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)

Several neutrophil protein kinases that undergo changes in activity during Fc gamma RII activation have been investigated. These kinases include calcium/calmodulin-dependent protein kinase II (CAMPKII), mitogen-activated protein kinase (MAPK), and histone H4 protein kinase (PKH4). They are rapidly and transiently activated in a dose-dependent manner by the cross-linking of Fc gamma RII. The activation of CAMPKII but neither PKH4 nor MAPK was inhibited by treating the cells with either a tyrosine kinase inhibitor, genistein, or an intracellular calcium chelator, BAPTA/AM. The superoxide production induced by cross-linking Fc gamma RII can be inhibited partially by various protein kinase inhibitors: 33% by protein kinase C inhibitor calphostin C, 30% by CAMPKII inhibitor KN-62, and 62% by tyrosine kinase inhibitor genistein. These results indicate that cross-linking of Fc gamma RII induces multiple signaling pathways that lead to the activation of various protein kinases. The activation of these kinases may be involved directly or indirectly in the regulation of superoxide production.
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PMID:Activation of multiple protein kinases induced by cross-linking of Fc gamma RII in human neutrophils. 753 49

The protein sequence of MAP kinase-activated protein kinase 2 (MAPKAP kinase 2) deduced from mouse cDNA sequence reveals structural features of the enzyme, which could be of importance for its function: a proline-rich SH3-binding domain N-terminal to the catalytic region, a MAP kinase phosphorylation site and a bipartite nuclear targeting sequence located C-terminal to the catalytic region. The catalytic domain itself has the strongest homology to calcium/calmodulin-dependent protein kinase II. Northern blot analysis demonstrates a 3.5 kb MAPKAP kinase 2 transcript which is ubiquitously expressed and, hence, co-expressed with the mRNA of the recently identified substrate Hsp25 in all tissues analysed. However, the functional consequences of the nuclear targeting sequence present in MAPKAP kinase 2 suggest the existence of further substrates for the enzyme in the nucleus.
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PMID:The MAP kinase-activated protein kinase 2 contains a proline-rich SH3-binding domain. 826 98

In renal proximal tubules, the basolateral organic anion [p-aminohippurate (PAH)] transporter is functionally coupled to the sodium-dependent dicarboxylate transporter. This study was undertaken to elucidate whether protein kinases differentially modulate the activities of these transporters. In isolated S(2) segments of proximal tubules microdissected from rabbit kidneys, we investigated whether the transporters are regulated by tyrosine kinases, phosphatidylinositol 3-kinase (PI3K), and mitogen-activated protein kinase (MAPK). The tubules were collapsed; hence, tubular uptake of the marker substances [(3)H]PAH and [(14)C]glutarate reflects transport across the basolateral cell membrane. Genistein, a selective inhibitor of tyrosine kinase, diminished PAH uptake at 10(-7) M by 15.6 +/- 11.7% and at 10(-6) M by 25.6 +/- 9.1%. An inactive analog of genistein, diadzein, was without effect even at a concentration 100-fold higher than the lowest concentration of genistein, which produced significant reduction of PAH uptake. At 10(-7) M, wortmannin, a selective inhibitor of PI3K, reduced PAH uptake by 24.1 +/- 11.3% and, at 10(-6) M, it reduced it by 32.9 +/- 11.8%. The selective inhibitor of MAPK, PD98059, diminished PAH uptake at 5 x 10(-5) M by 23.2 +/- 6.8% and at 10(-4) M by 18.3 +/- 5.2%. Glutarate uptake was not reduced by any of these protein kinase inhibitors. Insulin had no effect on PAH uptake. These findings indicate that, in addition to protein kinase A, protein kinase C and calcium/calmodulin-dependent protein kinase II (former studies from this laboratory), as well as tyrosine kinases, PI3K, and MAPK, modulate renal basolateral PAH transport, whereas none of these protein kinases affects basolateral glutarate transport. Thus, the results provide evidence for differential regulation of basolateral transporters for PAH and dicarboxylates.
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PMID:Evidence for differential regulation of renal proximal tubular p-aminohippurate and sodium-dependent dicarboxylate transport. 1041 82

Rats were trained in one-trial step-down inhibitory avoidance and tested either 3 h or 31 days later. Ten minutes prior to the retention test, through indwelling cannulae placed in the CA1 region of the dorsal hippocampus, they received 0.5 microl infusions of: saline, a vehicle (2% dimethylsulfoxide in saline), the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5) (5.0 microg), the AMPA/kainate receptor blocker, cyanonitroquinoxaline dione (CNQX) (0.25 or 1.25 microg), the metabotropic receptor antagonist, methylcarboxyphenylglycine (MCPG) (0.5 or 2.5 microg), the inhibitor of calcium/calmodulin-dependent protein kinase II (KN62) (3.5 microg), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), the stimulant of the same enzyme, Sp-cAMPs (0.1 or 0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK) kinase, PD098059 (10 or 50 microM). CNQX, KN62 and PD098059 were dissolved in the vehicle; the other drugs were dissolved in saline. All these drugs, at the same doses, had been previously found to affect short- and long-term memory formation of this task. Retrieval measured 3 h after training (short-term memory) was blocked by CNQX and MCPG, and was unaffected by all the other drugs. In contrast, retrieval measured at 31 days was blocked by MCPG, Rp-cAMPs and PD098059, enhanced by Sp-cAMPs, and unaffected by CNQX, AP5 or KN62. The results indicate that, in CA1, glutamate metabotropic receptors are necessary for the retrieval of both short- and long-term memory; AMPA/kainate receptors are necessary for short-term but not long-term memory retrieval, and NMDA receptors are uninvolved in retrieval. Both the PKA and MAPK signalling pathways are required for the retrieval of long-term but not short-term memory.
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PMID:Different hippocampal molecular requirements for short- and long-term retrieval of one-trial avoidance learning. 1084 Jan 35

