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 X-gene product (HBx) of the hepatitis B virus plays essential roles in viral replication and the generation of hepatocellular carcinoma. Although the mechanism for HBx action is unclear, HBx may exert its pleiotropic functions through the stimulation of signal transduction pathways including the Ras/mitogen-activated protein kinase cascade and/or inactivation of the p53 function. Here, we investigated whether HBx has the ability to activate the Jak-STAT signaling pathway. As a first step, we established stable cell lines constitutively expressing HBx. In these HBx-expressing stable cells, the tyrosine phosphorylation of various STATs, including STAT3 and -5, was constitutively enhanced by HBx, and the concomitant increase in STAT-dependent DNA binding and transcriptional activation was observed. Furthermore, HBx specifically elevated tyrosine phosphorylation and in vitro kinase activity of Jak1, but not Jak2 or Tyk2, through protein to protein interaction with Jak1. These results clearly establish HBx as the inducer of the Jak-STAT signaling pathway, and at the same time, HBx-mediated Jak-STAT activation may provide a novel mechanism for the pleiotropic functions of HBx, including transformation and promiscuous transcriptional activation.
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PMID:HBx protein of hepatitis B virus activates Jak1-STAT signaling. 973 22

Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. This cytokine was cloned in 1985 and rapidly became used for treatment of anemia of renal failure, opening the way to the first clinical trials of a hematopoietic growth factor. The clonage of one chain of the Epo receptor followed in 1989, thereby opening the research on intracellular signal transduction induced by Epo. Epo is synthesized mainly by the kidney and the liver and sequences required for tissue-specific expression have been localized in the Epo gene. A 3'enhancer is responsible for hypoxia-inducible Epo gene expression. HIF-1 alpha and beta proteins bind to this enhancer. Gene regulation by hypoxia is widespread in many cells and involves numerous genes in addition to the Epo gene. The Epo receptor belongs to the cytokine receptor family and includes a p66 chain which is dimerized upon Epo activation; two accessory proteins defined by cross-linking remain to be characterized. Epo binding induces the stimulation of Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins including the Epo receptor itself. As a result, different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or the differentiation of erythroid cells are regulated after Epo stimulation are not known. Furthermore, target disruption of both Epo and Epo receptor showed that Epo was not involved in the commitment of the erythroid lineage and seemed to act mainly as a survival factor.
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PMID:Biology of erythropoietin. 979 57

Stimulation of the interleukin-6 (IL-6) signalling pathway occurs via the IL-6 receptor-glycoprotein 130 (IL-6R-gp130) receptor complex and results in the regulation of acute-phase protein genes in liver cells. Ligand binding to the receptor complex leads to tyrosine phosphorylation and activation of Janus kinases (Jak), phosphorylation of the signal transducing subunit gp130, followed by recruitment and phosphorylation of the signal transducer and activator of transcription factors STAT3 and STAT1 and the src homology domain (SH2)-containing protein tyrosine phosphatase (SHP2). The tyrosine phosphorylated STAT factors dissociate from the receptor, dimerize and translocate to the nucleus where they bind to enhancer sequences of IL-6 target genes. Phosphorylated SHP2 is able to bind growth factor receptor bound protein (grb2) and thus might link the Jak/STAT pathway to the ras/raf/mitogen-activated protein kinase pathway. Here we present data on the dose-dependence, kinetics and kinase requirements for SHP2 phosphorylation after the activation of the signal transducer, gp130, of the IL-6-type family receptor complex. When human fibrosarcoma cell lines deficient in Jak1, Jak2 or tyrosine kinase 2 (Tyk2) were stimulated with IL-6-soluble IL-6R complexes it was found that only in Jak1-, but not in Jak 2- or Tyk2-deficient cells, SHP2 activation was greatly impaired. It is concluded that Jak1 is required for the tyrosine phosphorylation of SHP2. This phosphorylation depends on Tyr-759 in the cytoplasmatic domain of gp130, since a Tyr-759-->Phe exchange abrogates SHP2 activation and in turn leads to elevated and prolonged STAT3 and STAT1 activation as well as enhanced acute-phase protein gene induction. Therefore, SHP2 plays an important role in acute-phase gene regulation.
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PMID:Activation of the protein tyrosine phosphatase SHP2 via the interleukin-6 signal transducing receptor protein gp130 requires tyrosine kinase Jak1 and limits acute-phase protein expression. 979 95

