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)

We have investigated signaling pathways leading to angiotensin II (Ang II) activation of mitogen-activated protein kinase (MAPK) in hepatocytes. MAPK activation by Ang II was abolished by the Ang II type 1 (AT1) receptor antagonist losartan, but not by the Ang II type 2 (AT2) receptor antagonist PD123319. Ang II (100 nM) induced a rapid phosphorylation of Src (peak approximately 2 min) and focal adhesion kinase (FAK, peak approximately 5 min) followed by a decrease to basal levels in 30 min. An increased association between FAK and Src in response to Ang II was detected after 1 min, which declined to basal levels after 30 min. Treatment with the Src kinase inhibitor PP-1 inhibited FAK phosphorylation. Downregulation of PKC, intracellular Ca2+ chelator BAPTA or inhibitors of PKC, Src kinase, MAPK kinase (MEK), Ca2+/calmodulin dependent protein kinase, phosphatidylinositol 3-kinase all blocked Ang II-induced MAPK phosphorylation. In contrast to other cells, there was no evidence for the role of EGF receptor transactivation in the activation of MAPK by Ang II. However, PDGF receptor phosphorylation is involved in the Ang II stimulated MAPK activation. Furthermore, Src/FAK and Ca/CaM kinase activation serve as potential links between the Ang II receptor and MAPK activation. These studies offer insight into the signaling network upstream of MAPK activation by AT1 receptor in hepatocytes.
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PMID:Angiotensin II activation of focal adhesion kinase and pp60c-Src in relation to mitogen-activated protein kinases in hepatocytes. 1203 95

ZNC(C)PR can facilitate the learning and memory in rat. Transgenic experiments have revealed that long-term memory depended on cyclic AMP-response element binding protein, CREB. CREB phosphorylation at serine-133 is essential for it's transcriptional activity. Here, it was demonstrated that ZNC(C)PR could induce CREB phosphorylation at serine-133 in both rat hippocampus and rat hippocampus slices. ZDC(C)PR antagnist of ZNC(C)PR , PTX(inhibitor of G(o)/G(I) protein coupled receptor), GF109203x(inhihitor of PKC), PD98059( inhibitor of MAPK ) but not KN-62(inhibitor of CaMKII) could inhibit the phosphorylation of CREB induced by ZNC(C)PR.
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PMID:ZNC(C)PR Induces Phosphorylation of CREB in Rat Hippocampus. 1205 67

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. While a growing body of literature indicates that postsynaptic GABA receptors are regulated by phosphorylation, there is discrepancy as to the specific effects of phosphorylation on GABA receptor function. Here, we have identified phosphorylation sites on the human rho1 GABA receptor for six protein kinases widely expressed in the brain: protein kinase C (PKC); cAMP-dependent protein kinase (PKA); calmodulin-dependent kinase (CaMKII); casein kinase (CKII); mitogen-activated protein kinase (MAPK); and cGMP-dependent protein kinase (PKG). We demonstrate that in nearly all cases, the consensus sites and actual phosphorylation sites do not agree supporting the risk of relying on a sequence analysis to identify potential phosphorylation sites. In addition, of the six kinases examined, only CKII phosphorylated the human rho2 subunit. Site-directed mutagenesis of the phosphorylation sites, or activation/inhibition of select kinase pathways, did not alter the receptor sensitivity or maximal GABA-activated current of the rho1 GABA receptor expressed in Xenopus laevis oocytes suggesting phosphorylation of rho1 does not directly alter receptor properties. This study is a first and necessary step towards elucidating the regulation of rho1 GABA receptors by phosphorylation.
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PMID:Phosphorylation of the recombinant rho1 GABA receptor. 1217 59

Glutamate, the major excitatory neurotransmitter, induces a signal from the membrane to the nucleus that regulates gene expression. The gene encoding the chick kainate binding protein undergoes a glutamate-dependent transcriptional regulation via an activator protein-1 site within its promoter region. To characterize this event, cultured chick Bergmann glia cells were exposed to glutamate, and a dose-dependent increase in promoter activity was established. The glutamate effect is mediated through Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors. The signaling cascade includes phosphatidyl inositol 3-kinase, Ca(2+)/calmodulin-dependent protein kinase II, mitogen-activated protein kinase, and p90 ribosomal S6 kinase activation. The cAMP response-element binding protein becomes phosphorylated and activates fos transcription. Finally, the activator protein-1 complex binds to the glutamate response element in the chick kainate binding protein promoter region inducing its activity. We propose that the mitogen-activated protein kinase/p90 ribosomal S6 kinase pathway plays a critical role in glutamate-induced gene transcription.
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PMID:Glutamate-dependent transcriptional regulation of the chkbp gene: signaling mechanisms. 1223 70

