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)

Human mesangial cells in culture synthesize and secrete plasminogen activator inhibitor 1 (PAI-1) and tissue-type plasminogen activator (t-PA). Phorbol myristate acetate (PMA), a known activator of protein kinase C, induces a three to four-fold increase in t-PA and PAI-1 release over a period of 24 h, whereas cell-associated t-PA and PAI-1 levels remain relatively stable. A similar effect is obtained with oleylacetyl glycerol, a more physiologic protein kinase C activator. The effect of PMA is suppressed in the presence of H7, an inhibitor of cellular protein kinases, and by cycloheximide and actinomycin D, indicating a requirement for de novo protein and RNA synthesis, respectively. Northern blot analysis of PMA-treated cells reveals a rapid and transient increase in PAI-1 mRNA reaching a maximum after 4-8 h, whereas increase in t-PA mRNA levels requires 24 h. Activation of protein kinase A by addition of 8-bromocyclic AMP (8-bromo cAMP) has no significant effect on PAI-1 release but inhibits the PMA-mediated increases in PAI-1 antigen and mRNA. Addition of 8-bromo cAMP alone does not affect t-PA release. When added to PMA-stimulated cells, 8-bromo cAMP inhibits t-PA release in a dose-dependent manner, but causes a superinduction of t-PA mRNA. 8-bromo cAMP also induces a decrease in PMA-stimulated intracellular t-PA release. Similar inhibition is observed after stimulation of endogenous adenylate cyclase with prostaglandin E1 or isoproterenol. This indicates that protein kinase A activation may inhibit PMA-stimulated t-PA release via a post-transcriptional effect, e.g. inhibition of protein synthesis or activation of protein degradation. In conclusion, hormones or mediators which activate protein kinase C can stimulate t-PA and PAI-1 synthesis in human mesangial cells. Protein kinase A activation has no effect on the basal release of PAI-1 and t-PA by human mesangial cells, and, in contrast to endothelial cells, it inhibits both PMA-stimulated PAI-1 and t-PA releases. This cell-specific regulation of t-PA and PAI-1 seems to be mediated by differential transcriptional and post transcriptional mechanisms.
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PMID:Cell-specific regulation of plasminogen activator inhibitor 1 and tissue type plasminogen activator release by human kidney mesangial cells. 155 43

The present study was carried out to characterize the membrane conductive properties of RCCT-28A cells, a continuous cell line derived from rabbit cortical collecting duct (CCD). RCCT-28A cells have many phenotypic properties of acid-secreting intercalated cells (A-IC). Using the whole cell patch-clamp technique, we found that the cells are conductive to Cl-, but not to Na+ or K+. The beta-adrenergic agonists isoproterenol (2 x 10(-6) M) and adenosine 3',5'-cyclic monophosphate (cAMP, 10(-4) M) increased the whole cell Cl- conductance. Protein kinase A (150 nM) in the patch pipette (i.e., intracellular solution) also increased whole cell Cl- conductance. Because isoproterenol increases cAMP levels in these cells, we conclude that isoproterenol stimulates the Cl- conductance by increasing cell cAMP, which in turn activates protein kinase A. In contrast, vasopressin does not increase cAMP in these cells and did not increase the Cl- conductance. In conclusion, these experiments show that RCCT-28A cells, like A-IC, are conductive only to Cl-. Thus RCCT-28A cells are a good model with which to study Cl- channels in the collecting duct.
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PMID:Conductive properties of a rabbit cortical collecting duct cell line: regulation by isoproterenol. 156 71

