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)

Epidermal growth factor (EGF) treatment of A-431 cells induces a biphasic increase in the levels of inositol phosphates. The growth factor produces an initial, rapid increase in the level of inositol 1,4,5-trisphosphate (Ins-1,4,5-P3) due to hydrolysis of phosphatidyl-inositol-4,5-bisphosphate (Wahl, M., Sweatt, J. D., and Carpenter, G. (1987) Biochem. Biophys. Res. Commun. 142, 688-695). The level of inositol 1,3,4,5-tetrakisphosphate (Ins-1,3,4,5-P4) also rises rapidly in response to treatment with EGF. The initial formation (less than 1 min) of Ins-1,4,5-P3 and Ins-1,3,4,5-P4 does not require Ca2+ present in the culture medium. However, the addition of Ca2+ to the medium at levels of 100 microM or greater potentiates the growth factor-stimulated increases in the levels of all inositol phosphates at later times after EGF addition (1-60 min). The data suggest that EGF-receptor complexes initially stimulate the enzyme phospholipase C in a manner that is independent of an influx of extracellular Ca2+. The presence of Ca2+ in the medium allows prolonged growth factor activation of phospholipase C. Treatment of A-431 cells with Ca2+ ionophores (A23187 and ionomycin) did not mimic the activity of EGF in producing a rapid increase in the formation of the Dowex column fraction containing Ins-1,4,5-P3, Ins-1,3,4,5-P4, and inositol 1,3,4-trisphosphate (InsP3). However, the initial EGF-stimulated formation of inositol phosphates was substantially diminished in cells loaded with the Ca2+ chelator Quin 2/AM. EGF receptor occupancy studies indicated that maximal stimulation of InsP3 accumulation by EGF requires nearly full (75%) occupancy of available EGF binding sites, while half-maximal stimulation requires 25% occupancy. 12-O-Tetradecanoylphorbol-13-acetate (TPA), an exogenous activator of Ca2+/phospholipid-dependent protein kinase (protein kinase C), causes a dramatic, but transient, inhibition of the EGF-stimulated formation of inositol phosphates. Tamoxifen and sphingosine, reported pharmacologic inhibitors of protein kinase C activity, potentiate the capacity of EGF to induce formation of inositol phosphates. Neither TPA nor tamoxifen significantly affects the 125I-EGF binding capacity of A-431 cells; however, TPA appeared to enhance internalization of the ligand. Ligand occupation of the EGF receptor on the A-431 cell appears to initiate a complex signaling mechanism involving production of intracellular messengers for Ca2+ mobilization and activation of protein kinase C.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of epidermal growth factor-stimulated formation of inositol phosphates in A-431 cells by calcium and protein kinase C. 325 77

Epidermal growth factor (EGF) or phorbol 12-myristate 13-acetate (PMA) stimulated mouse embryo palate mesenchyme (MEPM) cells to incorporate [32P]O(3-)4 into a protein with an apparent molecular weight of 80 kDa, in vitro. Agents known to elevate intracellular levels of cyclic AMP did not stimulate phosphorylation of this phosphoprotein. Since there is a significant amount of evidence obtained with other cells indicating that phosphorylation of such an 80-kDa phosphoprotein reflects specifically the activation of protein kinase C in response to PMA and other agents, including mitogens, these findings raise the possibility that EGF may activate protein kinase C in MEPM cells.
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PMID:Effects of epidermal growth factor and phorbol 12-myristate 13-acetate on protein phosphorylation in mouse embryo palate mesenchyme cells in vitro. 326 83

Epidermal growth factor (EGF) as well as phorbol 12-myristate 13-acetate (TPA) stimulate de novo synthesis of PGHS (prostaglandin H synthase)-1 and PGHS-2 mRNA, resulting in increased production of PGE2 in rat tracheal epithelial cells (RTE, EGV-6 cells). Stimulation of PGE2 production by TPA is more potent than that by EGF. Staurosporine and H-7, protein kinase C (PKC) inhibitors, suppressed the increase of mRNA and PGE2 levels caused by TPA, but not that caused by EGF. On the other hand, methyl 2,5-dihydroxycinnamate, a tyrosine kinase inhibitor (TKI), suppressed the increase of mRNA and PGE2 levels caused by EGF, but not that caused by TPA. These results indicate that EGF stimulates de novo synthesis of PGHS-1 and PGHS-2 mRNA through a signal transduction pathway which is independent from PKC-associated mechanisms but dependent upon the tyrosine kinase activity of the EGF receptor.
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PMID:EGF and TPA stimulate de novo synthesis of PGHS-1 and PGHS-2 through different signal transduction pathways. 748 87

