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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transcription factor Elk-1 is a component of ternary complex factor and regulates gene expression in response to a wide variety of extracellular stimuli. Phosphorylation of the C-terminal domain of Elk-1, especially at serine 383, is important for its transactivation activity. Recently mitogen-activated protein kinases, such as extracellular signal-regulated kinase, stress-activated protein kinase, and p38 mitogen-activated protein kinase have been demonstrated to be Elk-1 kinases. However, negative regulators of Elk-1, such as protein phosphatases, still remain to be identified. Here we report that COS cell lysates were able to dephosphorylate an extracellular signal-regulated kinase-phosphorylated glutathione S-transferase-Elkc fusion protein, including serine 383. The phosphatase activity was inhibited by cyclosporin A (a calcineurin inhibitor) but not by okadaic acid (a PP1 and PP2A inhibitor). Purified calcineurin also could efficiently dephosphorylate glutathione S-transferase-Elkc in vitro. Pretreatment of COS cells with cyclosporin A significantly enhanced epidermal growth factor-induced serine 383 Elk-1 phosphorylation whereas ionomycin inhibited the Elk-1 phosphorylation. These data provide both in vitro and in vivo evidence that calcineurin is the major Elk-1 phosphatase and plays a critical role in Elk-1 regulation. The identification of calcineurin as the major Elk-1 phosphatase may provide a mechanism for Elk-1 regulation by Ca2+ signals as well as a possible biochemical basis for the neurotoxicity and nephrotoxicity of the immunosuppressant drug cyclosporin A.
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PMID:The calcium/calmodulin-dependent protein phosphatase calcineurin is the major Elk-1 phosphatase. 936 95

Organization of intermediate filament, a major component of cytoskeleton, is regulated by protein phosphorylation/dephosphorylation, which is a dynamic process governed by a balance between the activities of involved protein kinases and phosphatases. Blocking dephosphorylation by protein phosphatase inhibitors such as okadaic acid (OA) leads to an apparent activation of protein kinase(s) and to genuine activation of phosphatase-regulated protein kinase(s). Treatment of 9L rat brain tumor cells with OA results in a drastically increased phosphorylation of vimentin, an intermediate filament protein. In-gel renaturing assays and in vitro kinase assays using vimentin as the exogenous substrate indicate that certain protein kinase(s) is activated in OA-treated cells. With specific protein kinase inhibitors, we show the possible involvement of the cdc2 kinase- and p38 mitogen-activated protein kinase (p38MAPK)-mediated pathways in this process. Subsequent in vitro assays demonstrate that vimentin may serve as an excellent substrate for MAPK-activated protein kinase-2 (MAPKAPK-2), the downstream effector of p38MAPK, and that MAPKAPK-2 is activated with OA treatment. Comparative analysis of tryptic phosphopeptide maps also indicates that corresponding phosphopeptides emerged in vimentin from OA-treated cells and were phosphorylated by MAPKAPK-2. Taken together, the results clearly demonstrate that MAPKAPK-2 may function as a vimentin kinase in vitro and in vivo. These findings shed new light on the possible involvement of the p38MAPK signaling cascade, via MAPKAPK-2, in the maintenance of integrity and possible physiological regulation of intermediate filaments.
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PMID:Identification of mitogen-activated protein kinase-activated protein kinase-2 as a vimentin kinase activated by okadaic acid in 9L rat brain tumor cells. 977 16

