Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two chromatographically distinct stress-activated protein kinase kinases (SAPKKs) have been identified in several mammalian cells, termed SAPKK2 and SAPKK3, which activate the MAP kinase family member RK/p38 but not JNK/SAPK in vitro. Here we demonstrate that SAPKK2 is identical or very closely related to the MAP kinase kinase family member MKK3. However, under our assay conditions, SAPKK3 was the major activator of RK/p38 detected in extracts prepared from stress- or interleukin-1-stimulated epithelial (KB) cells, from bacterial lipopolysaccharide and tumour necrosis factor alpha-stimulated THP1 monocytes or from rabbit skeletal muscle. The activated form of SAPKK3 was purified from muscle to near homogeneity, and tryptic peptide sequences were used to clone human and murine cDNAs encoding this enzyme. Human SAPKK3 comprised 334 amino acids and was 78% identical to MKK3. The murine and human SAPKK3 were 97% identical in their amino acid sequences. We also cloned a different murine cDNA that appears to encode a SAPKK3 protein truncated at the N-terminus. SAPKK3 is identical to the recently cloned MKK6.
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PMID:Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. 886 44

RAFTK, a novel nonreceptor protein kinase, has been shown to be involved in focal adhesion signal transduction pathways in neuronal PC12 cells, megakaryocytes, platelets, and T cells. Because focal adhesions may modulate cytoskeletal functions and thereby alter phagocytosis, cell migration, and adhesion in monocyte-macrophages, we investigated the role of RAFTK signaling in these cells. RAFTK was abundantly expressed in THP1 monocytic cells as well as in primary alveolar and peripheral blood-derived macrophages. Colony-stimulating factor-1 (CSF-1)/macrophage colony-stimulating factor (M-CSF) stimulation of THP1 cells increased the tyrosine phosphorylation of RAFTK; similar increases in phosphorylation were also detected after lipopolysaccharide stimulation. RAFTK was phosphorylated with similar kinetics in THP1 cells and peripheral blood-derived macrophages. Immunoprecipitation analysis showed associations between RAFTK and the signaling molecule phosphatidylinositol-3 (PI-3) kinase. PI-3 kinase enzyme activity also coprecipitated with the RAFTK antibody, further confirming this association. The CSF-1/M-CSF receptor c-fms and RAFTK appeared to associate in response to CSF-1/M-CSF treatment of THP1 cells. Inhibition of RAFTK by a dominant-negative kinase mutant reduced CSF-1/M-CSF-induced MAPK activity. These data indicate that RAFTK participates in signal transduction pathways mediated by CSF-1/M-CSF, a cytokine that regulates monocyte-macrophage growth and function.
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PMID:The related adhesion focal tyrosine kinase (RAFTK) is tyrosine phosphorylated and participates in colony-stimulating factor-1/macrophage colony-stimulating factor signaling in monocyte-macrophages. 957 36

The senile plaques of Alzheimer's disease are foci of local inflammatory responses, as evidenced by the presence of acute phase proteins and oxidative damage. Fibrillar forms of beta-amyloid (Abeta), which are the primary constituents of senile plaques, have been shown to activate tyrosine kinase-dependent signal transduction cascades, resulting in inflammatory responses in microglia. However, the downstream signaling pathways mediating Abeta-induced inflammatory events are not well characterized. We report that exposure of primary rat microglia and human THP1 monocytes to fibrillar Abeta results in the tyrosine kinase-dependent activation of two parallel signal transduction cascades involving members of the mitogen-activated protein kinase (MAPK) superfamily. Abeta stimulated the rapid, transient activation of extracellular signal-regulated kinase 1 (ERK1) and ERK2 in microglia and ERK2 in THP1 monocytes. A second superfamily member, p38 MAPK, was also activated with similar kinetics. Scavenger receptor and receptor for advanced glycated end products (RAGE) ligands failed to activate ERK and p38 MAPK in the absence of significant increases in protein tyrosine phosphorylation, demonstrating that scavenger receptors and RAGE are not linked to these pathways. Importantly, the stress-activated protein kinases (SAPKs) were not significantly activated in response to Abeta. Downstream effectors of the MAPK signal transduction cascades include MAPKAP kinases, such as RSK1 and RSK2, as well as transcription factors. Exposure of microglia and THP1 monocytes to Abeta resulted in the activation of RSK1 and RSK2 and phosphorylation of cAMP response element-binding protein at Ser133, providing a mechanism for Abeta-induced changes in gene expression.
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PMID:beta-Amyloid fibrils activate parallel mitogen-activated protein kinase pathways in microglia and THP1 monocytes. 961 22

