Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Postsynaptic membranes from the electric organ of Torpedo californica, rich in the nicotinic acetylcholine receptor, were shown to contain an endogenous tyrosine protein kinase. This endogenous kinase phosphorylated three major proteins with molecular masses corresponding to 50 kDa, 60 kDa, and 65 kDa. The phosphorylation of these three proteins occurred exclusively on tyrosine residues under the experimental conditions used and was abolished by 0.1% Nonidet P-40 and stimulated by Mn2+. The 50-kDa, and 60-kDa, and 65-kDa phosphoproteins were demonstrated to be the beta, gamma, and delta subunits, respectively, of the nicotinic acetylcholine receptor by purification of the phosphorylated receptor using affinity chromatography. The endogenous tyrosine kinase specifically phosphorylated the beta, gamma, and delta subunits rapidly to a final stoichiometry of approximately equal to 0.5 mol of phosphate per mol of sub-unit. Two-dimensional phosphopeptide mapping of the phosphorylated beta, gamma, and delta subunits, after limit proteolysis with trypsin or thermolysin, indicated that each subunit was phosphorylated on a single site. Locations are proposed for the amino acid residues phosphorylated on the receptor by the tyrosine-specific protein kinase and by two other protein kinases (cAMP-dependent protein kinase and protein kinase C) which phosphorylate the receptor.
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PMID:Phosphorylation of the nicotinic acetylcholine receptor by an endogenous tyrosine-specific protein kinase. 659 75

In isolated rat hepatocytes angiotensin II and phorbol 12-myristate 13-acetate (PMA) induce the expression of c-fos. We studied the possible transduction pathway(s) involved in this effect using inhibitors of serine-threonine and tyrosine protein kinases. Calphostin and staurosporine, inhibitors of protein kinase C and other serine-threonine protein kinases, block in a dose-dependent manner the effect of angiotensin II and PMA. Interestingly, genistein also blocks the induction of this proto-oncogene, suggesting a role for tyrosine protein kinases. Inhibitors of serine-threonine protein phosphatases, such as okadaic acid, microcystin LR and calyculin also induce c-fos expression. These data suggest that protein phosphatases exert a tonic inhibitory control of c-fos expression. The effect of these phosphatase inhibitors were not blocked by staurosporine, calphostin or genistein. Our results suggest that the expression of c-fos in rat hepatocytes is regulated by complex phosphorylation-dephosphorylation cascade(s) probably involving serine/threonine and tyrosine protein kinase and protein phosphatase activities.
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PMID:Protein kinases and phosphatases modulate c-fos expression in rat hepatocytes. Effects of angiotensin II and phorbol myristate acetate. 753 72

We have previously shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) gene expression induced by interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the murine stromal cell line +/+.1-LDA 11 involves activation of phospholipase A2 (PLA2). Furthermore, induction of GM-CSF gene expression due to release of arachidonic acid as a result of PLA2 activation was mediated by the transcriptional factor c-jun. In the present study, we have investigated the potential mechanism involved in the induction of c-jun gene expression by arachidonic acid. Arachidonic acid induced transcription of c-jun mRNA. Downregulation of protein kinase C (PKC) by chronic exposure of stromal cells to the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA; 400 nmol/L) did not effect c-jun expression induced by arachidonate. Moreover, pretreatment of cells with the PKC inhibitor, calphostin C (1 mumol/L), caused a marked decrease of c-jun expression induced by TPA, but had no influence on c-jun expression induced by arachidonate. To explore the hypothesis that a tyrosine kinase signalling pathway, independent of PKC activation, was involved in arachidonate-induced c-jun expression, stromal cells were pretreated with the protein tyrosine kinase inhibitor, genistein, before challenge with arachidonic acid. Arachidonate 50 mumol/L)-induced c-jun expression was inhibited, in a dose- and time-dependent manner, by genistein. Genistein similarly inhibited c-jun expression in stromal cells exposed to IL-1 (500 U/mL) plus TNF-alpha (500 U/mL). The potential role of a tyrosine kinase pathway in arachidonate-mediated c-jun expression was further investigated by assaying the tyrosine kinase activity of cells challenged with arachidonic acid, IL-1, and TNF-alpha. Exposure of stromal cells to arachidonic acid induced a 2.1-fold increase in intracellular tyrosine kinase activity determined by phosphorylation of the synthetic peptide, raytide, in the presence of [gamma-32P]-ATP. Similarly, IL-1 and TNF-alpha induced 1.7- and 2.4-fold increases in tyrosine protein kinase activity, respectively. The effect of arachidonic acid on tyrosine kinase activity was inhibited by genistein and was enhanced by sodium vanadate. The increase of protein tyrosine kinase activity detected in arachidonate-stimulated cells was associated, in a dose- and time-dependent fashion, with tyrosine phosphorylation of 240-, 40-, and 29-kD substrates. These results are consistent with the hypothesis that a tyrosine phosphorylation process is triggered by arachidonate as an early event in the signalling pathway that leads to increased expression of c-jun.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Arachidonic acid induces c-jun gene expression in stromal cells stimulated by interleukin-1 and tumor necrosis factor-alpha: evidence for a tyrosine-kinase-dependent process. 757 89

