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:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphorylation of the Na+/H+ exchanger in human platelets is apparently controlled by the balancing activities of protein kinase C (PKC) and protein phosphatase (PP). To explore cellular expressions of these activities, we have examined the impact of modulation of PKC and PP on Na+/H+ exchange activity, its pHi set point and intracellular pH (pHi). These parameters were followed spectrofluorimetrically in BCECF-loaded platelets. Phorbol 12-myristate 13-acetate (PMA) and dihexanoylglycerol (DHG), which stimulate PKC, and okadaic acid, which inhibits PP 1 and 2A, elevate the measured parameters in concert, while staurosporine, which inhibits protein kinases, had opposite effects. The stimulatory and inhibitory effects are similarly very rapid, being discerned within seconds. It is concluded that: (a) phosphorylation of the Na+/H+ exchanger is the common origin of the diverse effects of PMA, DHG, okadaic acid and staurosporine, (b) Na+/H+ exchange properties are tightly regulated by phosphorylation and dephosphorylation, and (c) the exchanger plays a major role in pHi regulation in platelets.
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PMID:Modulation of Na+/H+ exchange and intracellular pH by protein kinase C and protein phosphatase in blood platelets. 165 31

Okadaic acid, a potent tumor promoter and inhibitor of phosphoserine/threonine protein phosphatases 1 and 2A, produces a large increase in epidermal growth factor (EGF) receptor phosphorylation in several cell types. The increases are limited to phosphoserine and phosphothreonine residues. 12-O-Tetradecanoylphorbol-13-acetate (TPA), a distinct tumor promoter and protein kinase C activator, also induces serine/threonine phosphorylation of the EGF receptor and is known to modulate receptor functions. Comparison of okadaic acid and TPA influences on the EGF receptor show significant differences. Okadaic acid did not promote phosphorylation of Thr-654, a major site of TPA-induced phosphorylation. However, other sites of phosphorylation were similar for the two tumor promoters. In vitro experiments with purified protein phosphatase 2A demonstrate the insensitivity of Thr-654 phosphorylation, which regulates EGF receptor function, to dephosphorylation by this okadaic acid-sensitive protein phosphatase. In contrast to TPA, okadaic acid did not attenuate the tyrosine kinase activity or ligand binding capacity of the EGF receptor. However, okadaic acid did produce a decrease in EGF-stimulated inositol phosphate formation in a manner distinct from that of TPA.
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PMID:Okadaic acid-induced hyperphosphorylation of the epidermal growth factor receptor. Comparison with receptor phosphorylation and functions affected by another tumor promoter, 12-O-tetradecanoylphorbol-13-acetate. 165 56

Okadaic acid, dinophysistoxin-1 (35-methylokadaic acid), and calyculin A are the okadaic acid class of non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoters, which do not bind to the phorbol ester receptors in cell membranes or activate protein kinase C in vitro. They have potent tumor-promoting activities on mouse skin, as strong as TPA-type tumor promoters, such as TPA, teleocidin, and aplysiatoxin. DNA samples isolated from tumors induced by dimethylbenz[alpha]anthracene and each of the okadaic acid class tumor promoters had the same mutation at the second nucleotide of codon 61 (CAA to CTA) in the c-H-ras gene. Okadaic acid receptors, protein phosphatases 1 and 2A, are present in the particulate as well as cytosolic fractions of various mouse tissues. The apparent "activation" of protein kinases by the okadaic acid class tumor promoters, after their incubation with 32P-ATP, protein kinases, and protein phosphatases, was observed. This activation was caused by inhibition of protein phosphatases 1 and 2A by the okadaic acid class tumor promoters. Treatment of primary human fibroblasts and human keratinocytes with the okadaic acid class tumor promoters induced the hyperphosphorylation of a 60-kDa protein in nuclear and cytosolic fractions, due to the inhibition of protein phosphatases. The 60-kDa protein is a proteolytic fragment of nucleolin, a major nonhistone protein and is designated as "N-60." The mechanisms of action of the okadaic acid class tumor promoters are discussed with emphasis on the inhibition of protein phosphatase activity.
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PMID:Mechanisms of action of okadaic acid class tumor promoters on mouse skin. 166 50

The delta-subunit of the nicotinic acetylcholine receptor from Torpedo californica electric tissue isolated form receptor purified in the absence of protein phosphatase inhibitors contains a total of four phosphate groups. Three of these are shown to represent phosphoserine groups. The fourth possible represents phosphotyrosine. The phosphate groups are localized within the primary structure: We found phosphoserine in positions delta S361 and delta S377, the predicted sites phosphorylated by PKA and PKC, respectively. In addition, we found that position delta S362 is also phosphorylated. Phosphorylation experiments with the synthetic peptide delta L357-delta K368 show that phosphorylation of this novel site can be catalyzed by PKA and by PKC. It is concluded that the delat-subunit of the acetylcholine receptor is stably and not transiently phosphorylated. Implications for the physiological functions of receptor phosphorylation are discussed.
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PMID:Phosphorylation sites of the nicotinic acetylcholine receptor. A novel site detected in position delta S362. 170 13

