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 immunosuppressant drug FK506 (tacrolimus) accelerates nerve regeneration in vivo and increases neurite elongation in vitro. We have proposed that the mechanism involves binding to the FK506-binding protein 52, a chaperone component of mature steroid receptor complexes, and a subsequent 'gain-of-function' involving p23 dissociation from Hsp-90 in the complex and extracellular signal-regulated kinase (ERK) activation. Here, we tested the involvement of the ERK and p23 in neurite elongation by FK506 in human SH-SY5Y cells. FK506 (10 nM) increased ERK1/2 phosphorylation at 12 and 24 h, eliciting a 3.5-fold increase at 24 h, which was inhibited in a concentration-dependent manner by an antibody (JJ3) to recombinant human p23. Neurite elongation by FK506 (10 nM), determined by measuring neurite lengths at 96 and 168 h, was completely blocked by the mitogen-activated protein kinase inhibitor PD 098059 (10 microM) and prevented, in a concentration-dependent fashion, by the p23 antibody. Taken together, the results demonstrate the functional role for ERK and p23 in the neurite elongation activity of FK506 and reveal a novel signal transduction pathway involving p23 activation of ERK. We suggest that compounds that stimulate or mimic p23 may be useful for accelerating nerve regeneration.
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PMID:FK506 requires stimulation of the extracellular signal-regulated kinase 1/2 and the steroid receptor chaperone protein p23 for neurite elongation. 1506 99

Members of the FKBP family play various functions within the cell. For T cell biology essential is their involvement in the regulation of cytokine genes transcription, mainly at the level of nucleocytoplasmic transport of transcription factors. FKBP12 is the mediator of immunosuppressive action of FK506. When complexed with the drug, FKBP12 blocks nuclear import of NFAT and formation of AP-1 heterodimer, due to inhibition of calcium-dependent phosphatase calcineurin and JNK/p38 pathways. Suppression of these two, and possibly some other signaling pathways leads to prevention of IL-2 expression and T cell activation. FKBP51 and FKBP52 are natural components of glucocorticoid receptor complex and direct regulators of its activity. Upon ligand binding FKBP51, maintaining receptor in the cytoplasm, is exchanged by FKBP52, which allows translocation of the complex to the nucleus. Thereby FKBPs take a part in the regulation of immune response by glucocorticoids.
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PMID:[FK506 - binding proteins in the regulation of transcription factors activity in T cells]. 1507 60

Adenosine enhances nerve growth factor (NGF)-induced neurite outgrowth in PC12 cells. We found that adenosine increases NGF-induced phosphorylation of extracellular signal-regulated kinase (ERK), but decreases the duration of phosphorylation of p38 mitogen-activated protein (MAP) kinase. Therefore, we further examined the involvement of protein phosphatase in these effects of adenosine. FK506, a specific calcineurin inhibitor, inhibited the enhancing effect of adenosine on the NGF-induced neurite outgrowth and increased the duration of p38 MAP kinase phosphorylation without affecting ERK phosphorylation. These results suggest that adenosine decreases the duration of p38 MAP kinase via calcineurin activation, which contributes to the enhancement of NGF-induced neurite outgrowth.
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PMID:Calcineurin contributes to the enhancing effect of adenosine on nerve growth factor-induced neurite outgrowth via the decreased duration of p38 mitogen-activated protein kinase phosphorylation. 1515 59