We assayed mitogen-activated protein (MAP) kinase phosphorylation in a human monocyte cell line (THP1) during their infection by Toxoplasma gondii. In addition, we tested the effect of specific MAP kinase inhibitors (PD098059 and SB203580) on parasite invasion. MAP kinase phosphorylation was increased in the cytosol and membrane fractions of THP1 infected with T. gondii. The MAP kinase phosphorylation of uninfected THP1 cells was not significantly modified by incubation for 20 h with 1000 U/ml of IFN-gamma. However, IFN-gamma treatment of infected cells significantly reduces the increase in phosphorylation caused by parasite infection. There was also MAP kinase activity in the cytosol and membrane fractions of extracellular T. gondii tachyzoites. IFN-gamma altered the distribution of activity in subcellular fractions of extracellular T. gondii tachyzoites. This indicates that IFN-gamma directly affects parasite MAP kinase activity. The results provide evidence that MAP kinase pathways participate in the infection by T. gondii and that the decrease in MAP kinase activity in infected cells caused by IFN-gamma may be involved in mediating their protective signals.
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PMID:Interferon-gamma signal transduction during parasite infection: modulation of MAP kinases in the infection of human monocyte cells (THP1) by Toxoplasma gondii. 999 Jun 48

The biochemical pathways involved in CD40 signaling have been extensively studied in B cells and B cell lines, and appear to be primarily initiated by recruitment of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) signaling proteins to the CD40 cytoplasmic domain. Signaling pathways activated through CD40 in monocytes/macrophages have not been characterized as well as in B cells. Using human monocytes and the human monocytic cell line THP1, we examined signal transduction events induced by CD40 engagement with its ligand, CD154. In human monocytes, all TRAF mRNAs were expressed constitutively and CD40 ligation resulted in a strong up-regulation of TRAF1 mRNA. In THP1 cells, CD40 ligation induced expression of TRAF1 and TRAF5 mRNAs. Engagement of CD40 in both monocytes and THP1 cells led to the rapid and transient activation of the extracellular signal-regulated kinases (ERK) 1 and 2, and to low levels of JNK activation. No CD40-dependent activation of p38 mitogen-activated protein kinase (MAPK) was found. In CD154-stimulated monocytes and THP1 cells the upstream ERK1/2 activator, MAPK kinase (MEK) 1/2, and downstream substrate, c-Myc, were activated. By blocking activation of ERK1/2 with a MEK-specific inhibitor, PD98059, CD40-dependent secretion of the pro-inflammatory cytokines, TNF-alpha, IL-6 and IL-8, was demonstrated to be linked to the ERK1/2 pathway. The ERK1/2 pathway did not appear to be involved in up-regulating TRAF1 and TRAF5 mRNAs in THP1 cells. Collectively, these results suggest distinct differences between B cells and monocytic cells in CD40-dependent activation of MAPK pathways.
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PMID:CD40-mediated signaling in monocytic cells: up-regulation of tumor necrosis factor receptor-associated factor mRNAs and activation of mitogen-activated protein kinase signaling pathways. 1122 96

Host cell invasion is essential for the pathogenicity of the obligate intracellular protozoan parasite Toxoplasma gondii. In the present study, we evaluated the ability of T. gondii tachyzoites to trigger phosphorylation of the different mitogen-activated protein kinases (MAPK) in human monocytic cells THP1. Kinetic experiments show that the peak of extracellular-signal-regulated kinase (ERK1/2), P38 and cjun-NH2 terminal kinase (JNKs) phosphorylation occurs between 10 and 60 min. The use of specific inhibitors of ERK1/2, P38 and JNK1/2 phosphorylation indicates the specificity of MAPKs phosphorylation during invasion. Signaling through cellular and parasite mitogen-activated protein (MAP) kinase pathways appears to be critical for T. gondii invasion.
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PMID:Activation of the cellular mitogen-activated protein kinase pathways ERK, P38 and JNK during Toxoplasma gondii invasion. 1266 50

