Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vgf gene encodes one of the most rapidly induced neuronal mRNAs identified in NGF-treated PC12 cells. Maximal inhibition of VGF mRNA induction was achieved using K-252a, an inhibitor of the NGF-receptor Trk tyrosine kinase, and by mutating both Y490 (SHC association site) and Y785 (PLC-gamma 1 association site) of Trk. Inhibitors of the NGF-activated protein kinase N (PKN) were found to partially and in some cases transiently block VGF induction by NGF while in PKA-deficient PC12 cells, VGF induction by NGF was comparable to that observed in parental PC12 cells. The binding of NGF to Trk therefore activates redundant signal transduction pathways which converge to regulate vgf gene expression.
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PMID:Stimulation of vgf gene expression by NGF is mediated through multiple signal transduction pathways involving protein phosphorylation. 787 12

1. In an air pouch-type allergic inflammation model in rats, leucocytes that had infiltrated into the pouch fluid collected 4 h after the antigen challenge produced proteinaceous chemotactic factors for neutrophils when they were incubated in the medium. 2. To clarify the mechanism of activation of the infiltrated leucocytes in producing these factors, the effects of protein kinase inhibitors on neutrophil chemotactic factor production were examined. 3. When the infiltrated leucocytes were incubated for 4 h in medium containing the non-selective protein kinase inhibitor K-252a (1-100 ng ml-1, 2.14-214 nM), the tyrosine kinase inhibitor genistein (1-50 micrograms ml-1, 3.7-185 microM), and the more selective protein kinase C inhibitor H-7 (5-100 micrograms ml-1, 13.7-274 microM); neutrophil chemotactic activity in the conditioned medium was decreased in a concentration-dependent manner, but the adenosine 3':5'-cyclic monophosphate (cAMP)-dependent protein kinase inhibitor H-89 (1-1000 ng ml-1, 2.24-2240 nM) showed no effect. 4. Isoelectric focusing of the conditioned medium revealed that the leucocytes produced two neutrophil chemotactic factors, leucocyte-derived neutrophil chemotactic factor (LDNCF) 1 and LDNCF-2. Treatment of the leucocytes with K-252a, genistein, and H-7, but not H-89, inhibited production of both LDNCF-1 and LDNCF-2. 5. These results suggest that activation of tyrosine kinase and protein kinase C, but not cAMP-dependent protein kinase, is responsible for the production of LDNCF-1 and LDNCF-2. 6. The steroidal anti-inflammatory drug dexamethasone and the protein synthesis inhibitor cycloheximide inhibited neutrophil chemotactic factor production in a concentration-dependent manner. Time-course experiments showed that the inhibitory effect by dexamethasone was apparent even 30 min after the incubation.7. Mechanism for inhibiting the production of LDNCF-1 and LDNCF-2 by dexamethasone is also discussed.
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PMID:Possible roles of protein kinases in neutrophil chemotactic factor production by leucocytes in allergic inflammation in rats. 788 5

We have investigated the effects of inhibitors of protein kinases and protein phosphatases on the NMDA receptor-independent potentiation of evoked and miniature (m) excitatory postsynaptic currents (EPSCs) induced by the entry of Ca2+ via voltage-gated Ca2+ channels in hippocampal CA1 pyramidal neurons. Voltage pulse-induced potentiation was markedly attenuated when evoked in the presence of the protein kinase blockers KN-62, K-252a, or H-7. Bath application of the protein phosphatase inhibitor calyculin A converted the usual transient potentiation of both evoked and spontaneous EPSCs induced by voltage pulses into a more sustained potentiation. Similarly, the introduction of the phosphatase inhibitors microcystin LR or okadaic acid into postsynaptic cells, via patch pipettes, also resulted in a sustained increase in the amplitude of mEPSCs. We propose that entry of Ca2+ into CA1 neurons activates calcium/calmodulin-dependent protein kinase II, which leads to an enhanced responsiveness of synaptic AMPA receptor channels. The enhancement is transient, however, owing to postsynaptic phosphatase activity.
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PMID:A role for protein kinases and phosphatases in the Ca(2+)-induced enhancement of hippocampal AMPA receptor-mediated synaptic responses. 791 94

The antimicrobial activities of twenty-two substances structurally related to staurosporine, aglycone in the indolocarbazole and bis-indole series were examined against Streptomyces chartreusis and Streptomyces griseus, Bacillus cereus, Escherichia coli, Candida albicans and Botrytis cinerea. Inhibition of sporulation was examined also on the two species of Streptomyces. Unlike literature reports for efficient protein kinase inhibitors, staurosporine and K-252a, no evident correlation could be found either between protein kinase inhibitory potencies and inhibition of sporulation of the Streptomyces species, or protein kinase inhibitory potencies and growth of all microorganisms tested. A weak activity against C. albicans was observed for the chloro-indolocarbazole compounds as already reported for structurally related substances from the cyanobacterium Tolypothrix tjipanasensis.
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PMID:Antimicrobial activities of indolocarbazole and bis-indole protein kinase C inhibitors. 807 Nov 25