The aim of this study was to determine whether FK506, which has been shown to be effective for the treatment of refractory RA, affects the synthesis of matrix metalloproteinases (MMPs) in rheumatoid synovial fibroblasts. Synovial fibroblasts isolated from rheumatoid synovium were incubated in 6-well culture plates for 24 h with FK506 and interleukin-1beta, alone and in combination. Samples of supernatants were assayed by ELISA or immunoblottings using anti-MMP-13 specific antibodies. In addition, synovial fibroblasts pretreated with FK506 were stimulated with IL-1beta for 10 min and cellular lysates were subjected to anti-phospho-specific mitogen-activated protein kinase (MAPK). Unstimulated synovial fibroblasts produced low levels of MMP-3 and 13. IL-1beta-induced substantial output of these MMPs into cell supernatants. FK506 had no detectable effects on IL-1beta-induced MMP-2 induction. FK506, however, significantly suppressed MMP-13 production from IL-1beta-stimulated synovial fibroblasts. FK506 also prevented IL-1beta-stimulated JNK activation and transcriptional activation of AP-1 in these cells. Our results indicate that FK506 is capable of regulating MMP-13 synthesis via JNK pathway in rheumatoid synonvium.
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PMID:FK506 suppresses the stimulation of matrix metalloproteinase 13 synthesis by interleukin-1beta in rheumatoid synovial fibroblasts. 1586 Feb 18

Bupleuran 2IIc, a pectic polysaccharide isolated from the roots of bupleurum falcatum L., was previously characterized as a T-cell-independent B cell mitogen. This study focuses on elucidating the mechanism by which bupleuran 2IIc induces cyclin D2 production for inducing mitogenesis in murine B cells. Bupleuran 2IIc was digested with endo-alpha-(1-->4)-D-polygalacturonase and the resulting bupleuran 2IIc/PG-1 ("ramified" region) strongly stimulated cyclin D2 expression. When murine B cells were stimulated with bupleuran 2IIc/PG-1, phosphorylation of tyrosine residues of a number of proteins was observed. Cyclin D2 expression by bupleuran 2IIc/PG-1 was inhibited by the tyrosine kinase inhibitors, genistein and herbimycin A, and the Src family tyrosine kinase inhibitor, PP2, suggesting a possible role for tyrosine kinases. The stimulation by bupleuran 2IIc/PG-1 of cyclin D2 expression was significantly decreased by inhibitors, PI 3-kinase (LY294002 and Wortmannin), PLCgamma (U73122), PKC (H-7), receptor-operated calcium entry inhibitor (SK&F 96365), and calcineurin (FK506). Both PD98059 and U0126, highly selective inhibitors of MEK1 and MEK1/2, respectively, did not strongly suppress the expression of cyclin D2 after stimulation by bupleuran 2IIc/PG-1. The results suggest that (1) bupleuran 2IIc/PG-1 is the active site for induction of cyclin D2 by bupleuran 2IIc, (2) the expression of the cyclin D2 gene by bupleuran 2IIc/PG-1 may be mediated via the activation of PI 3-kinase and PLCgamma followed by activation of PKC and calcium mobilization, and (3) the ERK1/2 cascade is not a central signaling pathway for bupleuran 2IIc/PG-1-induced cyclin D2 expression.
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PMID:A possible signal transduction pathway for cyclin D2 expression by a pectic polysaccharide from the roots of bupleurum falcatum L. in murine B cell. 1595 64

To investigate the function of dimerization of the TRH receptor, a controlled dimerization system was developed. A variant FK506 binding protein (FKBP) domain was fused to the receptor C terminus and dimerization induced by incubating cells with dimeric FKBP ligand, AP20187. The TRH receptor-fusion bound hormone and signaled normally. Addition of dimerizer to cells expressing the receptor-FKBP fusion dramatically increased the fraction of receptor running as dimer on SDS-PAGE. AP20187 caused dimerization in a time- and concentration-dependent manner, acting within 1 min. Dimerizer had no effect on TRH receptors lacking the FKBP domain, and its effects were blocked by excess monomeric FKBP ligand. AP20187-induced dimerization did not cause receptor phosphorylation, inositol phosphate production, or ERK1/2 activation, and dimerizer did not alter signaling by TRH. Induced dimerization did, however, alter TRH receptor trafficking. TRH promoted greater receptor internalization in cells treated with AP20187 but not monomeric ligand, based on loss of surface binding sites and immunostaining. Dimerization increased the rate of internalization of TRH receptors and decreased the apparent rate of receptor recycling. AP20187 enhanced the small amount of TRH-induced receptor internalization when the receptor-FKBP fusion protein was expressed in cells lacking beta-arrestins. The results show that controlled dimerization of the TRH receptor potentiates hormone-induced receptor trafficking.
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PMID:Regulated dimerization of the thyrotropin-releasing hormone receptor affects receptor trafficking but not signaling. 1602 Apr 81

