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)

Plant recognition of pathogens leads to rapid activation of MPK3 and MPK6, two Arabidopsis mitogen-activated protein kinases (MAPKs), and their orthologs in other species. Here, we report that synthesis of camalexin, the major phytoalexin in Arabidopsis, is regulated by the MPK3/MPK6 cascade. Activation of MPK3/MPK6 by expression of active upstream MAPK kinase (MAPKK) or MAPKK kinase (MAPKKK) was sufficient to induce camalexin synthesis in the absence of pathogen attack. Induction of camalexin by Botrytis cinerea was preceded by MPK3/MPK6 activation, and compromised in mpk3 and mpk6 mutants. Genetic analysis placed the MPK3/MPK6 cascade upstream of PHYTOALEXIN DEFICIENT 2 (PAD2) and PAD3, but independent or downstream of PAD1 and PAD4. Camalexin induction after MPK3/MPK6 activation was preceded by rapid and coordinated up-regulation of multiple genes encoding enzymes in the tryptophan (Trp) biosynthetic pathway, in the conversion of Trp to indole-3-acetaldoxime (IAOx, a branch point between primary and secondary metabolism), and in the camalexin biosynthetic pathway downstream of IAOx. These results indicate that the MPK3/MPK6 cascade regulates camalexin synthesis through transcriptional regulation of the biosynthetic genes after pathogen infection.
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PMID:A fungal-responsive MAPK cascade regulates phytoalexin biosynthesis in Arabidopsis. 1837 93

Tie2 is an endothelial receptor tyrosine kinase. An amino-acid substitution of tryptophan for arginine at residue 849 (Tie2-R849W) leads to a ligand-independent activation of its kinase activity. This mutation has been associated with familial venous malformations (VMs), manifested by variable thickness or lack of smooth-muscle cells in the veins of patient lesions. The underlying mechanism for Tie2-R849W action in endothelial cells remains elusive. In this study, we used adenoviral infection to differentiate the effects of ectopic Tie2 (wild type, kinase-dead K855A, or constitutively active R849W) expression on endothelial cellular behaviors and Tie2-mediated downstream targets. Ectopic Tie2 reduced endothelial cell proliferation and serum withdrawal-induced apoptosis, while stimulating migration. When comparing R849W with K855A and its wild-type counterpart, a functional tyrosine kinase activity was required only for migration, and constitutively active Tie2-R849W conferred highest resistance to serum-induced apoptosis, but lowest ability to maintain tube-like structures formed on Matrigel. We further demonstrated that Tie2-R849W chronically induced STAT1 tyrosine phosphorylation and the promoter activity of STAT1-responsive IFN-regulatory factor 1 (IRF1). Although STAT1 phosphorylation required JNK and p38MAPK activation, only JNK activation was essential for IRF1 promoter activation by Tie2-R849W. Additional studies are needed to study the role of STAT1 activation in VMs.
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PMID:Tie2-R849W mutant in venous malformations chronically activates a functional STAT1 to modulate gene expression. 1840 23

The US is currently experiencing an epidemic of methamphetamine (Meth) use as a recreational drug. Recent studies also show a high prevalence of HIV-1 infection among Meth users. We report that Meth enhances HIV-1 infectivity of dendritic cells as measured by multinuclear activation of a galactosidase indicator (MAGI) cell assay, p24 assay, and LTR-RU5 amplification. Meth induces increased HIV-1 infection in association with an increase in the HIV-1 coreceptors, CXCR4 and CCR5, and infection is mediated by downregulation of extracellular-regulated kinase (ERK2) and the upregulation of p38 mitogen-activated protein kinase (MAPK). A p38 inhibitor (SB203580) specifically reversed the Meth-induced upregulation of the CCR5 HIV-1 coreceptor. The dopamine D2 receptor antagonist RS +/- sulpiride significantly reversed the Meth-induced upregulation of CCR5, demonstrating that the Meth-induced effect is mediated via the D2 receptor. These studies report for the first time that Meth fosters HIV-1 infection, potentially via upregulating coreceptor gene expression. Further, Meth mediates its regulatory effects via dopamine receptors and via downregulating ERK2 with a reciprocal upregulation of p38 MAPK. Elucidation of the role of Meth in HIV-1 disease susceptibility and the mechanism through which Meth mediates its effects on HIV-1 infection may help to devise novel therapeutic strategies against HIV-1 infection in high-risk Meth-using HIV-1-infected subjects.
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PMID:Methamphetamine enhances HIV-1 infectivity in monocyte derived dendritic cells. 1895 26