To investigate the involvement of N-methyl-D-aspartate (NMDA) receptor, protein kinase C (PKC) and calmodulin on long-term potentiation (LTP) formation in the superior colliculus (SC), the effects of an NMDA receptor antagonist (D-APV), PKC inhibitors (H-7, K-252a, K-252b, polymyxin B), a protein kinase A (PKA) inhibitor (H-8) and a calcium/calmodulin-dependent kinase inhibitor (calmidazolium) on LTP formation were studied in guinea pig SC slices. APV (100 microM) masked the expression of LTP by tetanic stimulation, but the LTP once formed was not influenced by application of APV. LTP was blocked by application of H-7 (100 microM), but LTP reappeared 20 min after removal of H-7 from the perfusion medium without further tetanic stimulation. On the other hand, established LTP was also inhibited by application of H-7 even 90 min after the tetanic stimulation. Application of K-252a (500 nM) inhibited LTP formation, but K-252b (500 nM) had no inhibitory effect on LTP formation since K-252b, unlike K-252a, cannot permeate the cell membrane. Tetanic stimulation was applied 20 min after application of polymyxin B (1 microM) to the medium but it could not induce LTP, while established LTP was not influenced by the drug. Application of calmidazolium (50 microM) inhibited LTP formation, but had no inhibitory effect on LTP once formed. These results suggest that both the NMDA receptor and calmodulin system are involved in the induction of LTP after tetanic stimulation. This leads to PKC activation which maintains the LTP.
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PMID:NMDA receptor, protein kinase C and calmodulin system participate in the long-term potentiation in guinea pig superior colliculus slices. 809 59

Effects of okadaic acid (OA) and calyculin-A (CL-A), selective inhibitors of protein phosphatases 1 (PP1) and 2A (PP2A), on the release of serotonin from the rat basophilic leukemia cell line (RBL-2H3) were investigated. Both OA and CL-A induced the long-lasting release of serotonin in an extracellular Ca(2+)-independent manner. CL-A did not increase intracellular Ca2+ concentration in the fura-2-loaded cells. CL-A was 100-fold more potent than OA in inducing the release, suggesting that PP1 is a dominant protein phosphatase in regulating RBL-2H3 cells. The CL-A-induced release of serotonin was completely inhibited by the nonselective protein kinase inhibitors, staurosporine and K-252a. CL-A induced phosphorylation of several cellular proteins in RBL-2H3 cells, which could be inhibited by staurosporine. These findings suggest that the release of serotonin is subject to tonic, Ca(2+)-independent, inhibition by PP1 in RBL-2H3 cells.
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PMID:Protein phosphatase inhibitors induce the release of serotonin from rat basophilic leukemia cells (RBL-2H3). 816 51

A previous study showing that ethanol (ETOH) blocked [3H]choline incorporation into phosphatidylcholine (PC) suggested an inhibition of PC biosynthesis in human leukemic monocyte-like U937 cells. The mechanism of the inhibitory action of ETOH was investigated. Cells were pulsed with [3H]choline for 30 min and chased in the presence or absence of ETOH for up to 6 h. PC biosynthesis was inhibited drastically within 1 h after exposure to ETOH which increased intracellular cAMP appreciably. After a 3-h treatment, ETOH significantly inhibited both choline kinase (CK) and the cytosolic CTP: cholinephosphate cytidylyltransferase (CT). The inactivated CT was no longer stimulated by exogenous phosphatidylglycerol (PG). There was no evidence for redistribution of CT activity between cytosol and microsomes. When cells were exposed to 8-Bromo-cAMP ranging from 100 to 300 microM, PC biosynthesis remained unaffected despite the drastically elevated cAMP. These results seem to suggest that the raised cAMP is not a prerequisite for the inhibition of PC biosynthesis in U937 cells. Following pretreatment with protein kinase inhibitors (H-89 and K-252a), PC biosynthesis was decreased significantly and the inhibitory effect of ETOH was potentiated. Taken together, our results suggest that the inhibition of PC biosynthesis and the inhibitory effect of ETOH are independent of the activation of cAMP-dependent protein kinase. Unlike protein kinase inhibitors, pretreatment with tyrosine kinase inhibitors (erbstatin, genistein and tyrphostin 25) resulted in differential effects on PC biosynthesis and on the inhibitory action of ETOH. Genistein stimulated PC biosynthesis by 30 per cent as well as partially preventing/reversing the ETOH action, while tyrphostin 25 produced a synergistic inhibition. The relevance of tyrosine phosphorylation/dephosphorylation to the regulation of PC biosynthesis and ETOH action remains to be established.
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PMID:Mechanism by which ethanol inhibits phosphatidylcholine biosynthesis in human leukemic monocyte-like U937 cells. 816 30