A126-1B2 cells, a PKA (cAMP-dependent protein kinase)-deficient variant of PC12 cells, but not parental PC12 cells, form processes within 15-30 min of exposure to both nerve growth factor (NGF) and activators of protein kinase C when grown on tissue culture plastic (Glowacka and Wagner, J Neurosci Res 25: 453-462, 1990). Time-lapse microscopy has demonstrated that these processes are formed by a novel mechanism, i.e., rapid movement of the cell body away from a point of attachment, which morphologically resembles a growth cone. These "fast" neurites are attached to the substratum at a number of points, which display membrane activity in the form of active ruffling and the extension of filopodia and membrane pleats. Thus, these processes are formed by a mechanism distinct from that used by PC12 and other neuronal cells to form processes in culture. Wild-type PC12 cells also migrate and form fast neurites in response to a combination of NGF and phorbol 12-myristate 13-acetate (PMA), when they are grown in conditioned media or plates, suggesting that a secreted factor that can bind to the substratum is essential for the rapid formation of these neurites. Similarly, wild-type PC12 cells grown on a laminin-coated substratum also migrate and form "fast neurites" in response to a combination of NGF and PMA. This rapid migration is attenuated by an anti-alpha 1, beta 1-integrin antisera, implicating a laminin-integrin interaction; and it is inhibited by alpha-lactalbumin, suggesting an involvement of a beta 1,4 galactosyltransferase in the response. The formation of fast neurites is not dependent on concurrent protein synthesis, but it is inhibited by lithium, cytochalasin D, and methylthioadenosine or pretreatment of cells with NGF. Thus PC12 cells grown on the appropriate substrate have the ability to migrate rapidly and thereby form neuron-like processes within minutes of exposure to NGF and PMA. This morphological response to a combination of agents may provide an alternative means by which nerve cells form connections. Alternatively, it may reflect a mechanism that facilitates cellular migration during developmental processes.
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PMID:Synergistic effects of nerve growth factor and phorbol 12-myristate 13-acetate on rapid motility and process formation in PC12 cells: the role of laminin. 157 76

The effects of protein phosphorylation and dephosphorylation on glucose transport activity reconstituted from adipocyte membrane fractions and its relationship to the phosphorylation state of the adipose/muscle-type glucose transporter (GLUT4) were studied. In vitro phosphorylation of membranes in the presence of ATP and protein kinase A produced a stimulation of the reconstituted glucose transport activity in plasma membranes and low-density microsomes (51% and 65% stimulation respectively), provided that the cells had been treated with insulin prior to isolation of the membranes. Conversely, treatment of membrane fractions with alkaline phosphatase produced an inhibition of reconstituted transport activity. However, in vitro phosphorylation catalysed by protein kinase C failed to alter reconstituted glucose transport activity in membrane fractions from both basal and insulin-treated cells. In experiments run under identical conditions, the phosphorylation state of GLUT4 was investigated by immunoprecipitation of glucose transporters from membrane fractions incubated with [32P]ATP and protein kinases A and C. Protein kinase C stimulated a marked phosphate incorporation into GLUT4 in both plasma membranes and low-density microsomes. Protein kinase A, in contrast to its effect on reconstituted glucose transport activity, produced a much smaller phosphorylation of the GLUT4 in plasma membranes than in low-density microsomes. The present data suggest that glucose transport activity can be modified by protein phosphorylation via an insulin-dependent mechanism. However, the phosphorylation of the GLUT4 itself was not correlated with changes in its reconstituted transport activity.
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PMID:Phosphorylation of the adipose/muscle-type glucose transporter (GLUT4) and its relationship to glucose transport activity. 163 3