In the developing cerebellum, switching of subunit composition of NMDA receptors occurs in granule cells from NR2B subunit-containing receptors to NR2C subunit-containing receptors. This switching of subunit composition plays an important role in the establishment of functional mossy fiber-granule cell synaptic transmission in the mature cerebellar network. The mechanism underlying NR2C upregulation in developing granule cells, however, has to date remained to be determined. In granule cells cultured in low (5 mm) KCl, brain-derived neurotrophic factor (BDNF) upregulated NR2C mRNA via the TrkB-extracellular signal-regulated kinase (ERK) 1/2 cascade and promoted the formation of an NR2C-containing NMDA receptor complex. In granule cells cultured in high (25 mm) KCl, depolarization stimulated voltage-sensitive Ca2+ channels. The resultant increase in intracellular Ca2+ activated Ca2+/calmodulin-dependent calcineurin phosphatase and blocked NR2C mRNA upregulation. Interestingly, the depolarization-induced Ca2+ increase simultaneously upregulated BDNF mRNA via Ca2+/calmodulin-dependent protein kinase (CaMK). Consequently, when calcineurin was inhibited by its inhibitor FK506 under the depolarizing condition, the CaMK-mediated increase in BDNF became a stimulatory signal, and the endogenous BDNF autocrine system was capable of upregulating NR2C mRNA via the common TrkB-ERK cascade. The importance of the BDNF-TrkB pathway was further supported by a significant reduction in NR2C in normally migrated granule cells of TrkB(-/-) knock-out mice in vivo. The convergent mechanism of the BDNF and Ca2+ signaling cascades thus plays an important regulatory role in NR2C induction in granule cells during cerebellar development.
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PMID:Neuronal depolarization controls brain-derived neurotrophic factor-induced upregulation of NR2C NMDA receptor via calcineurin signaling. 1622 64

Immunosuppressants such as cyclosporinA and FK506 (tacrolimus) are widely prescribed to treat numerous disorders and to treat organ transplant recipients. However, cyclosporine A and FK506 are both known to produce hypomagnesaemia. The mechanism of this effect is still unclear. The present study determined the effects of immunosuppressant treatment on the parathyroid hormone (PTH) mediated Mg(2+) uptake and the mitogen-activated protein kinase (MAPK) activation in mouse distal convoluted tubule (MDCT) cells. The intracellular Ca(2+) and Mg(2+) concentrations in a single MDCT cell were measured by using the fluorescentdye Fura-2 AM and Mag-fura-2 AM, respectively. Cyclosporine A and FK506 illicited a transient increase of intracellular Ca(2+) from a basal level of 99 +/- 16 nM to 685 +/- 105 and 608 +/- 96 nM, respectively. In order to determine the Mg(2+) transport, the MDCT cells were Mg(2+)-depleted by culturing them in Mg(2+)-free media for 16 h, and the Mg(2+) uptake was measured by microfluorescence after placing the depleted cells in 1.5mM MgCl(2). The mean rate of Mg(2+) uptake, d([Mg(2+)](i))/dt, was 140 +/- 16 nM/s in the control MDCT cells. PTH increased the Mg(2+) uptake more than 2 times in this cell. Cyclosporine A (10 microM) and FK506 (0.1 microM) did not affect the basal Mg(2+)uptake (140 +/- 16 and 142 +/- 14 nM/s, respectively), but they inhibited the PTH-stimulated Mg(2+) entry, decreasing it from 248+/-12 to 147 +/- 7 and 148 +/- 14 nM/s, respectively. These effects were inhibited by L685818, which is a potent competitive antagonist of FK506. PTH stimulated the extracellular signal-regulated kinase1/2 (ERK1/2) protein synthesis. This PTH-stimulated ERK1/2 activation was inhibited by cyclosporine A and FK506. In the present study, the role of ERK1/2 activation on the PTH-dependent magnesium uptake was examined in MDCT cells, and we showed that immunosuppressants inhibit the hormone-stimulated Mg(2+) uptake into the MDCT cells by inhibiting the MAPK pathway.
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PMID:Immunosuppressants inhibit hormone-stimulated Mg2+ uptake in mouse distal convoluted tubule cells. 1643 32