We have examined the regulation of the AP-1 transcription complex in the IL-1-responsive murine T cell thymoma cell line EL-4 6.1 C10. Our results demonstrate that AP-1-mediated gene expression in T cells may be regulated by several signaling pathways and factors, including IL-1, protein kinase C, protein kinase A (PKA), and one or more serine/threonine-specific protein phosphatases. The activation of protein kinase C results in an increase in nuclear AP-1 DNA binding activity, as well as enhanced gene expression. IL-1 and agents that elevate intracellular cAMP levels do not, by themselves, induce AP-1 activation, but they synergize with phorbol esters. IL-1 and forskolin may enhance AP-1 function by different mechanisms, because forskolin enhanced gene expression without producing an increase in nuclear AP-1 DNA binding, whereas IL-1 increased AP-1-binding activity and gene expression. These observations, in conjunction with the lack of a demonstrable effect of IL-1 on cAMP production in EL-4 cells, are consistent with the view that IL-1 enhances AP-1 activation by a pathway that does not directly involve cAMP and PKA. However, the induction of AP-1 activity by IL-1 and phorbol esters is dependent upon the presence of PKA, as evidenced by the loss of AP-1 inducibility in cells transfected with a cDNA encoding protein kinase inhibitor, a specific inhibitor of PKA. The effect of protein kinase inhibitor on AP-1 activation in response to IL-1 and tetradecanoyl-phorbol-13-acetate was reversed in the presence of the serine/threonine protein phosphatase inhibitor okadaic acid. Thus, the level of AP-1 activity in T cells may be determined by the balance between the activities of several serine/threonine protein kinases and phosphatases.
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PMID:Activation of AP-1 by IL-1 and phorbol esters in T cells. Role of protein kinase A and protein phosphatases. 171 7

Effects of troponin phosphorylation on Ca2(+)-stimulated MgATPase activity of bovine cardiac actomyosin were examined. Phosphorylation by protein kinase C of troponin I and troponin T subunits in troponin or troponin-tropomyosin complex resulted in a decreased Ca2(+)-stimulated MgATPase activity in reconstituted actomyosin, and this effect was reversed by subsequent dephosphorylation by protein phosphatase 1. It was further observed that protein kinase C phosphorylation of either troponin I or troponin T subunits led to a similar inhibition of Ca2(+)-stimulated actomyosin MgATPase activity. In all cases, EC50 values (concentrations causing 50% stimulation) for Ca2+ were not appreciably affected by troponin phosphorylation by protein kinase C. Data from phosphorylation site analysis suggests that phosphorylation of threonine 144 in troponin I and possibly threonine 280 or threonine 199 in troponin T might be important for the observed decrease of Ca2(+)-stimulated actomyosin MgATPase. It is suggested that inhibition of actomyosin MgATPase caused by protein kinase C phosphorylation of troponin I and/or troponin T represents a new mechanism that can account for in part the reported negative inotropic effect of phorbol esters on various cardiac preparations.
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PMID:Protein kinase C phosphorylation of cardiac troponin I or troponin T inhibits Ca2(+)-stimulated actomyosin MgATPase activity. 182 28

Protein phosphorylation and dephosphorylation are involved in regulation of cell growth. We tested the hypothesis that the growth inhibitory effect of transforming growth factor beta 1 (TGF-beta 1) involves activation of protein phosphatases. Exposure of human keratinocytes in culture to 400 pM TGF-beta 1 for 48 h led to 80% inhibition of DNA synthesis as measured by nuclear labeling. Incubation of cultured keratinocytes with 400 pM TGF-beta 1 rapidly activated (within 30 min) protein serine/threonine phosphatase, measured using phosphorylase as a substrate. Based on several criteria, including neutralization of activity with specific antibodies and inhibitor-2, TGF-beta 1-activated phosphorylase phosphatase was identified as protein phosphatase 1. TGF-beta 1 did not have rapid effects on protein serine/threonine phosphatase activity (type 2A) measured with histone phosphorylated by protein kinase C or on protein tyrosine phosphatase activity. However, protein tyrosine phosphatase was activated at 48 h, coincident with growth arrest. Differentiation, induced by the combination of TGF-beta 1 plus calcium or by serum, was not accompanied by further serine/threonine or tyrosine phosphatase activation. We conclude that induction of growth arrest in keratinocytes by TGF-beta 1 involves acute activation of protein phosphatase 1, while activation of protein tyrosine phosphatase may represent an additional mechanism for maintaining cells in a growth-arrested state.
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PMID:Growth arrest induced by transforming growth factor beta 1 is accompanied by protein phosphatase activation in human keratinocytes. 184 73