Alterations in the cAMP signal transduction pathway are associated with mouse lung neoplasia, cAMP effects are mediated by activating cAMP-dependent protein kinase isozymes, PKA I and PKA II. E9, a tumorigenic cell line, exhibited decreased PKA I levels compared to C10 cells, a nontumorigenic cell line of similar epithelial origin. Western immunoblots of PKA subunit proteins demonstrated low concentrations of both the catalytic (C) and regulatory (RI) PKA I subunits. Although RII (regulatory subunit of PKA II) concentrations were similar in both cell lines, RII from E9 cells was more highly phosphorylated than in C10 cells. RII phosphorylation status regulates cAMP activation of PKA II. Northern-blot analysis of mRNA content indicated diminished expression of both C and RI mRNA in E9 relative to C10 cells. Several endogenous PKA substrate proteins present in C10 cells were minimally phosphorylated by PKA in E9 cells. Forskolin, which raises cellular cAMP content, increased phosphorylation of a protein doublet in intact C10 cells, but not in E9 cells. Decreased PKA I expression and alterations in RII phosphorylation in lung neoplasia may contribute to anomalous regulation by cAMP, thereby diminishing cAMP-mediated growth inhibitory effects.
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PMID:Alterations in the cAMP signal transduction pathway in mouse lung tumorigenesis. 164 8

Many proteins including ion channels are regulated by phosphorylation. We tested the effect of 10 U/ml catalytic subunit protein kinase A on 260-pS Ca(2+)-activated K+ channels in excised inside-out membrane patches from freshly dispersed smooth muscle cells of the canine proximal colon. At +50 mV with 10(-7) M Ca2+ and -50 mV with 10(-6) M Ca2+, open probability of the channels was increased to 270 +/- 48% of control (n = 12). This increase was due to a shift in voltage-dependent activation by 13.9 +/- 3.2 mV (n = 3) to more negative potentials. Protein kinase A in the absence of ATP had no effect on channel activity (n = 3). Regulation by phosphorylation must be accompanied by dephosphorylation. We tested the effect of two potent inhibitors of protein phosphatases, calyculin A and okadaic acid. Application of 10(-9) to 10(-6) M of each inhibitor in the presence of protein kinase A further increased open probability by up to 250%. Calyculin A appeared to be less effective in increasing open probability than okadaic acid, suggesting that the phosphatase involved is neither type 1, 2A, nor 2B. Calyculin A in the absence of protein kinase A was ineffective. These data suggest that endogenous phosphatases are found in excised membrane patches and that a balance between phosphorylation and dephosphorylation may provide an important control of colonic motility.
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PMID:Regulation of Ca(2+)-activated K+ channels by protein kinase A and phosphatase inhibitors. 165 53

NF-kappa B is a DNA-binding regulatory factor able to control transcription of a number of genes, including human immunodeficiency virus (HIV) genes. In T cells, NF-kappa B is activated upon cellular treatment by phorbol esters and the cytokine tumor necrosis factor alpha (TNF alpha). In the present work, we investigated the molecular events leading to NF-kappa B activation by TNF alpha in a human T cell line (Jurkat) and its subclone JCT6, which presents a deficiency in the PKA transduction pathway. We found that in both cell lines, both phorbol ester and TNF alpha were able to activate NF-kappa B. Phorbol activation was positively modulated by Ca2+ influx while TNF alpha activation was not. Furthermore, while PMA activation was inhibited by the PKC inhibitor staurosporin, the TNF alpha effect was unchanged. TNF alpha did not activate cAMP production and its signal was not modulated by cAMP activators. Moreover, cAMP activators did not activate NF-kappa B in Jurkat cells. Thus, TNF alpha-induced NF-kappa B activation was found to be mediated by none of the major signal-mediating kinases such as protein kinase C (PKC), protein kinase A, or Ca(2+)-regulated kinases. Furthermore, we found that cytoplasmic acidification facilitated NF-kappa B activation by both TNF alpha and PKC, by a mechanism that increases NF-kappa B/I kappa B dissociation without affecting the NF-kappa B translocation step.
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PMID:NF-kappa B activation by tumor necrosis factor alpha in the Jurkat T cell line is independent of protein kinase A, protein kinase C, and Ca(2+)-regulated kinases. 165 56