Fludioxonil is employed as an agricultural fungicide to control plant-pathogenic fungi such as Botrytis cinerea. Cryptococcus neoformans is a basidiomycetous human fungal pathogen that causes fatal disease in immunocompromised hosts. This paper demonstrates that three different signalling cascades regulate sensitivity of C. neoformans to fludioxonil. Fludioxonil inhibited growth of the serotype A sequence reference strain H99 but not that of the sequenced serotype D strain JEC21. In the drug-sensitive wild-type strain, fludioxonil exposure activated the Hog1 osmosensing pathway, and hog1Delta mutations conferred fludioxonil resistance. Fludioxonil treatment caused cell growth inhibition following cell swelling and cytokinesis defects in the sensitive wild-type but not in a hog1Delta mutant strain, suggesting that Hog1 activation results in morphological cellular defects. Fludioxonil exerted a fungistatic effect on the wild-type strain H99, but exhibited fungicidal activity against calcineurin mutant strains, indicating that the calcineurin pathway contributes to drug resistance in this fungus. Combination of fludioxonil and the calcineurin inhibitor FK506 synergistically inhibited C. neoformans growth. mpk1Delta MAPK mutant strains exhibited fludioxonil hypersensitivity, indicating that this pathway also contributes to drug resistance. These studies provide evidence that the broad-spectrum antifungal drug fludioxonil exerts its action via activation of the Hog1 MAPK pathway and provide insight into novel targets for synergistic antifungal drug combinations.
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PMID:Calcineurin, Mpk1 and Hog1 MAPK pathways independently control fludioxonil antifungal sensitivity in Cryptococcus neoformans. 1651 40

The aim of this study was to examine possible interactions of ERK and calcineurin in cardioprotection afforded by delta-opioid receptor stimulation. Infarction was induced in rat hearts by 20-min coronary occlusion and reperfusion. Tissue ERK level and calcienurin activity were determined by immunoblotting and an assay using a phosphopeptide substrate, respectively. Administration of a delta-opioid receptor agonist, D-Ala2-D-Leu5-enkephalin (DADLE, 1 mg/kg), before ischemia increased the phospho-ERK levels during ischemia and reduced infarct size (as percentage of risk area, %IS/AR) from 47.7 +/- 2.3% to 23.2 +/- 2.5%. This protection was abolished by 10 mg/kg of natrindole hydrochloride (NTI), a delta-opioid receptor antagonist. PD98059, a MEK1/2 inhibitor, abolished both ERK1/2 activation and infarct size limitation by DADLE. Calcineurin inhibitors, cyclosporine-A (5 mg/kg) and FK506 (3.5 mg/kg), reduced %IS/AR (27.4 +/- 4.4% and 29.9 +/- 3.4%, respectively). The protective effects of these calcineurin inhibitors were inhibited by PD98059, and the combination of DADLE with cyclosporine-A or FK506 did not afford further cardioprotection. DADLE significantly suppressed myocardial calcineurin activity, and this effect was inhibited by NTI. Suppression of calcineurin activity by FK506 was associated with modest activation of ERK1/2. These results suggest that suppression of calcineurin and activation of ERK1/2 are interacting mechanisms involved in cardioprotection by delta-opioid receptor activation.
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PMID:Activation of ERK and suppression of calcineurin are interacting mechanisms of cardioprotection afforded by delta-opioid receptor activation. 1661 6


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