We have reported that treatment with okadaic acid, a potent protein phosphatase inhibitor, has the ability to enhance the synthesis of the 78-kDa glucose-regulated protein (GRP78). This article reports our investigation of another protein phosphatase inhibitor, calyculin A, demonstrating the signaling pathways elicited by the protein phosphatase inhibitors that lead to the induction of grp78. Our data showed that the induction process is abolished by SB203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38(MAPK)). Phosphorylation-activation of p38(MAPK) in the treated cells was indicated by its own phosphorylation, as shown by double Western blotting analyses and directly confirmed by the in vitro kinase assay using MAPK-activated protein kinase-2, a well-known downstream effector of p38(MAPK), as a substrate. The involvement of p38(MAPK) in this process is further substantiated by using transient transfection assays with a plasmid, pGRP78-Luc, which contains a 0.72-kbp stretch of the grp78 promoter. By exploiting the same transfection assay, we demonstrated that the up-regulation of the grp78 promoter by the protein phosphatase inhibitors is suppressed in the presence of the cytoplasmic calcium chelator bis(aminophenoxy)ethane N,N'-tetraacetic acid, the mitochondria calcium uniporter inhibitor ruthenium red as well as the antioxidants N-acetyl cysteine and pyrrolidinedithiocarbamate. Taken together, our results lead us to conclude that treatment with the protein phosphatase inhibitors would activate the signaling pathways involving p38(MAPK) and mitochondrial calcium-mediated oxidative stress and that these pathways must act in concert in order to confer the induction of grp78 by okadaic acid and calyculin A.
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PMID:Activation of p38 mitogen-activated protein kinase and mitochondrial Ca(2+)-mediated oxidative stress are essential for the enhanced expression of grp78 induced by the protein phosphatase inhibitors okadaic acid and calyculin A. 1065 78

We examined the possibility that p38 mitogen-activated protein kinase and caspase-3 would be activated for execution of apoptosis and excitotoxicity, the two major types of neuronal death underlying hypoxicischemic and neurodegenerative diseases. Mouse cortical cell cultures underwent widespread neuronal apoptosis 24 h following exposure to 10-30 nM calyculin A, a selective inhibitor of Ser/Thr phosphatase I and IIA. Activity of p38 was increased 2-4 h following exposure to 30 nM calyculin A. Addition of 3-10 microM PD169316, a selective p38 inhibitor, partially attenuated calyculin A neurotoxicity. Activity of caspase-3-like proteases was increased in cortical cell cultures exposed to 30 nM calyculin A for 8-16 h as shown by cleavage of DEVD-p-nitroanilide and phosphorylated tau. Proteolysis of tau was completely blocked by addition of 100 microM N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk), a broad-spectrum inhibitor of caspases, but incompletely by 10 microM PD169316. Calyculin A neurotoxicity was partially sensitive to 100 microM z-VAD-fmk. Cotreatment with 10 microM PD169316 and 100 microM z-VAD-fmk showed additive neuroprotection against calyculin A. Neither PD169316 nor z-VAD-fmk showed a beneficial effect against excitotoxic neuronal necrosis induced by exposure to 20 microM NMDA. Thus, caspase-3-like proteases and p38 likely contribute to calyculin A-induced neuronal apoptosis but not NMDA-induced neuronal necrosis.
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PMID:Synergetic activation of p38 mitogen-activated protein kinase and caspase-3-like proteases for execution of calyculin A-induced apoptosis but not N-methyl-d-aspartate-induced necrosis in mouse cortical neurons. 1082 Feb 6

Heat-shock proteins are found in organisms as diverse as slime moulds, bacteria, plants and higher eukarycotes. They play fundamental roles in cell function, ranging from protein folding to transmembrane protein movement, to serving as scaffolds or frameworks for the assembly of enzyme signalling complexes such as the steroid receptors. Intracellular concentrations may be high, in the range of structural proteins such as actin, with which they often interact. Therefore, it is not surprising that heat-shock proteins are present in blood platelets, and recent studies point to important roles in platelet function. The small heat-shock protein, hsp27, becomes phosphorylated following cell stimulation with thrombin and associates with the actin-rich cytoskeleton. Phosphorylation results from activation of a protein kinase cascade involving the p38 mitogen-activated protein kinase (MAPK), the MAPKAP-K2 kinase, as well as PRAK, or p38-regulated protein kinase. Intriguingly, platelet hsp27 can associate with platelet factor XIII, suggesting a role for regulation of transglutaminase activity in stabilizing fibrin-platelet clots. The higher molecular-weight heat-shock proteins hsc70 and hsp90 are also present in platelets, being found in a large phosphorylated complex that contains the catalytic and myosin-targeting subunits of protein phosphatase 1 (PP1). Platelet adhesion to collagen via the alpha 2 beta 1 integrin causes the rapid dissociation of this complex and dephosphorylation of components. These results suggest that hsc70 and hsp90 can serve as signalling scaffolds, helping regulate function, including platelet adhesion and spreading via modulation of protein phosphatase activity. Hsp27, on the other hand, may be more involved in controlling actin polymerization during the platelet shape change and subsequent aggregation.
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PMID:Heat-shock proteins and platelet function. 1093 76