We have examined the effects of the protein kinase inhibitor KT5926 on NGF-promoted responses in PC12 and PC12-C41 cells (a subclone of the parental cell line). Our findings reveal that this compound specifically and reversibly prevents the NGF-induced outgrowth and regeneration of neurites. In addition, neurites of NGF-pretreated cells cease further elongation upon exposure to KT5926. However, preexisting neurite networks in the cultures remain intact in the presence of the drug. The inhibition of neuritic growth appears to occur at least in part at the level of growth cones since KT5926 also causes these structures to collapse and inhibits NGF-promoted reactivation of NGF-deprived growth cones. Although KT5926 is an analogue of K-252a, which blocks all responses to NGF, it does not affect other NGF-elicited cellular responses examined, including NGF-dependent priming of cells, gp140prototrk autophosphorylation, immediate-early gene induction, and phosphorylation of several known cytoskeletal proteins (MAP 1.2/1B, chartin MAPs, and beta-tubulin). However, phosphate incorporation into a cytoskeletally localized 58 kDa phosphoprotein, designated pp58, is selectively reduced in KT5926-treated cultures (+/- NGF). Although KT5926 is an in vitro inhibitor of myosin light chain kinase and calmodulin-dependent protein kinase II, inhibition of these two kinase activities by ML-9 and KN-62, respectively, applied alone or together, does not mimic the effects of KT5926 on neurite growth and on pp58 phosphorylation. Taken together, our findings suggest that KT5926, via a previously unidentified protein kinase inhibitory activity, differentially interferes with NGF-promoted growth cone function and consequently affects neuritic outgrowth. This compound should therefore be a useful tool for dissecting the mechanism of NGF actions and affords a means to identify phosphoproteins that play specific roles in neurite growth/elongation.
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PMID:KT5926 selectively inhibits nerve growth factor-dependent neurite elongation. 818 31

In previous studies, we demonstrated that while okadaic acid stimulates glucose metabolism, it suppresses the bioresponses of insulin itself in rat adipocytes (Shisheva and Shechter, Endocrinology 129: 2279-2288, 1991). Both stimulation and suppression were attributed to okadaic acid-dependent inhibition of protein phosphatases 1 and 2A. We report here that exposure of adipocytes to staurosporine prior to okadaic acid restored insulin-stimulated actions on glucose metabolism. The effect was half-maximal at staurosporine concentrations as low as 70 nM and was fully expressed (80-87% of the control) at 400-500 nM. Similarly, the insulin-like effect of pervanadate, which was also suppressed by okadaic acid, was restored completely with staurosporine pretreatment. Staurosporine was less effective in restoring cell responses inhibited by high concentrations of okadaic acid, or when added to the cells after okadaic acid. Cell resensitization was unique to staurosporine and could not be produced by various agents that reduce cellular protein kinase A- or protein kinase C-dependent phosphorylation, such as phenylisopropyl adenosine (PIA), K-252a and GF 109203X. Staurosporine (400 nM) partially reversed lipolysis induced by okadaic acid but not that induced by beta-adrenergic stimulation. PIA, which antagonized okadaic acid-induced lipolysis to the same extent as staurosporine, was not capable of restoring insulin responses. Further studies aimed at elucidating this reversing effect revealed that staurosporine did not reactivate okadaic acid-inhibited protein phosphatases 1 and 2A in both cellular and cell-free systems. In summary, we report here a unique dynamic system in which insulin and pervanadate bioeffects can be fully suppressed and again re-expressed without reactivation of protein phosphatase 1 or 2A. The precise site for both effects, although still obscure, appears to be downstream from autophosphorylated insulin receptor.
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PMID:A dynamic system for suppression and re-expression of insulin and pervanadate bioresponses in rat adipocytes. Treatment with okadaic acid and staurosporine. 818 65

Evidence for the modulation of the P2z-purinoceptor for extracellular ATP in dissociated rat parotid cells is presented in studies using compounds that inhibit protein kinases. Preincubation of acinar cells with the protein kinase catalytic-site inhibitors K-252a and staurosporine, as well as with the regulatory-domain inhibitor sphingosine, specifically potentiates the elevation in cytosolic Ca2+ concentration ([Ca2+]i) mediated by extracellular ATP, but has no effect on the [Ca2+]i elevation mediated by muscarinic receptors through phospholipase C activation. Phorbol dibutyrate (PDBu), which activates protein kinase C (PKC), has no modulatory effect on ATP-mediated [Ca2+]i elevation. Further, pretreatment with PDBu does not reverse or block the effects of K-252a or sphinogosine, arguing against the involvement of PKC. Other pharmacological manipulations indicate that neither calmodulin-dependent nor cyclic-AMP-dependent kinases are involved. Neither the peak intracellular Ca2+ mobilization nor the sustained Ca2+ entry in response to carbachol or to a Ca2+ ionophore (4-bromo-A23187) is altered by the kinase inhibitors that potentiate the [Ca2+]i response to ATP, indicating that effects on the ATP response are not due to non-specific permeability changes, nor to decreased Ca2+ removal from the cytosol. ATP-mediated influx of Mn2+ as well as ATP-induced membrane depolarization are potentiated in cells preincubated with K-252a, directly demonstrating that cation influx is enhanced through a P2z-specific route. These results show that P2z responses (or purinoceptors) can be modulated and suggest that phosphorylation events are involved.
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PMID:Modulation of extracellular ATP-induced Ca2+ responses: role of protein kinases. 821 26


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