Human and mouse studies indicate that TLRs are important in mycobacterial infections. We investigated TLR gene expression in fresh unstimulated blood and bronchoalveolar lavage from patients with pulmonary tuberculosis using a well-validated, real-time PCR. A human splice variant of TLR1, designated hsTLR1, was found in all donors tested. hsTLR1 mRNA lacks exon 2, which is a 77-bp region of the 5'-untranslated region, but contains the same coding sequence as TLR1. Compared with the matched controls, whole blood from patients had increased levels of mRNA encoding TLR2 (p = 0.0006), TLR1 (p = 0.004), hsTLR1 (p = 0.0003), TLR6 (p < 0.0001), and TLR4 (p = 0.0002). By contrast, expression of these TLRs was not increased in bronchoalveolar lavage. An increased level of hsTLR1 mRNA was found in both CD3- (p = 0.0078) and CD4+ cells (p = 0.028), resulting in an increased ratio of hsTLR1 mRNA to TLR1 and to TLR6 mRNA. An in vitro study in THP1 cells suggested that this relative increase in hsTLR1 might be attributable to a direct effect of mycobacterial components because it could be mimicked by mycobacterial preparations in the absence of IFN-gamma or T cells and by the TLR1/2 agonist Pam3CysK4. Half-life studies using blood from patients with pulmonary tuberculosis and THP1 cells exposed to Myobacterium tuberculosis in vitro showed p38 MAPK-independent stabilization of mRNAs encoding hsTLR1 and TLR1. We conclude that M. tuberculosis exerts direct effects on patterns of TLR expression, partly via changes in mRNA half-life. The significance of these changes in the pathogenesis of disease deserves further investigation.
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PMID:Myobacterium tuberculosis induces selective up-regulation of TLRs in the mononuclear leukocytes of patients with active pulmonary tuberculosis. 1649 59

Toll-like receptor (TLR) family members recognize specific molecular patterns within pathogens. Signaling through TLRs results in a proximal event that involves direct binding of adaptor proteins to the receptors. We observed that TIRAP/Mal, an adaptor protein for TLR2 and TLR4, binds protein kinase Cdelta (PKCdelta). TIRAP/Mal GST-fusion protein and a TIRAP/Mal antibody were able to precipitate PKCdelta from rat peritoneal macrophage and THP1 cell lysates. Truncation mutants of TIRAP/Mal showed that the TIR domain of TIRAP/Mal is responsible for binding. TLR2- and TLR4-mediated phosphorylation of p38 MAPK, IKK, and IkappaB in RAW264.7 cells were abolished by depletion of PKCdelta. These results suggest that PKCdelta binding to TIRAP/Mal promotes TLR signaling events.
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PMID:Protein kinase Cdelta binds TIRAP/Mal to participate in TLR signaling. 1716 67

Oxidative modifications of proteins are fundamental biochemical events that regulate cellular signaling, protein expression, and function. The redox status is balanced by reductants in which GSH plays a major role. This study investigated whether or not p21Waf1 expression and TNFalpha biosynthesis in macrophage differentiation/activation were regulated by GSH modulators and whether or not the JNK and ERK pathway were involved. We observed an increase of p21Waf1 expression and TNFalpha biosynthesis in the THP1 monocyte/macrophage cell line treated with PMA. Treatment of THP1 cultures with NAC prior to adding PMA abrogates the expression of p21Waf1 mRNA and decreases the level of TNFalpha whereas GSH depletion by BSO enhances the levels of TNFalpha with minor effects on p21Waf1 expression. To assess whether or not ERK and JNK were involved in the redox mechanism of p21Waf1 and TNFalpha, we used pharmacological inhibitors for JNK and ERK. Both PD98095 and dicoumarol were capable of blocking TNFalpha production but had only a small effect on p21Waf1 expression. We next observed that activation of JNK was significantly inhibited in cells pretreated with NAC with no effect on ERK. Taken together, our findings suggest that the modulation of GSH regulate the magnitude the cell response to PMA in which JNK and ERK have a particular role in redox signaling.
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PMID:Regulation of p21Waf1 expression and TNFalpha biosynthesis by glutathione modulators in PMA induced-THP1 differentiation: involvement of JNK and ERK pathways. 1792 36

A novel class of fused pyrazole-derived inhibitors of p38alpha mitogen-activated protein kinase (MAPK) is disclosed. These inhibitors were evaluated for their ability to inhibit the p38alpha enzyme, the secretion of TNFalpha in a LPS-challenged THP1 cell line and TNFalpha-induced production of IL-8 in 50% human whole blood. This series was optimized through a SAR investigation to provide inhibitors with IC(50) values in the low single-digit nanomolar range in whole blood. Further investigation of their pharmacokinetic profiles led to the identification of two potent and orally bioavailable p38 inhibitors 10 m and 10 q. Inhibitor 10 m was found to be efficacious in vivo in the inhibition of TNFalpha production in LPS-stimulated Lewis rats with an ED(50) of 0.1mg/kg while 10 q was found to have an ED(50) of 0.05-0.07 mg/kg.
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PMID:Part 1: Structure-Activity Relationship (SAR) investigations of fused pyrazoles as potent, selective and orally available inhibitors of p38alpha mitogen-activated protein kinase. 1957 47


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