, chromatin remodeling and transcriptional regulation. Functional differences between MK2 and MK3 could result from the more prominent proline-rich SH3-targeting region in MK2, but are not reported so far. Since MK2 and MK3 are the main downstream targets of p38alpha responsible for posttranscriptional stimulation of cytokine biosynthesis, both enzymes are promising targets for the development of small molecule inhibitors which can be used in anti-inflammatory therapy. MK2-knockout mice show decreased LPS-induced cytokine biosynthesis and increased protection against collagen-induced arthritis. Recently generated MK2/3 double knockout mice show further reduction of LPS-induced cytokine production.
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PMID:MK2 and MK3--a pair of isoenzymes? 1850 1

The p75 neurotrophin receptor (p75(NTR)) functions as a tumor suppressor in prostate epithelial cells, where its expression declines with progression to malignant cancer. Previously, we showed that treatment with R-flurbiprofen or ibuprofen induced p75(NTR) expression in several prostate cancer cell lines leading to p75(NTR)-mediated decreased survival. Using the 2-phenyl propionic acid moiety of these profens as a pharmacophore, we screened an in silico database of 30 million compounds and identified carprofen as having an order of magnitude greater activity for induction of p75(NTR) levels and inhibition of cell survival. Prostate (PC-3 and DU-145) and bladder (T24) cancer cells were more sensitive to carprofen induction of p75(NTR)-associated loss of survival than breast (MCF-7) and fibroblast (3T3) cells. Transfection of prostate cell lines with a dominant-negative form of p75(NTR) before carprofen treatment partially rescued cell survival, showing a cause-and-effect relationship between carprofen induction of p75(NTR) levels and inhibition of survival. Carprofen induced apoptotic nuclear fragmentation in prostate but not in MCF-7 and 3T3 cells. Furthermore, small interfering RNA knockdown of the p38 mitogen-activated protein kinase (MAPK) protein prevented induction of p75(NTR) by carprofen in both prostate cell lines. Carprofen treatment induced phosphorylation of p38 MAPK as early as within 1 min. Expression of a dominant-negative form of MK2, the kinase downstream of p38 MAPK frequently associated with signaling cascades leading to apoptosis, prevented carprofen induction of the p75(NTR) protein. Collectively, we identify carprofen as a highly potent profen capable of inducing p75(NTR)-dependent apoptosis via the p38 MAPK pathway in prostate cancer cells.
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PMID:Carprofen induction of p75NTR-dependent apoptosis via the p38 mitogen-activated protein kinase pathway in prostate cancer cells. 1897 93

IRAK2, a member of the interleukin-1 receptor-associated kinase (IRAK) family, has been implicated in Toll-like receptor (TLR)-mediated signaling. We generated IRAK2-deficient mice to examine its function in detail. These mice are resistant to lipopolysaccharide-induced septic shock, because of impaired TLR4-mediated induction of pro-inflammatory cytokines and chemokines. Although IRAK2 deficiency did not affect TLR4-mediated NFkappaB activation, a reduction of lipopolysaccharide (LPS)-mediated mRNA stabilization contributed to the reduced cytokine and chemokine production observed in bone marrow-derived macrophages from IRAK2-deficient mice. Furthermore, the ratios of LPS-induced cytokine and chemokine mRNAs in translation-active (polysomal) versus translation-inactive (free ribosomes) pools were reduced in IRAK2-deficient macrophages compared with wild type macrophages. Importantly, LPS-induced phosphorylation of MKK3/6, MNK1, and eIF4E was significantly reduced in IRAK2-deficient macrophages compared with wild type macrophages. Moreover, LPS stimulation induced an interaction of IRAK2 with TRAF6, MKK3/6, and MK2, implicating a critical role for mitogen-activated protein kinase signaling in LPS-induced IRAK2-mediated post-transcriptional control. These results reveal that IRAK2 is required for LPS-mediated post-transcriptional control of cytokine and chemokine expression, which plays an essential role in TLR4-induced septic shock.
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PMID:Interleukin-1 receptor-associated kinase 2 is critical for lipopolysaccharide-mediated post-transcriptional control. 1922 18

The innate immune system provides an initial defense system against microbial infections and contributes to the development of adaptive immune response. Type I interferons play a pivotal role for the first line of defense against virus infections, and dendritic cells (DCs) are important sensors of pathogens responsible for priming of adaptive immune responses in lymphoid organs. Here we have investigated the role and mechanisms of activation of the MAPK pathway in innate immune responses induced by Sendai virus, a negative sense single-stranded RNA virus. Both p38 and JNK were activated in fibroblasts and DCs after infection with Sendai virus in a manner dependent on virus replication and RIG-I. Virus replication was also required for stimulation of interferon production in both cell types and interleukin-12 production in DCs. Blocking of p38 MAPK activation by the specific inhibitor SB202190 abolished the expression of these cytokines. p38 MAPK exerted its function independent of the MAPK-activated protein kinases MK2, MNK, and MSK1/2. We also observed that TRAF2 and TAK1 were essential for RIG-I-mediated activation of p38 MAPK. Interestingly, the kinase activity of p38 MAPK was required for its own phosphorylation, which was kinetically associated with TAB1 interaction. By contrast, the canonical p38 upstream kinase MKK3 was not involved in the p38-dependent response. Thus, activation of p38 MAPK by RIG-I proceeds via a TRAF2-TAK1-dependent pathway, where the enzymatic activity of the kinase plays an essential role. The p38 MAPK in turn stimulates important processes in the innate antiviral response.
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PMID:RIG-I-mediated activation of p38 MAPK is essential for viral induction of interferon and activation of dendritic cells: dependence on TRAF2 and TAK1. 1922 20

The structurally related MAPK-activated protein kinases (MAPKAPKs or MKs) MK2, MK3 and MK5 are involved in multiple cellular functions, including cell-cycle control and cellular differentiation. Here, we show that after deregulation of cell-cycle progression, haematopoietic stem cells (HSCs) in MK2-deficient mice are reduced in number and show an impaired ability for competitive repopulation in vivo. To understand the underlying molecular mechanism, we dissected the role of MK2 in association with the polycomb group complex (PcG) and generated a MK2 mutant, which is no longer able to bind to PcG. The reduced ability for repopulation is rescued by re-introduction of MK2, but not by the Edr2-non-binding mutant of MK2. Thus, MK2 emerges as a regulator of HSC homeostasis, which could act through chromatin remodelling by the PcG complex.
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PMID:MAPKAP kinase MK2 maintains self-renewal capacity of haematopoietic stem cells. 1936 45


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