The conversion of the egg to a zygote requires the initiation of several signaling pathways that act in an orchestrated fashion to rapidly remodel the egg. Architectural elements within the egg can serve to localize components of these signaling pathways and colocalization of such components provides the opportunity for interaction between different signaling pathways. This study examines the localization as well as the state of activation of two different kinases, MAP kinase and calcium/calmodulin-dependent protein kinase II (CaM KII). The meiotic spindle serves as a site for enrichment of these kinases. However, activated MAP kinase and activated CaM KII exhibit a developmental stage-specific pattern of localization that represents a subset of the area occupied by the distribution of the total mass of MAP kinase and CaM KII. Suppression of CaM KII activity results in reduction in the amount of MAP kinase as well as a decreased level of activity of MAP kinase. Since CaM KII becomes active as a result of fertilization, the former kinase could serve to potentiate MAP kinase activity and the colocalization of these two kinases may facilitate such an interaction.
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PMID:Colocalization of CaM KII and MAP kinase on architectural elements of the mouse egg: potentiation of MAP kinase activity by CaM KII. 1114 23

Pavlovian conditioning involves the association of initially neutral conditioned stimuli (CS) with unconditioned stimuli (US) that elicit a response. In contextual fear conditioning in rodents, the CS is the context of a training apparatus and the US is a foot shock. Retrieval of memory of the training is tested by presenting the CS alone. But a retrieval test also initiates extinction of the conditioned response. That is, presentation of the CS alone results in new learning, i.e., the CS no longer predicts the US. Here we report that extinction is triggered by two hippocampal signaling pathways underlying retrieval (the cAMP-dependent protein kinase and the mitogen-activated protein kinase pathways) and two other mechanisms that become activated at the same time and are not necessary for retrieval (N-methyl-D-aspartate glutamatergic receptors and the calcium/calmodulin-dependent protein kinase II signaling pathway). Thus, the molecular mechanisms underlying acquisition and/or consolidation of the memory for extinction are similar to those described for the acquisition and/or consolidation of the original contextual fear.
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PMID:The role of NMDA glutamate receptors, PKA, MAPK, and CAMKII in the hippocampus in extinction of conditioned fear. 1262 57

Calcium signal is important for the regulation of meiotic cell cycle in oocytes, but its downstream mechanism is not well known. The functional roles of calcium/calmodulin-dependent protein kinase II (CaMKII) in meiotic maturation and activation of pig oocytes were studied by drug treatment, Western blot analysis, kinase activity assay, indirect immunostaining, and confocal microscopy. The results indicated that meiotic resumption of both cumulus-enclosed and denuded oocytes was prevented by CaMKII inhibitor KN-93, Ant-AIP-II, or CaM antagonist W7 in a dose-dependent manner, but only germinal vesicle breakdown (GVBD) of denuded oocytes was inhibited by membrane permeable Ca2+ chelator BAPTA-AM. When the oocytes were treated with KN-93, W7, or BAPTA-AM after GVBD, the first polar body emission was inhibited. A quick elevation of CaMKII activity was detected after electrical activation of mature pig oocytes, which could be prevented by the pretreatment of CaMKII inhibitors. Treatment of oocytes with KN-93 or W7 resulted in the inhibition of pronuclear formation. The possible regulation of CaMKII on maturation promoting factor (MPF), mitogen-activated protein kinase (MAPK), and ribosome S6 protein kinase (p90rsk) during meiotic cell cycles of pig oocytes was also studied. KN-93 and W7 prevented the accumulation of cyclin B and the full phosphorylation of MAPK and p90rsk during meiotic maturation. When CaMKII activity was inhibited during parthenogenetic activation, cyclin B, the regulatory subunit of MPF, failed to be degraded, but MAPK and p90rsk were quickly dephosphorylated and degraded. Confocal microscopy revealed that CaM and CaMKII were localized to the nucleus and the periphery of the GV stage oocytes. Both proteins were concentrated to the condensed chromosomes after GVBD. In oocytes at the meiotic metaphase MI or MII stage, CaM distributed on the whole spindle, but CaMKII was localized only on the spindle poles. After transition into anaphase, both proteins were translocated to the area between separating chromosomes. All these results suggest that CaMKII is a multifunctional regulator of meiotic cell cycle and spindle assembly and that it may exert its effect via regulation of MPF and MAPK/p90rsk activity during the meiotic maturation and activation of pig oocytes.
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PMID:Involvement of calcium/calmodulin-dependent protein kinase II (CaMKII) in meiotic maturation and activation of pig oocytes. 1282 87