Chlamydia pneumoniae elementary bodies were demonstrated to increase the proliferation of murine fibroblast cell line L-929 and rapidly activate p44/p42 mitogen-activated protein kinase (MAPK) in a protein kinase C (PKC) and protein kinase A (PKA)-independent way. Ca(2+)/calmodulin-dependent protein kinase (CaM kinase) inhibitor KN-62 significantly enhanced C. pneumoniae-induced MAPK phosphorylation, suggesting negative control of CaM kinase pathway on the MAPK cascade. In in vitro infection assay, the upstream MAPK kinase 1/2 inhibitor U0126 increased 2.5-fold C. pneumoniae infectivity in L-929 cells, while KN-62 reduced the infection by 36%. Our findings provide insight into the molecular mechanisms of bacterium-host cell interactions and demonstrate the protective role of MAPK in murine fibroblasts, suggesting novel therapeutic approaches to the treatment and prevention of chlamydial infections.
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PMID:KN-62 enhances Chlamydia pneumoniae-induced p44/p42 mitogen-activated protein kinase activation in murine fibroblasts and attenuates in vitro infection. 1239 15

To investigate regulation of D2 receptor (D2R) gene expression by protein kinases, we evaluated effects of constitutively active MAPK kinase kinase (MEKK), Ca2+/calmodulin-dependent protein kinase (CaMK) II, CaMKIV and cyclic AMP-dependent protein kinase (PKA) on D2R promoter activity using luciferase reporter gene assays. A 1.5-kbp fragment containing the rat D2R promoter was cloned upstream of the reporter and transfected into D2R-expressing NB2A cells or nonexpressing NG108-15 and C6 glioma cells. MEKK and CaMKII, but not CaMKIV and PKA, increased promoter activity 4.5- and 1.5-fold, respectively, in NB2A cells. Inhibitory effects of a MEK inhibitor and lack of effect by dominant negative (DN)-JNK1 or DN-p38MAPK revealed that ERK but not JNK and p38MAPK is involved in MEKK-induced promoter activation. Deletion and mutation of the promoter revealed that the MEKK-responsive region was Sp1 site B between nucleotides -56 and -47. Overexpression of Sp1 suppressed promoter activity without affecting MEKK-induced activation. Interestingly, overexpression of Zif268 increased promoter activity through the region between nucleotides -56 and -36. Increased activity by Zif268 was additive with CaMKII-induced activation but not with activation induced by MEKK. Co-transfection with CaMKII stimulated nuclear translocation of Zif268. These results suggest that ERK and CaMKII positively regulate the D2R promoter and that Zif268 is a potential transcription factor for the CaMKII-dependent pathway.
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PMID:Activation of the rat dopamine D2 receptor promoter by mitogen-activated protein kinase and Ca2+/calmodulin-dependent protein kinase II pathways. 1242 50

ATP-gated ion channel P2X receptors are expressed on the surface of most immune cells and can trigger multiple cellular responses, such as membrane permeabilization, cytokine production, and cell proliferation or apoptosis. Despite broad distribution and pleiotropic activities, signaling pathways downstream of these ionotropic receptors are still poorly understood. Here, we describe intracellular signaling events in Jurkat cells treated with millimolar concentrations of extracellular ATP. Within minutes, ATP treatment resulted in the phosphorylation and activation of p56(lck) kinase, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase but not p38 kinase. These effects were wholly dependent upon the presence of extracellular Ca(2+) ions in the culture medium. Nevertheless, calmodulin antagonist calmidazolium and CaM kinase inhibitor KN-93 both had no effect on the activation of p56(lck) and ERK, whereas a pretreatment of Jurkat cells with MAP kinase kinase inhibitor P098059 was able to abrogate phosphorylation of ERK. Further, expression of c-Jun and c-Fos proteins and activator protein (AP-1) DNA binding activity were enhanced in a time-dependent manner. In contrast, DNA binding activity of NF-kappa B was reduced. ATP failed to stimulate the phosphorylation of ERK and c-Jun N-terminal kinase and activation of AP-1 in the p56(lck)-deficient isogenic T cell line JCaM1, suggesting a critical role for p56(lck) kinase in downstream signaling. Regarding the biological significance of the ATP-induced signaling events we show that although extracellular ATP was able to stimulate proliferation of both Jurkat and JCaM1 cells, an increase in interleukin-2 transcription was observed only in Jurkat cells. The nucleotide selectivity and pharmacological profile data supported the evidence that the ATP-induced effects in Jurkat cells were mediated through the P2X7 receptor. Taken together, these results demonstrate the ability of extracellular ATP to activate multiple downstream signaling events in a human T-lymphoblastoid cell line.
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PMID:Signaling through P2X7 receptor in human T cells involves p56lck, MAP kinases, and transcription factors AP-1 and NF-kappa B. 2151 30