We have previously demonstrated that the exposure of mouse microvascular endothelium (MME) to tumor necrosis factor-alpha (TNF) led to the increased binding of mouse mastocytoma cells (P815) to endothelial monolayers (Bereta et al., in press). In the current study we examined the possible involvement of protein kinases in TNF signal transduction in the endothelial cells. PKA does not appear to play a role in the potentiation of binding by TNF. We found that the TNF-generated signal is inhibited by H-7 and sangivamycin, but not by staurosporine. TNF did not cause translocation of PKC to the cell membrane and its effect could not be completely mimicked by PMA nor by PMA in the presence of calcium-raising agents. Thus, we concluded that the "classical" PKC pathway is not completely responsible for TNF signalling in this system. We also found that staurosporine itself strongly enhanced adhesion of tumor cells to endothelium, utilizing a mechanism distinct from that of TNF. Although the data provide evidence for the role of kinases in the effect of TNF on binding of tumor cells to MME, this role appears to be a complex one.
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PMID:Studies on the role of protein kinases in the TNF-mediated enhancement of murine tumor cell-endothelial cell interactions. 165 14

We have investigated the effects of stimulation of adenosine 3',5'-cyclic monophosphate-dependent protein kinase (protein kinase A) and Ca(2+)-diacylglycerol-dependent protein kinase (protein kinase C) on the delayed rectifier K+ current (IK) in guinea pig ventricular cells using a whole cell arrangement of the patch-clamp procedure. Stimulation of either protein kinase C or A resulted in enhanced IK activity. Augmentation of IK observed during stimulation of protein kinase A occurred in a markedly voltage-dependent manner, with the largest increases occurring at potentials near the threshold for IK activation. Enhancement of IK during stimulation of protein kinase C followed a different pattern, with minimal effects of the enzyme near IK threshold. Neither protein kinase A nor C altered the kinetics of IK activation, although both kinases slightly changed the kinetics of deactivation. Both kinases increased IK maximal conductance, but the effects of each kinase on the voltage-dependence of activation differed. Protein kinase A shifted IK activation toward more negative voltages but did not affect the slope of the activation curve. Protein kinase C, in contrast, changed the slope of the IK activation curve, with only a small effect on the half-maximal voltage of activation. These contrasting effects on the voltage dependence of IK activation are consistent with actions of the kinases at distinct sites on or near the IK channel protein.
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PMID:Distinct voltage-dependent regulation of a heart-delayed IK by protein kinases A and C. 166 3

While a cAMP-dependent protein kinase (protein kinase A) has been suggested to phosphorylate epidermal growth factor (EGF) receptor in vitro, both intrinsic and EGF- or potent phorbol tumor promoter-induced phosphorylation of EGF receptor were found to be depressed in human epidermoid carcinoma A431 cells by prior incubation of the cells with various protein kinase A activators (e.g. cholera toxin, forskolin, cAMP analogues, or a combination of prostaglandin E1 and 3-isobutyl-1-methylxanthine). Protein kinase A activators did not change significantly either the number of EGF receptors or their affinity for EGF. The tryptic phosphopeptide map of EGF receptors from cells treated with cholera toxin alone or cholera toxin followed by EGF revealed unique peptides whose serine phosphorylation was preferentially depressed. However, the catalytic subunit of protein kinase A phosphorylated no threonine and little serine in the EGF receptors in the plasma membranes of isolated A431 cells in vitro, while serine residues in an unidentified 170-kDa membrane protein(s) other than EGF receptor were heavily phosphorylated. Pretreatment of the cells with forskolin blocked 1,2-diacylglycerol induction by EGF; growth inhibition by nanomolar levels of EGF could be partially restored by the presence of forskolin. These results indicate that an increase in intracellular cAMP modulates the EGF receptor signal transduction system by reducing EGF-induced production of diacylglycerol without direct phosphorylation of EGF receptors by protein kinase A in A431 cells.
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PMID:cAMP-mediated modulation of signal transduction of epidermal growth factor (EGF) receptor systems in human epidermoid carcinoma A431 cells. Depression of EGF-dependent diacylglycerol production and EGF receptor phosphorylation. 169 23


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