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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the concentration- and time-dependent effects of two related protein kinase inhibitors, KT5926 and K-252a, on neurite formation and nerve growth cone migration of chick embryo sensory neurons. The effects of these drugs on neurite formation over an 18-h period were dissimilar. KT5926 stimulated neurite formation at concentrations between 100 and 500 nM and inhibited neurite formation at 5 microM. K-252a had no stimulatory effects on neurite formation, and it inhibited neurite formation at concentrations above 50 nM. This difference may occur because K-252a inhibits activation of the nerve growth factor receptor trk A, while KT5926 does not inhibit trk A. Both drugs, however, had similar immediate effects on growth cone migration. Growth cone migration and lamellipodial spreading were rapidly stimulated by 500 nM concentrations of KT5926 and K-252a. At 2 microM levels of either drug, growth cone spreading was still stimulated, but growth cone migration was inhibited by both drugs. These results show that changes in protein phosphorylation/dephosphorylation can rapidly regulate the cellular machinery that is responsible for driving growth cone migration and neurite elongation. The different effects of 2 microM concentrations of either KT5926 or K-252a on growth cone spreading versus migration suggests that the actin-dependent protrusive motility of the growth cone leading margin is regulated differently by changes in protein phosphorylation and dephosphorylation than the cytoskeletal mechanism that drives neurite elongation.
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PMID:Concentration-dependent stimulation and inhibition of growth cone behavior and neurite elongation by protein kinase inhibitors KT5926 and K-252a. 924 Mar 72

The MPM-2 antibody labels mitosis-specific and cell cycle-regulated phosphoproteins. The major phosphoproteins of mitotic chromosomes recognized by the MPM-2 antibody are DNA topoisomerase II (topoII) alpha and beta. In immunofluorescence studies of PtK1 cytoskeletons, prepared by detergent lysis in the presence of potent phosphatase inhibitors, the MPM-2 antibody labels phosphoproteins found at kinetochores, chromosome arms, midbody and spindle poles of mitotic cells. In cells extracted without phosphatase inhibitors, labeling of the MPM-2 antibodies at kinetochores is greatly diminished. However, in cytoskeletons this epitope can be regenerated through the action of kinases stably bound at the kinetochore. Various kinase inhibitors were tested in order to characterize the endogenous kinase responsible for these phosphorylations. We found that the MPM-2 epitope will not rephosphorylate in the presence of the broad specificity kinase inhibitors K-252a, staurosporine and 2-aminopurine. Several other inhibitors had no effect on the rephosphorylation indicating that the endogenous MPM-2 kinase at kinetochores is not p34cdc2, casein kinase II, MAP kinase, protein kinase A or protein kinase C. The addition of N-ethylmaleimide inactivated the endogenous kinetochore kinase; this allowed testing of several purified kinases in the kinetochore rephosphorylation assay. Active p34cdc2-cyclin B, casein kinase II and MAP kinase could not generate the MPM-2 phosphoepitope. However, bacterially expressed NIMA from Aspergillus and ultracentrifuged mitotic HeLa cell extract were able to catalyze the rephosphorylation of the MPM-2 epitope at kinetochores. Furthermore, fractionation of mitotic HeLa cell extract showed that kinases that create the MPM-2 epitope at kinetochores and chromosome arms are distinct. Our results suggest that multiple kinases (either soluble or kinetochore-bound), including a homolog of mammalian NIMA, can create the MPM-2 phosphoepitope. The kinetochore-bound kinase that catalyzes the formation of the MPM-2 phosphoepitope may play an important role in key events such as mitotic kinetochore assembly and sister chromatid separation at anaphase.
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PMID:MPM-2 antibody-reactive phosphorylations can be created in detergent-extracted cells by kinetochore-bound and soluble kinases. 937 53