Nicotine treatment triggers calcium influx into neuronal cells, which promotes cell survival in a number of neuronal cells. Phosphoinositide (PI) 3-kinase and downstream PI3-kinase target Akt have been reported to be important in the calcium-mediated promotion of survival in a wide variety of cells. We investigated the mechanisms of nicotine-induced phosphorylation of Akt in PC12h cells, in comparison with nicotine-induced ERK phosphorylation. Nicotine induced Akt phosphorylation in a dose-dependent manner. A nicotinic acetylcholine receptor (nAChR) alpha7 subunit-selective inhibitor had no significant effect on nicotine-induced Akt phosphorylation, while a non-selective nAChR antagonist inhibited the phosphorylation. L-type voltage-sensitive calcium channel (VSCC) antagonists, calmodulin antagonist, and Ca2+/calmudulin-dependent protein kinase (CaM kinase) inhibitor prevented the nicotine-induced Akt phosphorylation. Three epidermal growth factor receptor (EGFR) inhibitors prevented the nicotine-induced phosphorylation of both extracellular signal-regulated protein kinase (p42/44 MAP kinase, ERK) and Akt. In contrast, an inhibitor of the Src family tyrosine kinase prevented the nicotine-induced Akt phosphorylation but not ERK phosphorylation. These results suggested that nicotine induces the activation of both PI3-kinase/Akt and ERK pathways via common pathways including non-alpha7-nAChRs, L-type VSCC, CaM kinase II and EGFR in PC12h cells, but Src family tyrosine kinases only participate in the pathway to activate Akt.
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PMID:Nicotine-induced phosphorylation of Akt through epidermal growth factor receptor and Src in PC12h cells. 1247 91

Wnt signaling controls a variety of developmental processes. The canonical Wnt/beta-catenin pathway functions to stabilize beta-catenin, and the noncanonical Wnt/Ca(2+) pathway activates Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). In addition, the Wnt/Ca(2+) pathway activated by Wnt-5a antagonizes the Wnt/beta-catenin pathway via an unknown mechanism. The mitogen-activated protein kinase (MAPK) pathway composed of TAK1 MAPK kinase kinase and NLK MAPK also negatively regulates the canonical Wnt/beta-catenin signaling pathway. Here we show that activation of CaMKII induces stimulation of the TAK1-NLK pathway. Overexpression of Wnt-5a in HEK293 cells activates NLK through TAK1. Furthermore, by using a chimeric receptor (beta(2)AR-Rfz-2) containing the ligand-binding and transmembrane segments from the beta(2)-adrenergic receptor (beta(2)AR) and the cytoplasmic domains from rat Frizzled-2 (Rfz-2), stimulation with the beta-adrenergic agonist isoproterenol activates activities of endogenous CaMKII, TAK1, and NLK and inhibits beta-catenin-induced transcriptional activation. These results suggest that the TAK1-NLK MAPK cascade is activated by the noncanonical Wnt-5a/Ca(2+) pathway and antagonizes canonical Wnt/beta-catenin signaling.
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PMID:The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. 1248 67

Calcium signaling plays a critical role in various cell types by activation of receptors and Ca2+ channels in response to neurotransmitters, hormones, growth, factors etc. Although a variety of functions of intracellular Ca2+ are reported, Ca2+/calmodulin-dependent protein kinases (CaMK) are involved in their mediation. We have been studying on CaMK I, II, III, IV and K in the dynamic regulation in the cells in relation to functions. In this study, we elucidated the structures of the isoforms of CaMKII subunits with nuclear translocation signal (NTS). NTS is included in the variable domain following the regulatory domain with a sequence of KKRK. The isoforms of CaMK subunits such as alpha B, gamma A, gamma A.B, delta 3 and delta 7 contain NTS in the sequences of the structures. Transfection of the isoforms with NTS into NG108-15 cells stimulated the expression of brain-derived neurotrophic factor in the cytoplasm. Activation of CaMKII and IV and mitogen-activated protein kinase (MAPK) was observed during long-term potentiation (LTP) induction in the CA1 area of hippocampus. The activation of CaMKII was sustained for a long period, whereas that of CaMKIV and MAPK was transient. The results suggest that CaMKII is involved in LTP induction, while CaMKIV and MAPK are rather involved in LTP maintenance. We present and discuss our recent studies on regulation of CaMKs in neuronal functions.
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PMID:[Calcium signaling and brain functions]. 1249 66


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