Interferon-gamma (IFN gamma) is believed to play a role in the pathogenesis of autoimmune thyroid disease, as it is known to exert diverse effects on thyroid metabolism. These include induction of human leukocyte antigen class II expression, inhibition of gene expression of thyroglobulin and thyroid peroxidase, as well as inhibition of cellular proliferation. However, the mechanism of action of IFN gamma in thyrocytes has not been clearly defined. We studied the action of IFN gamma on the production of inositol phosphates and intracellular Ca2+ mobilization in primary cultures of human thyrocytes using the fluorescent Ca2+ indicator fura-2. IFN gamma increased the production of inositol mono-, bis-, and trisphosphates and caused a dose-dependent increase in intracellular Ca2+ ([Ca2+]i) at 37 C. Preincubation with 12-O-tetradecanoylphorbol-13-acetate, which activates protein kinase C, resulted in the abolition of the IFN gamma response, suggesting that protein kinase C was involved in a negative feedback loop resulting in inhibition of IFN gamma-induced [Ca2+]i rise. Prior release of intracellularly stored Ca2+ with thapsigargin, the microsomal Ca2+ pump inhibitor, also abolished the response of IFN gamma. Mobilization of [Ca2+]i resulted in Ca2+ entry across the plasma membrane, which could be blocked by La3+, the inorganic Ca2+ antagonist. The tyrosine protein kinase inhibitor, genistein, inhibited the production of inositol phosphates and the elevation of [Ca2+]i induced by IFN gamma, but had no effect on ATP, suggesting that tyrosine protein kinase is involved in the signaling transduction of IFN gamma. We conclude that the mobilization of intracellular Ca2+ and the production of inositol phosphates are two important signaling events for the action of IFN gamma in human thyrocytes.
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PMID:Interferon-gamma increases intracellular calcium and inositol phosphates in primary human thyroid cell culture. 758 38

The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth factor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine protein kinase activity. In Rat 1 fibroblasts, stimulation of mitogen-activated protein (MAP) kinase via the IGF1 receptor and the Gi-coupled receptor for lysophosphatidic acid (LPA), but not via the EGF receptor, is sensitive both to pertussis toxin treatment and to cellular expression of a specific G beta gamma subunit-binding peptide. The IGF1, LPA, and EGF receptor-mediated signals are all sensitive to inhibitors of tyrosine protein kinases, require p21ras activation, and are independent of protein kinase C. These data suggest that some tyrosine kinase growth factor receptors (e.g. IGF1 receptor) and classical G protein-coupled receptors (e.g. LPA receptor) employ a similar mechanism for mitogenic signaling that involves both tyrosine phosphorylation and G beta gamma subunits derived from pertussis toxin-sensitive G proteins.
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PMID:G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor. 762 49

We investigated the effect on differentiation of genistein, an inhibitor of tyrosine protein kinase, and 1-(-5 isoquinolinylsulfonyl)-2-methylpiperazine (H7), an inhibitor of protein kinase C, in neuroblastoma cell lines. Growth inhibition and expression of morphological and biochemical properties were examined in the human neuroblastoma cell lines TS12 and SJNKP. Genistein and H7 induced neurite outgrowth, increased acetylcholinesterase activity and cell growth inhibition in both cell lines. These results underline that tyrosine protein kinase and protein kinase C may play a key role in the control of differentiation and proliferation of neural cells.
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PMID:Inhibitors of protein kinases induce differentiation in human neuroblastoma cell lines. 765 25

We have previously demonstrated that HLA-DR molecule expression induced by IFN-gamma is associated with phosphatidylinositide turnover, activation of protein kinase C, and elevation of intracellular calcium. Because phosphorylation of phospholipase C-gamma 1 on tyrosine residues is known to be involved in the activation of phosphatidylinositide turnover, we investigated the role of tyrosine protein kinase (TPK) in the signal transduction for IFN-gamma-inducible DR molecule expression on T98G cells. The effects of three specific TPK inhibitors, genistein, herbimycin A, and tyrphostin, suggest that TPK is involved in the signal transduction. These inhibitors inhibited the IFN-gamma-inducible DR molecule expression in a dose-dependent manner. Being consistent with this, immunoblotting with an anti-phosphotyrosine mAb revealed that IFN-gamma induces a rapid increase in protein tyrosine phosphorylation. Genistein not only abrogated the IFN-gamma-induced enhancement of tyrosine phosphorylation, but also inhibited the IFN-gamma-induced production of inositol-4-5-triphosphate and the elevation of intracellular calcium. However, these three TPK inhibitors failed to inhibit the DR molecule expression induced by PMA and A23187. These findings suggest that the tyrosine phosphorylation is an early and critical event that precedes phosphatidylinositide turnover leading to activation of protein kinase C and elevation of intracellular calcium concentration during IFN-gamma-inducible DR molecule expression.
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PMID:Inhibition of tyrosine phosphorylation prevents IFN-gamma-induced HLA-DR molecule expression. 767 23