STAT proteins are activated by phosphorylation at specific tyrosine residue at the carboxy-terminus which is required for dimer-formation, nuclear translocation, DNA binding and transcriptional activity in cells treated with cytokines and growth factors. Recent studies have indicated that STATs are also phosphorylated by MAPK, or extracellular signal-regulated kinase (ERK) on serine. We investigated the role of ERK on the regulation of STAT activity. Here, we report that ERK2 activated by its upstream kinase, MEK1, represses Stat3 transcriptional activity induced by Src or Jak-2. To unravel the mechanism of repression, we further showed that Stat3 DNA binding activity and its tyrosine phosphorylation are also inhibited under the same conditions. ERK2 phosphorylates Stat3 on three serine-containing peptides and decreases its tyrosine phosphorylation induced by EGF treatment. We also detected an association of ERK2 and Stat3 in vivo which is modulated positively by activation of ERK2, but negatively by Jak2. We propose that MAP kinase cascade may negatively regulate Stat3 activities by decreasing its tyrosine phosphorylation and also possibly by association.
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PMID:Repression of Stat3 activity by activation of mitogen-activated protein kinase (MAPK). 987 31

The interaction of fibrinogen (Fg) with intercellular adhesion molecule-1 (ICAM) on B-lymphoid Raji cells results in mitogenesis (Gardiner, E. E., and D'Souza, S. E. (1997) J. Biol. Chem. 272, 15474-15480). Incubation of Raji with Fg resulted in the increased tyrosine phosphorylation of the receptor-associated tyrosine kinase, pp60(Src) and extracellular signal-regulated kinase-1 (ERK). The increase in ERK-1 phosphorylation was blocked by a peptide with sequence matching ICAM-1-(8-22) and corresponded to a decrease in ERK-1 enzymatic activity. 100 microM amounts of Fg peptide gamma-(117-133) caused an increase in tyrosine phosphorylation of ERK-1. These results are consistent with our previous report wherein ICAM-1-(8-22) blocked Fg-induced mitogenesis and Fg-gamma-(117-133) induced proliferation in Raji. The specific inhibitor of MEK, PD98059 (25 microM), abrogated the increased phosphorylation of ERK-1 and blocked Raji mitogenesis by >50%. Inhibitors of pp60(Src), geldanamycin (62 nM), and herbimycin A (2.5 microM) blocked >50% of Raji proliferation. These results indicate that the proliferation induced by Fg interactions with ICAM-1 is mediated in part by receptor-associated tyrosine kinases and ERK-1, and that the recognition sequences within Fg and ICAM-1 participate in the signaling process.
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PMID:Sequences within fibrinogen and intercellular adhesion molecule-1 (ICAM-1) modulate signals required for mitogenesis. 1020 14

Two distinct types of interferon, IFN-alpha/beta and IFN-gamma, commonly exhibit antiviral activities by transmitting signals to the interior of the cell via their homologous receptors. Receptor stimulation results in the activation of distinct combinations of Janus family protein tyrosine kinases (Jak PTKs); Jak1/Tyk2 and Jak1/Jak2 for IFN-alpha/beta and IFN-gamma, respectively. Jak PTK activation by these IFNs is commonly followed by tyrosine phosphorylation of the transcription factor Stat1 at Y701, which is essential for dimerization, translocation to the nucleus and DNA-binding activity. To gain full transcriptional activity, Stat1 also requires serine phosphorylation at S727. In this paper we demonstrate that Pyk2, which belongs to another PTK family, is critical for the Jak-mediated MAPK and Stat1 activation by IFN-gamma, but not IFN-alpha. Pyk2 is selectively associated with Jak2 and activated by IFN-gamma. Overexpression of PKM, a dominant interfering form of Pyk2, in NIH 3T3 cells results in a strong inhibition of the IFN-gamma-induced activation of Erk2, serine phosphorylation of Stat1 and Stat1-dependent gene transcription. Finally, the antiviral action of IFN-gamma, but not IFN-alpha, is severely impaired by PKM overexpression. Thus, the two types of IFN may utilize distinct Jak-mediated Erk2, and possibly other MAPK activation pathways for their antiviral action.
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PMID:Protein tyrosine kinase Pyk2 mediates the Jak-dependent activation of MAPK and Stat1 in IFN-gamma, but not IFN-alpha, signaling. 1022 62

Erythropoietin (Epo) controls the proliferation, differentiation and survival of the erythroid progenitors. Epo exerts its effects by binding to a cell surface receptor. The Epo receptor includes a p66 chain, which is dimerized upon Epo activation, and two accessory proteins, which have been defined by cross-linking. Epo binding induces stimulation of the Jak2 tyrosine kinase. Jak2 activation leads to the tyrosine phosphorylation of several proteins, including the Epo receptor itself. Different intracellular pathways are activated: Ras/MAP kinase, phosphatidylinositol 3-kinase and STAT transcription factors. However, the exact mechanisms by which the proliferation and/or differentiation of erythroid cells are regulated after Epo stimulation are not known. Target disruption of both Epo and Epo receptors showed that Epo is not involved in the commitment of the erythroid lineage; it seems to act mainly as a survival factor. Epo is synthesized largely by the kidney and the liver, and sequences required for tissue-specific expression have been localized in the Epo gene. A 3' enhancer is responsible for hypoxia-inducible Epo gene expression. Hypoxia-induced factor-1 (HIF-1) protein binds to this enhancer. In addition to anaemia of renal failure, the indication for treatment with epoetin has been extended to the anaemia of chronic diseases.
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PMID:The molecular biology of erythropoietin. 1033 64