The CD5 lymphocyte surface receptor is a group B member of the ancient and highly conserved scavenger receptor cysteine-rich superfamily. CD5 is expressed on mature T and B1a cells, where it is known to modulate lymphocyte activation and/or differentiation processes. Recently, the interaction of a few group B SRCR members (CD6, Spalpha, and DMBT1) with conserved microbial structures has been reported. Protein binding assays presented herein indicate that the CD5 ectodomain binds to and aggregates fungal cells (Schizosaccharomyces pombe, Candida albicans, and Cryptococcus neoformans) but not to Gram-negative (Escherichia coli) or Gram-positive (Staphylococcus aureus) bacteria. Accordingly, the CD5 ectodomain binds to zymosan but not to purified bacterial cell wall constituents (LPS, lipotheicoic acid, or peptidoglycan), and such binding is specifically competed by beta-glucan but not by mannan. The K(d) of the rshCD5/(1-->3)-beta-d-glucan phosphate interaction is 3.7 +/- 0.2 nM as calculated from tryptophan fluorescence data analysis of free and bound rshCD5. Moreover, zymosan binds to membrane-bound CD5, and this induces both MAPK activation and cytokine release. In vivo validation of the fungal binding properties of the CD5 ectodomain is deduced from its protective effect in a mouse model of zymosan-induced septic shock-like syndrome. In conclusion, the present results indicate that the CD5 lymphocyte receptor may sense the presence of conserved fungal components [namely, (1-->3)-beta-d-glucans] and support the therapeutic potential of soluble CD5 forms in fungal sepsis.
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PMID:The CD5 ectodomain interacts with conserved fungal cell wall components and protects from zymosan-induced septic shock-like syndrome. 1917 25

The use-dependent specification of neural circuits occurs during post-natal development with a conspicuous influence of environmental factors, such as malnutrition that interferes with the major steps of brain maturation. Serotonin (5-HT), derived exclusively from the essential aminoacid tryptophan, is involved in mechanisms of development and use-dependent plasticity of the central nervous system. We studied the effects of the nutritional restriction of tryptophan in the plasticity of uncrossed retinotectal axons following a retinal lesion to the contralateral retina during the critical period in pigmented rats. Litters were fed through their mothers with a low tryptophan content diet, based on corn and gelatin, a complemented diet with standard tryptophan requirements for rodents or standard laboratory diet. The results suggest a marked reduction in the plasticity of intact axons into denervated territories in the tryptophan restricted group in comparison to control groups. Tryptophan complementation between PND10-21 completely restored retinotectal plasticity. However, the re-introduction of tryptophan after the end of the critical period (between PND28-P41) did not restore the sprouting ability of uncrossed axons suggesting a time-dependent effect to the reversion of plasticity deficits. Tryptophan-restricted animals showed a reduced activity of matrix metalloproteinase-9 and altered expressions of phosphorylated forms of ERK1/2 and AKT. Our results demonstrate the influence of this essential aminoacid as a modulator of neural plasticity during the critical period through the reduction of serotonin content which alters plasticity-related signaling pathways and matrix degradation.
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PMID:Nutritional tryptophan restriction impairs plasticity of retinotectal axons during the critical period. 1941 66

Binding immunoglobulin protein (BiP) has been shown previously to have immunomodulatory functions. Herein we investigated whether BiP could affect the differentiation of monocytes into dendritic cells (DCs) and thence the development of regulatory T cells. Peripheral blood monocyte-derived DCs were matured with lipopolysaccharide in the presence or absence of BiP. DC development and T-cell changes were monitored by flow cytometry and regulatory T-cell function was measured by uptake of tritiated thymidine. More BiP-treated DCs (DC((BiP))s) expressed amounts of intracellular indoleamine 2,3-dioxygenase (IDO) and cell surface leucocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1), retained CD14 expression but down-regulated expression of human leucocyte antigen (HLA)-DR and CD86, and produced copious amounts of interleukin (IL)-10, when compared with control DCs. T cells co-cultured with DC((BiP))s developed regulatory function with increased surface expression of CD4(+) CD25(hi) CD27(hi) but with no concomitant increase in forkhead box P3 (Foxp3). These T cells also showed significantly higher levels of intracellular cytotoxic T-lymphocyte antigen (CTLA)-4. The latter could be inhibited by the presence of the IDO inhibitor 1 methyl tryptophan. The addition of neutralizing anti-IL-10 antibody or the specific mitogen-activated protein kinase (MAPK) p38 inhibitor SB203580 reversed the inhibition of DC differentiation by BiP. In conclusion, BiP is an immunomodulator able to arrest inflammation through induction of tolerogenic DCs and subsequent generation of T regulatory cells.
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PMID:Binding immunoglobulin protein-treated peripheral blood monocyte-derived dendritic cells are refractory to maturation and induce regulatory T-cell development. 1974 Mar 78