Aspirin-like drugs (ALD) induce calcium mobilization, an essential component of T cell activation, but do not induce the biosynthesis of IL-2. To understand the extent to which ALD may mimic mitogenic stimulation, we studied cytoplasmic and nuclear signaling steps in ALD-treated T cells. We found that ALD induce a transient activation of protein kinase (PKC) but have no effect (in comparison to anti-CD3 antibodies) on protein tyrosine phosphorylation nor on PCL gamma 1 tyrosine phosphorylation. ALD-induced calcium mobilization and PKC activation are independent of tyrosine protein kinase activity as shown by the lack of effect of herbimycin, a tyrosine-protein kinase-specific inhibitor. Although we detected no IL-2 mRNA in ALD-treated cells, the nuclei of these cells contain proteins capable of binding to three regulatory sequences in the IL-2 promoter region: NFAT, NF kappa B, and AP-1. These binding activities are expressed only in activated T cells. The expression of AP-1 depended on calcium mobilization and PKC activation. These data suggest that ALD cause transient but significant changes in T cell transmembrane signaling, although some events induced by stimulation with anti-CD3 antibodies are not induced by ALD. The signal is transmitted to the nucleus and induces DNA-binding activity by several transcription factors. However, the ALD stimulus is not capable of causing complete T cell activation.
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PMID:Induction of transcription factors in human T lymphocytes by aspirin-like drugs. 772 85

Phosphorylation, protein carboxyl methylation, and ADP-ribosylation were assayed in renal basolateral membranes and brush border membranes isolated from rats treated by subcutaneous administration of 5 or 10 mg/(kg.day) of cyclosporin A (CsA) for 10 days to investigate potential alterations in signal transduction in kidney cortex. Protein carboxyl methylation of class II measured in membranes and in cytosolic fraction was not affected by CsA treatment. ADP-ribosylation performed in the presence of pertussis or cholera toxin was also similar in control and treated rats. However, changes in phosphorylation of endogenous substrates were observed in membranes and cytosol isolated from rats treated with 10 mg/(kg.day) of CsA. Phosphorylation was increased for two brush border membrane proteins (56 and 77 kilodaltons (kDa)) by 47 and 24% and for two basolateral membrane proteins (51 and 80 kDa) by 28 and 29%, respectively. In the cytosolic fraction, phosphorylation of two proteins (31 and 65 kDa) was increased by 37% and that of 25- and 43-kDa proteins was reduced by 29%. Protein kinase A, protein kinase C, and tyrosine protein kinase activities were also determined in membranes. Increases in protein kinase C and tyrosine protein kinase activities were observed in basolateral membranes, but not in brush border membranes after cyclosporin A administration. Endogenous substrates for tyrosine kinase were also detected with an antiphosphotyrosine (PY20) monoclonal antibody. Densitometric analysis indicated that the phosphorylation of three proteins of high molecular masses (61, 132, and 183 kDa) was stimulated by CsA in basolateral membranes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclosporin treatment alters protein phosphorylation in kidney membranes. 781 48

Phorbol-12-myristate-13-acetate (PMA) induced a dose-dependent proliferation of human hepatocarcinoma cell line SMMC-7721. In the presence of 100 nmol/L PMA, the activity of alkaline phosphatase was decreased and gamma-glutamyltransferase increased in the cell, suggesting that PMA is a proliferative inducer of hepatocarcinoma cell. PMA (100 nmol/L) also lead to a cytosol to membrane translocation of protein kinase C (PKC) within 5 minutes and down regulation after 1 hour. The decline of PKC activity in cytosolic fraction was far faster than that of membranous fraction. After long-term treatment with PMA for 1-5 days, the activities of PKC in cytosolic or membranous fraction almost disappeared, but the tyrosine protein kinase in both subcellular fractions was increased, being most obviously on the third day of culture. The increase in cytosolic TPK was more than that of membranous TPK, further indicating that TPK is a marker of cell proliferation.
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PMID:[Effect of phorbol ester on protein kinase C and tyrosine protein kinase in human hepatocarcinoma cell line]. 790 36


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