The present article deals with the stimulation of membrane PLA2 induced by activated protein kinase C (PKC), and the effect of a deficiency in cellular PKC activity in reducing in PLA2 activity. The mode of glucocorticoid (GC) inhibition action in regulation of PLA2 activity, by enhancement of protein dephosphorylation in general, and PLA2 in particular, is hypothesized and discussed. Indirect evidence strongly suggests that activated PKC enzyme is essential for the stimulation of membrane PLA2 activity induced by the Ca2+ ionophore A23187 and other agonists. Our hypothesis suggests that membrane-associated PKC directly phosphorylates PLA2 leading to its activation. Dephosphorylation of activated PLA2, possibly by a serine/threonine protein phosphatase reduces PLA2 activity. GC could induce membrane protein phosphatases which mediate their inhibitory action on PLA2 activity. This mode of action of GC is complementary to their effect in reducting in elevated [Ca2+]i, which is essential for full expression of PLA2 activity. Thus, GC exhibits multiple actions which specifically culminate in suppression of PLA2 and other phospholipases (PI-PLC and PLD) and generally in cellular inactivation (relaxation) and reduction of allergic and inflammatory responses.
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PMID:A novel mechanism of glucocorticosteroid (GC) action in suppression of phospholipase A2 (PLA2) activity stimulated by Ca2+ ionophore A23187: induction of protein phosphatases. 184 70

Recently, the alpha-subunit of the inhibitory guanine-nucleotide-binding protein Gi2 (alpha-Gi2) has been shown to be a substrate for phosphorylation both by protein kinase C and also by other unidentified kinase(s) which are activated as a result of elevated cyclic AMP levels in intact rat hepatocytes [Bushfield, Murphy, Lavan, Parker, Hruby, Milligan & Houslay (1990) Biochem. J. 268, 449-457]. Here we show that the incorporation of [32P]Pi into alpha-Gi2 was enhanced 3-fold by incubation of intact hepatocytes with the tumour promoter and protein phosphatase (1 and 2A) inhibitor, okadaic acid. This action was both time- and concentration-dependent and was accompanied by a loss of guanine-nucleotide-induced inhibition of adenylate cyclase. The increased labelling of alpha-Gi2 induced by okadaic acid was partially additive with that elicited by 8-bromo cyclic AMP, but not with that elicited by the protein kinase C activator phorbol 12-myristate 13-acetate. We suggest that, in the absence of hormones, the activity of alpha-Gi2 is under the control of a dynamic phosphorylation/dephosphorylation system involving protein kinase C and protein phosphatases 1 and/or 2A. This highlights the regulation of kinases and phosphatases as both providing potentially important mechanisms for causing 'cross-talk' between different signalling systems, in this instance controlling cellular responsiveness through regulation of alpha-Gi2 phosphorylation.
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PMID:Okadaic acid identifies a phosphorylation/dephosphorylation cycle controlling the inhibitory guanine-nucleotide-binding regulatory protein Gi2. 190 Sep 86

Human promyelocytic leukemia cell line, HL-60, undergoes macrophagic differentiation when it is stimulated with TPA (12-O-tetradecanoylphorbol-13-acetate). We have cloned ETR101 cDNA whose mRNA was induced immediate early (30 min) and transiently by TPA. The mRNA is superinduced by addition of the protein synthesis inhibitor cycloheximide. The sequence of ETR101 cDNA (1826 base pairs) reveals that (i) it will encode a protein of 223 amino acids with a formula molecular weight of 24,200, (ii) the amino acid sequence is highly homologous to mouse chx1 protein whose mRNA was found recently to be enhanced in activated T lymphocytes in response to cycloheximide, (iii) the amino acid sequence is also weakly homologous to jun family gene products, and (iv) in the mRNA 3'-flanking region, there is a unique GUUUG sequence which is complementary to a part of B1 repetitive sequence and may be involved in mRNA degradation. ETR101 mRNA is induced by TPA in a wide variety of leukemia cells including myeloid, T-lymphoid, and B-lymphoid lineages. We have found that this mRNA is also induced by okadaic acid, a protein phosphatase inhibitor, and that TPA or cycloheximide act synergistically with okadaic acid. In addition, the induction is inhibited by protein kinase C inhibitors. Therefore, ETR101 mRNA level is controlled, either directly or indirectly, by protein phosphorylation.
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PMID:Expression of a novel immediate early gene during 12-O-tetradecanoylphorbol-13-acetate-induced macrophagic differentiation of HL-60 cells. 206 3


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