A compelling body of evidence suggests a role for Thy-1 (CD90), a cell surface glycoprotein of mouse T lymphocytes, in signal transduction resulting in T cell activation. Despite more than 3 decades of investigation, intracellular biochemical events governing the Thy-1 signaling cascade are only vaguely understood. We have employed selective pharmacological inhibitors of signaling molecules to compare downstream elements participating in the Thy-1 signal transduction pathway with those involved in the T cell receptor (TCR)/CD3-associated signaling pathway. Mitogenic anti-Thy-1 or anti-CD3 monoclonal antibody (mAb) were used to cause T cells from C57BL/6 mice to proliferate in the presence or absence of different pharmacological inhibitors. Cyclosporine A, herbimycin A, LY294002, calphostin C and PD98059 all inhibited anti-Thy-1-induced T lymphocyte proliferation, indicating the involvement of calcineurin, protein tyrosine kinases, phosphatidylinositol 3-kinase, protein kinase C, and MEK1 (MAPK kinase 1), respectively, in Thy-1 signaling. Similar results were obtained when T cells were stimulated through the TCR with anti-CD3 monoclonal antibody in the presence or absence of the different inhibitors. Interestingly, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 augmented anti-Thy-1-induced T cell proliferation, whereas anti-CD3-induced proliferative response was partially suppressed by the same inhibitor. The Thy-1 signal transduction pathway, therefore, shares a requirement for calcineurin and several major kinase families with the TCR signaling pathway. However, Thy-1 and TCR-associated signaling pathways are differentially regulated by p38 MAPK.
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PMID:Selective pharmacological inhibitors reveal differences between Thy-1- and T cell receptor-mediated signal transduction in mouse T lymphocytes. 1135 81

We have previously demonstrated that calcineurin and p38 mitogen-activated protein kinase (MAPK) are up-regulated in the hearts of mdx mice. However, the degree of up-regulation observed was variable, which may reflect variable levels of daily physical activities among the mice. To investigate whether or not exercise affects dystrophic features and activates intracellular signaling molecules in mdx hearts, we subjected mdx and C57BL/10 mice to treadmill exercise and examined intracellular signaling molecules in cardiac muscles, at the protein level. The heart to body weight ratio was significantly increased in exercised mdx mice. Histopathology in exercised mdx hearts showed extensive infiltration of inflammatory cells, together with increases in interstitial fibrosis and adipose tissues, all of which were not observed either in exercised C57BL/10 or non-exercised mdx hearts. Phosphorylated p38 MAPK, phosphorylated extracellular signal-regulated kinase 1/2 and calcineurin, but not phosphorylated c-Jun N-terminal kinase 1, were up-regulated in exercised mdx hearts compared to exercised C57BL/10 or non-exercised mdx hearts. These data suggest that physical exercise accelerates the dystrophic process through activation of intracellular signaling molecules in dystrophin-deficient hearts.
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PMID:Progression of dystrophic features and activation of mitogen-activated protein kinases and calcineurin by physical exercise, in hearts of mdx mice. 1204 63