We established previously that lipopolysaccharide (LPS) can induce the expression of LPS-binding sites on bone marrow cells (BMC). We now report that staurosporine (STP), a glycosylated indolocarbazole alkaloid with potent inhibitory activity for various protein kinases, can induce the same effect. With both agents, the newly expressed LPS receptor was found to be CD14. The STP-induced effect was independent of its protein kinase inhibitory activity because several other protein kinase inhibitors, such as the indolocarbazole K-252a, the bisindolylmaleimide RO-31-8220, the perylenequinone calphostin C, and the isoquinolinesulfonamide H7, did not induce CD14 expression. The observation that the STP analog K-252a with an identical polyaromatic aglycon moiety was inactive yet the analog UCN-01 with an identical glycoside ring was active suggests that the induction of CD14 expression is triggered by the sugar moiety of STP. Three lines of evidence show that the mechanism of CD14 expression induced by STP differs from that induced by LPS: (i) unlike LPS, STP can stimulate BMC from LPS-unresponsive C3H/HeJ mice, (ii) LPS and STP effects are additive at a saturating dose of LPS, and (iii) the protein kinase inhibitor K-252a inhibits the LPS-induced but not STP-induced stimulation. Therefore, our findings show that both a protein kinase-dependent (LPS-induced) and a protein kinase-independent (STP-induced) mechanism can lead to the expression of the LPS receptor CD14 on BMC. We also found that the STP-induced stimulation of BMC is modulated by cyclosporin A, vinblastine, and verapamil. This observation may suggest that the inducible effect of STP could be initiated by its interaction with P-glycoprotein, a membrane pump with drug efflux function that plays a critical role in the multidrug resistance of cancer cells.
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PMID:Lipopolysaccharide and the glycoside ring of staurosporine induce CD14 expression on bone marrow granulocytes by different mechanisms. 938 33

We investigated the antiviral mechanisms of K-252a, a broad non-specific protein kinase inhibitor which was isolated from Nocardiopsis sp. and its derivative (KT5926), against vesicular stomatitis virus (VSV) replication in BHK-21 cells. Although K-252a (5 microM) and KT5926 (15 microM) similarly suppressed the viral primary and secondary transcriptions and genomic RNA synthesis in vivo, the inhibitory mechanisms did not seem to be the same; phosphorylation of the viral NS protein was suppressed by K-252a, which might account for the decreased viral RNA synthesis caused by K-252a. On the other hand, KT5926, being known to preferentially inhibit myosin light chain kinase (MLCK), had little effect on NS protein phosphorylation. Cellular casein kinase II, which is believed to be involved in the phosphorylation of the N-terminal side (domain I) of NS protein, was not inhibited at all by KT5926 even at 15 microM under in vitro assay conditions, and was only weakly inhibited by K-252a at 1 to 10 microM. Neither inhibitor seemed to directly affect viral protein synthesis, but affected it indirectly as a secondary effect of reduced viral RNA synthesis. These results suggest that both the KT5926-sensitive and the KT5926-resistant but K-252a-sensitive functions are involved in the essential processes of viral RNA synthesis. The KT5926-sensitive function(s) might not be involved in the NS protein phosphorylation, but may participate in some other way in the process of virus replication. On the other hand, the KT5926-resistant, K-252a-sensitive function(s) are probably involved in NS protein phosphorylation. The possible nature of those functions is discussed.
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PMID:Studies on the antiviral mechanisms of protein kinase inhibitors K-252a and KT5926 against the replication of vesicular stomatitis virus. 963 7

The purpose of this study was to characterize the effect of the K-252a family of protein kinase inhibitors with emphasis on staurosporine (ST), on stimulation of the inducible nitric oxide synthase activity in rat alveolar NR8383 macrophages. We found that ST, but not K-252a, K-252b, KT-5720, and KT-5823, selectively enhanced the basal or the lipopolysaccharide (LPS)-induced nitric oxide production. ST-induced NO production was blocked by L-NAME, K-252a, and phosphatase inhibitors and could not be mimicked by other protein kinase C (PKC) inhibitors such as calphostine. An additive effect between ST and PMA on NO production was observed. LPS and PMA but not ST induced PKCbeta translocation from the cytosol to the membrane fraction. ST may induce and affect the state of phosphorylation of iNOS via PKC-independent mechanisms. ST provides an important pharmacological tool to investigate PKC-independent signal transduction pathways which regulate iNOS, induction, and activity in rat NR8383 macrophages.
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PMID:Protein kinase C-independent selective induction of nitric oxide synthase activity in rat alveolar macrophages by staurosporine. 985 66