25-Hydroxyvitamin D-1alpha-hydroxylase (lalpha-OHase) is expressed in prostate cells. The expression suggests that local production of 1,25-dihydroxyvitamin D could provide an important cell growth regulatory mechanism. However, there is differential expression of 1alpha-OHase activity among the primary cultures of prostate cells derived from cancerous, benign prostatic hypertrophy and normal tissue, and among noncancerous (PZHPV-7) and various cancer cell lines (PC-3, DU145). No activity was found in cancer cell line LNCaP. The observed marked decrease in 1alpha-OHase activity in prostate cancer cells suggests some defect of the 1alpha-OHase in these cells. Using luciferase reporter gene assay, we observed a step-wise decrease in the basal promoter activity in two truncated promoter fragments, AN2 (-1,100 bp) and AN5 (-394 bp), with the highest basal activities found in PZHPV-7 and with loss of promoter activity in LNCaP. In order to understand the mechanism underlying the differential promoter activities among different prostate cells, we investigated the possible role of phosphorylation of cyclic AMP response element binding protein (CREB) on the regulation of 1alpha-OHase promoter activity in the four prostate cell lines. First we compared the levels of CREB phosphorylation among PZHPV-7, DU145, PC-3 and LNCaP cells by Western blot analysis using antibody against phosphorylated CREB. We observed that CREB was phosphorylated to a greater extent in PZHPV-7 than in DU145 cells. No significant phosphorylation of CREB was found in PC-3 and LNCaP cells. Next, we utilized activators and inhibitors of protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinase kinase (MAPKK) and calcium/calmodulin-dependent protein kinase II (CaMKII) to determine which kinases might be involved in phosphorylating the CREB in PZHPV-7 cells. We demonstrated that forskolin (an activator of PKA) increased the AN2 basal promoter activity 50%, whereas H-89 (an inhibitor of PKA) inhibited the basal and forskolin-stimulated AN2 promoter activity 40% and 70%, respectively. We also showed that PD98059 (an inhibitor of MAPKK) decreased the AN2 promoter activity 70%. Phorbol 12-myristate 13-acetate (an activator of PKC), GF109203 (an inhibitor of PKC) and KN-93 (an inhibitor of CaMKII) had no effect on AN2 promoter activity in PZHPV-7 cells. Thus, our results suggest that differential phosphorylation of CREB through PKA and MAPK pathways may be involved in the regulation of 1alpha-OHase promoter activity.
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PMID:Vitamin D autocrine system and prostate cancer. 1289 25

Benzodiazepines are in wide clinical use for their sedative and tranquilizing actions, the former being mediated via alpha1-containing GABAA receptors. The signal transduction pathways elicited beyond the receptor are only poorly understood. Changes of transcript levels in cerebral cortex induced by acute diazepam administration were therefore compared by microarray analysis between wild-type and point mutated alpha1(H101R) mice, in which the alpha1 GABAA receptor subunit had been rendered insensitive to diazepam. In wild-type animals, diazepam reduced the expression levels of the alpha subunit of the calcium/calmodulin-dependent protein kinase II, as well as brain-derived neurotrophic factor, MAP kinase phosphatase, transcription factor GIF, c-fos and nerve growth factor induced gene-A. None of these transcripts was changed in the alpha1(H101R) mice after treatment with diazepam. Thus, the sedative action of diazepam is correlated with a selective down-regulation of transcripts involved in the regulation of neuronal plasticity and neurotrophic responses. Most transcript changes were transient except for the decrease of the CaMKIIalpha transcript which persisted even 40 h after the single dose of diazepam. This long-term alteration is likely to contribute to the resetting of the neuronal responsiveness, which may be involved in rebound phenomena and, under chronic treatment, in the development of tolerance and dependence.
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PMID:Diazepam-induced adaptive plasticity revealed by alpha1 GABAA receptor-specific expression profiling. 1500 62

Helicobacter pylori (H. pylori) infection of gastric epithelial cells has been shown to induce interleukin (IL)-8 production, but the signal transduction mechanism leading to IL-8 production has not been clearly defined. Here, we investigate the role of protein kinase C (PKC) in the mechanism of induction of IL-8 release by H. pylori in human gastric epithelial cells. In MKN45 cells, H. pylori-induced IL-8 release was enhanced by treatment with PKC inhibitors (GF109203X and calphostin C) and PKC depletion, which completely inhibited PKC activity. Moreover, PKC inhibitors and PKC depletion increased extracellular signal-regulated kinase (ERK) activity and phosphorylation, but not calcium/calmodulin-dependent protein kinase II (CaMK II) activity, in response to H. pylori infection. PKC activated by H. pylori inhibited activation of ERK induced by H. pylori without affecting the CaMK II activity and negatively regulated IL-8 production in human gastric epithelial cells.
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PMID:Protein kinase C activation by Helicobacter pylori in human gastric epithelial cells limits interleukin-8 production through suppression of extracellular signal-regulated kinase. 1503 7


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