Increasing evidence suggests molecular interactions between erbB2 and other receptor tyrosine kinases, and estrogenic compounds and their cognate receptors. We have recently reported that downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. On the basis of these data, we hypothesized that erbB3 may play a major role connecting these two sentinel pathways. Interactions were studied using mammary/breast cancer cell lines from wild-type rat c-neu gene transgenic mice and humans. Estradiol promoted cell proliferation and activated erbB2/neu tyrosine kinase, Akt, and mitogen-activated protein kinase signaling exclusively in mammary and breast epithelial cell lines with coexpression of both erbB2 and erbB3. Estradiol action was independent of the transgene promoter (MMTV-LTR) activity, both in vitro and in vivo, as well as c-neu transgene or endogenous erbB2 gene expression. Estrogen induction of cell growth promotion, erbB2/neu activation, and downstream signaling was abrogated by blockade of estrogen receptor (ER) with the pure ER antagonist ICI 182,780 or knockdown of erbB3 expression via specific siRNA. These data suggest that activation of both ER and erbB2/erbB3 signaling is requisite for estrogen-induced mitogenesis and erbB2/neu tyrosine kinase activation.
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PMID:Estrogenic promotion of ErbB2 tyrosine kinase activity in mammary tumor cells requires activation of ErbB3 signaling. 1986 7

GPR35 is a rhodopsin-like G protein-coupled receptor identified in 1998. It has been reported that kynurenic acid, a tryptophan metabolite, may act as an endogenous ligand for GPR35. However, the concentrations of kynurenic acid required to elicit the cellular responses are usually high, raising the possibility that another endogenous ligand may exist. In this study, we searched for another endogenous ligand for GPR35. Finally, we found that the magnitude of the Ca(2+) response induced by 2-acyl lysophosphatidic acid in the GPR35-expressing HEK293 cells was markedly greater than that in the vector-transfected control cells. Such a difference was not apparent in the case of 1-acyl lysophosphatidic acid. 2-Acyl lysophosphatidic acid also caused the sustained activation of RhoA and the phosphorylation of extracellular signal-regulated kinase, and triggered the internalization of the GPR35 molecule. These results strongly suggest that 2-acyl lysophosphatidic acid is an endogenous ligand for GPR35.
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PMID:GPR35 is a novel lysophosphatidic acid receptor. 2036 37

Large fractions of eukaryotic genomes contain repetitive sequences of which the vast majority is derived from transposable elements (TEs). In order to inactivate those potentially harmful elements, host organisms silence TEs via methylation of transposon DNA and packaging into chromatin associated with repressive histone marks. The contribution of individual histone modifications in this process is not completely resolved. Therefore, we aimed to define the role of reversible histone acetylation, a modification commonly associated with transcriptional activity, in transcriptional regulation of murine TEs. We surveyed histone acetylation patterns and expression levels of ten different murine TEs in mouse fibroblasts with altered histone acetylation levels, which was achieved via chemical HDAC inhibition with trichostatin A (TSA), or genetic inactivation of the major deacetylase HDAC1. We found that one LTR retrotransposon family encompassing virus-like 30S elements (VL30) showed significant histone H3 hyperacetylation and strong transcriptional activation in response to TSA treatment. Analysis of VL30 transcripts revealed that increased VL30 transcription is due to enhanced expression of a limited number of genomic elements, with one locus being particularly responsive to HDAC inhibition. Importantly, transcriptional induction of VL30 was entirely dependent on the activation of MAP kinase pathways, resulting in serine 10 phosphorylation at histone H3. Stimulation of MAP kinase cascades together with HDAC inhibition led to simultaneous phosphorylation and acetylation (phosphoacetylation) of histone H3 at the VL30 regulatory region. The presence of the phosphoacetylation mark at VL30 LTRs was linked with full transcriptional activation of the mobile element. Our data indicate that the activity of different TEs is controlled by distinct chromatin modifications. We show that activation of a specific mobile element is linked to a dual epigenetic mark and propose a model whereby phosphoacetylation of histone H3 is crucial for full transcriptional activation of VL30 elements.
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PMID:Epigenetic regulation of a murine retrotransposon by a dual histone modification mark. 2044 73

The enzyme 3-deoxy-D-arabino-heptulosonate-7-phosphate (DAHP) synthase (EC 4.1.2.15) catalyzes the first committed step in the shikimate pathway of tryptophan synthesis, an important precursor for the production of terpenoid indole alkaloids (TIAs). A full-length cDNA encoding nuclear coded chloroplast-specific DAHP synthase transcript was isolated from a Catharanthus roseus cDNA library. This had high sequence similarity with other members of plant DAHP synthase family. This transcript accumulated in suspension cultured C. roseus cells on ultraviolet (UV-B) irradiation. Pretreatment of C.roseus cells with variety of agents such as suramin, N-acetyl cysteine, and inhibitors of calcium fluxes and protein kinases and MAP kinase prevented this effect of UV-B irriadiation. These data further show that the essential components of the signaling pathway involved in accumulation DAHP synthase transcript in C. roseus cells include suramin-sensitive cell surface receptor, staurosporine-sensitive protein kinase and MAP kinase.
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PMID:UV-B induced transcript accumulation of DAHP synthase in suspension-cultured Catharanthus roseus cells. 2070 60


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