Previously we reported that a phorbol ester, phorbol 12, 13-dibutyrate (PDBu), increased the release of human growth hormone-binding protein (hGH-BP) in IM-9 cells, and that this phorbol ester-enhanced release was mediated by protein kinase Ca (PKCalpha). In the present study, the mechanisms of the phorbol ester-enhanced hGH-BP release were further investigated. Treatment of IM-9 cells with PDBu did not increase hGH-BPs (55-60 kDa) in the intracellular soluble fraction. When the cells were treated with trypsin to remove human growth hormone receptors (hGHRs) on the cell surface after stimulation, no hGH-BPs were detected in the culture supernatants, nor did treatment with bafilomycin A1 or chloroquine affect the PDBu-enhanced hGH-BP release. These results suggest that hGH-BPs released by PDBu stimulation are derived from cell surface hGHRs and not generated within the cells. Protein kinase inhibitors with broad specificities, K-252a and K-252b, inhibited the PDBu-enhanced release with almost the same dose-dependency, although only a trace amount of K-252b was incorporated into IM-9 cells than K-252a, suggesting that K-252b probably inhibits an ecto-kinase extracellularly. PDBu actually enhanced the phosphorylation of several extracellular proteins, and this enhanced phosphorylation was completely inhibited by K-252b treatment. Moreover, the PKCalpha-specific inhibitor bisindolylmaleimide III which inhibits PDBu enhanced hGH-BP release inhibited the PDBu-enhanced phosphorylation of extracellular proteins. On the other hand, the impermeable PKC inhibitor PKC inhibitor peptide 19-31 did not inhibit PDBu-enhanced release, suggesting that the target PKCalpha for PDBu is not present on the extracellular surface. Taken together, these results suggest that, in addition to intracellular PKCalpha, activation of an undefined ecto-kinase may also be involved in the PDBu-enhanced hGH-BP release.
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PMID:Role of ecto-kinase in phorbol ester-enhanced growth hormone-binding protein release from human IM-9 cells. 1043 24

Phenobarbital causes a multitude of effects in hepatocytes, including increased cell proliferation, inhibition of apoptosis and upregulation of xenobiotic and endobiotic metabolizing enzymes. In this study, the involvement of several protein kinase and phosphatase pathways on constitutive and phenobarbital-induced activities of CYP2A5, CYP2B10 and CYP1A1/2 in primary mouse hepatocytes was determined using well-defined chemical modulators of intracellular protein phosphorylation and desphosphorylation events. A 48-h treatment of the hepatocytes with 2-aminopurine, a nonspecific serine/threonine kinase inhibitor, elicited dose-dependent increases in both basal and phenobarbital-induced CYP2A5 catalytic activity (assayed as coumarin 7-hydroxylation), the maximal induction being 60-fold greater than the control value upon cotreatment with 1.5 mM phenobarbital and 10 mM 2-aminopurine. In contrast, phenobarbital induction of CYP2B10 (pentoxyresorufin O-deethylase) and CYP1A1/2 (ethoxyresorufin O-deethylase) activities were blocked by 2-aminopurine. Increases in CYP2A5 activity were also observed after exposure of the hepatocytes to other protein kinase inhibitors affecting the cell cycle, i.e. roscovitine, K-252a and rapamycin. Inhibitors of protein kinases A and C, as well as tyrosine kinases, did not appreciably affect CYP2A5 activity levels. The serine/threonine phosphatase inhibitors tautomycin, calyculin A and okadaic acid all reduced both basal and phenobarbital-induced CYP2A5, CYP2B10 and CYP1A1/2 activities. These results further strengthen the concept that hepatic CYP2A5 is regulated in a unique way compared with CYP2B10 and CYP1A.
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PMID:Modulation of murine phenobarbital-inducible CYP2A5, CYP2B10 and CYP1A enzymes by inhibitors of protein kinases and phosphatases. 1044 69