The MAP kinases have been suggested to play a role in intracellular signalling by PRL. A reporter gene construct, PRE3-CAT, which manifests PRL responsiveness through a Stat5-binding site (PRE), was induced by PRL in CHO cells expressing the PRL-R. A fusion protein (Gal4-Stat5(695)), containing the C-terminal domain of Stat5a (amino acids 695-794) linked to the DNA-binding domain of Gal4 (Gal4 DBD), strongly activated transcription of a luciferase reporter gene. Therefore, the Stat5 C-terminus, which contains a potential MAP kinase phosphorylation site, exhibits a modular transactivating function. A kinase-defective mutant of Erk2 (iMAPK) caused a dose-dependent suppression of PRL-stimulated PRE3-CAT, and also inhibited the induction of PRE3-CAT by Jak2 over-expression. Correspondingly, over-expression of the MAP kinase activator v-Src increased the PRL-stimulated level of PRE3-CAT. Gal4-Stat5(695) activity was not modulated by PRL or Jak2, consistent with the absence of the relevant tyrosine phosphorylation site at residue 694. Gal4-Stat5(695) was not inhibited by iMAPK, indicating that the C-terminal transactivation region of Stat5a is not sensitive to direct modulation of a MAP kinase pathway. These results suggest that alteration of Erk2 activity by growth factors may modulate PRL-induced gene expression by a mechanism upstream of Stat5.
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PMID:Prolactin-independent modulation of the beta-casein response element by Erk2 MAP kinase. 1035 95

Communication between cells of the central nervous system (CNS) and of the immune system is accomplished by a network of cytokines and growth factors. Certain cytokines and growth factors cause activation of microglia, contributing to inflammatory states in the CNS. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has numerous effects on microglia, ranging from induction of proliferation to changes in morphology. GM-CSF is also a growth factor for cells of the myeloid lineage, and the signal tranduction induced by GM-CSF in these cells has been extensively studied. Most notably, the importance of the Jak/STAT and MAP kinase pathways in mitogenesis has been shown in many different systems. We show here that primary microglia and a microglia cell line, BV-2, have a Jak/STAT expression pattern and GM-CSF inducibility similar to that of monocytes and macrophages. Primary microglia and BV-2 cells expressed identical Jak/STATs: Jakl, Jak2, Jak3, Tyk2, STAT1alpha/beta, STAT3, STAT5A, STAT5B, and STAT6. In addition, GM-CSF induced Jak2, STAT5A, and STAT5B in BV-2 cells, as it does in monocytes and macrophages. Immunocytochemical analysis showed that STAT5 translocates to the nucleus following GM-CSF stimulation of microglia. We also found the MAP kinases, ERK1 and ERK2, to be phosphorylated in microglia and BV-2 cells following induction by GM-CSF. Jak2, STAT5A, STAT5B, and ERKs are known to be important in controlling cellular proliferation. Drugs that block these pathways may become tools to control inflammation in the CNS by limiting microglial proliferation.
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PMID:Signal transduction pathways induced by GM-CSF in microglia: significance in the control of proliferation. 1038 53

We compared the role of tyrosine kinases in alpha(1A)-adrenergic receptor (AR) and growth factor receptor stimulation of mitogen-activated protein kinase pathways in PC12 cells. Norepinephrine (NE) (noradrenaline), epidermal growth factor (EGF) and nerve growth factor (NGF) caused different patterns of tyrosine phosphorylation in PC12 cells stably expressing alpha(1A)-ARs. NE increased tyrosine phosphorylation of focal adhesion-related kinase Pyk2 and a 70 kDa protein, probably paxillin, whereas EGF strongly stimulated tyrosine phosphorylation of the EGF receptor and cytokine-activated kinase Jak2. The EGF receptor inhibitor AG1478 inhibited activation of extracellular signal-regulated kinases (ERKs) by EGF but not by NE. EGF and NGF strongly activated tyrosine phosphorylation of Shc and caused association of Src-homology collagen (Shc) with growth-factor-receptor-bound protein 2 (Grb2); however, neither NE nor UTP caused substantial activation of the Shc/Grb2 pathway. NE, UTP, EGF and NGF all increased tyrosine phosphorylation of Src, and this was inhibited by the Src inhibitor PP2. However, PP2 inhibited ERK activation in response to NE and UTP, but not in response to EGF or NGF. PP2 also completely blocked NE-induced PC12 cell differentiation, but had no measurable effect on NGF-induced differentiation. These studies show that activation of mitogen-activated protein kinase pathways by G-protein-coupled receptors and tyrosine kinase receptors proceed through distinct molecular pathways in PC12 cells, and support an obligatory role for Src activation in mitogenic responses to alpha(1A)-ARs in these cells.
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PMID:Activation of tyrosine kinases by alpha1A-adrenergic and growth factor receptors in transfected PC12 cells. 1058 78


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