In this report, we identify myogenin as an important transcriptional target under the control of three intracellular signaling pathways, namely, the p38 mitogen-activated protein kinase- (MAPK), calcium-calmodulin-dependent protein kinase- (CaMK), and calcineurin-mediated pathways, during skeletal muscle differentiation. Three cis-elements (i.e., the E box, myocyte enhancer factor [MEF] 2, and MEF3 sites) in the proximal myogenin promoter in response to these three pathways are defined. MyoD, MEF2s, and Six proteins, the trans-activators bound to these cis-elements, are shown to be activated by these signaling pathways. Our data support a model in which all three signaling pathways act in parallel but nonredundantly to control myogenin expression. Inhibition of any one pathway will result in abolished or reduced myogenin expression and subsequent phenotypic differentiation. In addition, we demonstrate that CaMK and calcineurin fail to activate MEF2s in Rhabdomyosarcoma-derived RD cells. For CaMK, we show its activation in response to differentiation signals and its effect on the cytoplasmic translocation of histone deacetylases 5 are not compromised in RD cells, suggesting histone deacetylases 5 cytoplasmic translocation is necessary but not sufficient, and additional signal is required in conjunction with CaMK to activate MEF2 proteins.
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PMID:p38 Mitogen-activated protein kinase-, calcium-calmodulin-dependent protein kinase-, and calcineurin-mediated signaling pathways transcriptionally regulate myogenin expression. 1205 61

Collagen and the cross-linked collagen-related peptide (CRP-XL) each induced platelet p38 mitogen-activated protein kinase (p38) phosphorylation after 2 min. Subsequent dephosphorylation occurred in platelets activated with collagen, but not with CRP-XL, demonstrating glycoprotein VI-independent regulation of p38. Okadaic acid and fostriecin, inhibitors specific for protein phosphatase 2A (PP2A), blocked p38 dephosphorylation, and PP2A co-immunoprecipitated with phospho-p38. In addition, use of phenylarsine oxide suggested that tyrosine phosphatases and PP2A may act in concert to dephosphorylate p38. Finally, regulation of p38 in collagen-stimulated Glanzmann's platelets was indistinguishable from that in normal platelets, showing that p38 regulation is independent of integrin alphaIIbbeta3.
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PMID:P38 mitogen-activated protein kinase dephosphorylation is regulated by protein phosphatase 2A in human platelets activated by collagen. 1229 94

One of the immediate early microglial genes that are up-regulated in response to proinflammatory stimuli is cyclo-oxygenase 2 (COX-2). In the present study, we have investigated the effects of alpha-tocopherol (alpha TocH), an essential constituent of the nervous system, on the activation of COX-2 in lipopolysaccharide (LPS)-stimulated mouse BV-2 microglia. In unstimulated BV-2 cells, COX-2 mRNA and protein were almost undetectable but were strongly up-regulated in response to LPS. Activation of COX-2 protein synthesis in LPS-stimulated BV-2 cells involved activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (MAPK) pathway and was sensitive to the protein kinase C (PKC) inhibitors staurosporine and chelerythrine, and the MAP kinase/ERK kinase 1/2 inhibitors PD98059 and U0126. Supplementation of BV-2 cells with alpha TocH before LPS stimulation resulted in pronounced up-regulation of protein phosphatase 2A (PP2A) activity, down-regulation of PKC activity, ERK1/2 phosphorylation and nuclear factor kappa B (NF kappa B) activation. As a result, COX-2 protein levels and prostaglandin E(2) production were significantly lower in alpha TocH-supplemented cells. The effects of alpha TocH on PKC activity could be reverted by calyculin A and okadaic acid, two PP inhibitors. In summary, our results suggest that alpha TocH activates microglial PP2A activity and thereby silences an LPS-activated PKC/ERK/NF kappa B signalling cascade resulting in significantly attenuated COX-2 protein synthesis. These in vitro results imply that alpha TocH could induce quiescence to pathways that are associated with acute or chronic inflammatory conditions in the central nervous system.
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PMID:Vitamin E (alpha-tocopherol) attenuates cyclo-oxygenase 2 transcription and synthesis in immortalized murine BV-2 microglia. 1242 20


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