The incubation of rat peritoneal macrophages in the presence of staurosporine, a non-specific protein kinase inhibitor, induced interleukin-6 (IL-6) production in a time- and concentration-dependent manner at 6.3-63 nM, but at 210 nM, the stimulant effect on IL-6 production was reduced. The levels of IL-6 mRNA as determined by a reverse transcription-polymerase chain reaction were also increased by staurosporine in parallel with the ability to induce IL-6 production. Compounds structurally related to staurosporine including K-252a (non-specific protein kinase inhibitor) and KT-5720 (inhibitor of cyclic AMP-dependent protein kinase, PKA), did not increase IL-6 production by peritoneal macrophages. Staurosporine-induced increases in IL-6 production and expression of IL-6 mRNA were decreased by the PKC inhibitors, H-7 (2.7-27 microM), Ro 31-8425 (1-10 microM) and calphostin C (0.3-3 microM) and by the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY294002 (30-100 microM), but were further increased by the protein tyrosine kinase (PTK) inhibitor, genistein (12-37 microM). The staurosporine-induced increase in IL-6 production was not affected by the PKA inhibitor, H-89 (0.1-3 microM). These findings suggest that the induction of IL-6 production by staurosporine is secondary to elevation of IL-6 mRNA level, which, in turn, is positively regulated by the activation of PKC and PI 3-kinase and negatively regulated by the activation of PTK. PKA does not appear to play a significant role.
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PMID:Participation of protein kinases in staurosporine-induced interleukin-6 production by rat peritoneal macrophages. 1045 80

A critical period of protein kinase activity required for the induction of long-term potentiation (LTP) was determined in area CA1 or hippocampal slices using the broad-range and potent protein kinase inhibitors K-252a and staurosporine. As reported previously, K-252a and staurosporine blocked LTP induction when applied before, during, and after high-frequency stimulation (HFS). In contrast, K-252a did not block LTP when applied only before and during HFS and washed out immediately after HFS. K-252a and staurosporine both attenuated LTP magnitude when applied immediately after or as late as 5 min after HFS. However, K-252a applications beginning 30-45 min after HFS did not affect LTP expression significantly. K-252a had no detectable effect on isolated N-methyl-D-aspartate (NMDA) receptor-mediated EPSPs but significantly inhibited the in situ phosphorylation of specific hippocampal proteins (synapsin I, MARCKS, and B-50). In addition, K-252a attenuated 4 beta-phorbol-12,13-dibutyrate (PDBu)-enhanced synaptic transmission. Our results indicate that there is a critical period of protein kinase activity required for LTP induction that extends for approximately 20 min after HFS. In addition, our results suggest that protein kinase activity during and immediately after HFS is not sufficient for LTP induction. These results provide new information about the mechanisms that underlie LTP induction and expression and provide evidence for persistent and/or Ca(2+)-independent protein kinase activity involvement in LTP.
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PMID:A critical period of protein kinase activity after tetanic stimulation is required for the induction of long-term potentiation. 1046 68

Neurotrophins are a family of structurally related proteins that regulate the survival, differentiation and maintenance of function of different populations of peripheral and central neurons. They are also essential for modulating activity-dependent neuronal plasticity. Here we show that neurotrophins elicit action potentials in central neurons. Even at low concentrations, brain-derived neurotrophic factor (BDNF) excited neurons in the hippocampus, cortex and cerebellum. We found that BDNF and neurotrophin-4/5 depolarized neurons just as rapidly as the neurotransmitter glutamate, even at a more than thousand-fold lower concentration. Neurotrophin-3 produced much smaller responses, and nerve growth factor was ineffective. The neurotrophin-induced depolarization resulted from the activation of a sodium ion conductance which was reversibly blocked by K-252a, a protein kinase blocker which prefers tyrosine kinase Trk receptors. Our results demonstrate a very rapid excitatory action of neurotrophins, placing them among the most potent endogenous neuro-excitants in the mammalian central nervous system described so far.
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PMID:Neurotrophin-evoked rapid excitation through TrkB receptors. 1055 98


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