The rapid activation of gene expression by growth factors frequently involves the nucleocytoplasmic redistribution of proteins which regulate the transcription of discrete sets of genes. In particular, it has become apparent that protein kinases and transcription factors including protein kinase A, mitogen activated protein kinase, protein kinase C, NF-kappa B and Stat91, can rapidly migrate from the cytosol to the nucleus in response to a wide variety of extracellular stimuli. Furthermore, it is assumed that these proteins represent important components of the signal transduction pathways which operate between the plasma membrane and the nucleus. Here two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) has been used to detect proteins which undergo rapid growth factor stimulated nucleocytoplasmic redistribution. Epidermal growth factor and insulin influenced the association of 15 individual protein spots with the nucleus. Estimates of the abundance of these proteins revealed that they represented approximately 1/1000 to 1/5000 of total nuclear protein. To permit identification by microsequencing, five of the protein spots have been recovered from multiple 2-D PAGE gels and concentrated by one-dimensional elution-concentration gel electrophoresis. The data obtained demonstrate that 2-D PAGE can be used to: (i) analyse putative regulators of growth factor activated gene transcription, and (ii) purify sufficient amounts of these proteins to facilitate identification by microsequence analysis.
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PMID:Analysis of growth factor stimulated nucleocytoplasmic protein transport using two-dimensional gel electrophoresis. 749 71

Epidermal growth factor (EGF) increases 12-lipoxygenase mRNA by about 2-fold with a lag period of 4 to 8 hr, which precedes the increase in 12-lipoxygenase activity by 2 to 4 hr in human epidermoid carcinoma A431 cells. Induction of 12-lipoxygenase expression in human erythroleukemia cells by phorbol 12-myristate 13-acetate (PMA) has been reported previously. The present report describes a study of the involvement of protein kinase C (PKC) in EGF-induced 12-lipoxygenase expression in A431 cells. EGF-induced 12-lipoxygenase expression was inhibited by methyl 2,5-dihydroxycinnamate, a tyrosine kinase inhibitor. Staurosporine and calphostin C, which are two PKC inhibitors, inhibited EGF-induced enzyme activity and mRNA expression of 12-lipoxygenase. 1,2-Dioctanoyl-sn-glycerol (a membrane-permeant diacylglycerol) and PMA significantly induced enzyme activity and mRNA expression. Simultaneous treatment of cells with EGF and PMA did not exhibit an additive effect, suggesting that EGF and PMA share a common biochemical pathway in 12-lipoxygenase induction. Expression of mRNA for PKC alpha, delta and zeta was detected in A431 cells, whereas no mRNA expression for PKC beta 1, gamma and epsilon was observed. Taken together, these results suggest that EGF-induced 12-lipoxygenase expression is at least in part mediated by the PKC signal transduction pathway.
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PMID:Induction of 12-lipoxygenase expression by epidermal growth factor is mediated by protein kinase C in A431 cells. 752 31

Epidermal growth factor (EGF), 20 ng/ml, stimulated myelin basic protein (MBP) phosphorylation in crude extracts from human keratinocyte primary cultures. In order to identify the involved kinases, we separated by fast protein liquid chromatography proteins participating in MBP phosphorylation. We detected three MBP kinase activities in the keratinocyte crude extracts. The first MBP kinase activity was the only one stimulated by EGF and reacted with anti-mitogen-activated protein kinase (MAPK) antiserum recognising p42mapk and p44mapk isoforms. However, when protein kinase C (PKC) was either inhibited by the PKC inhibitor GF 109203X or depleted by a prolonged TPA treatment, the stimulation of MBP phosphorylation by EGF was strongly inhibited. The second MBP kinase activity eluted was due to a PKC isoform reacting with an anti-PKC zeta antibody, and the third was not identified. With this work, we have thus shown that, in human keratinocytes, EGF activates MAPK activity by a PKC-dependent pathway.
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PMID:Epidermal growth factor stimulates mitogen-activated protein kinase by a PKC-dependent pathway in human keratinocytes. 753 73

Epidermal growth factor (EGF) is a single polypeptide of 53 amino acid residues which is involved in the regulation of cell proliferation. Egf exerts its effects in the target cells by binding to the plasma membrane located EGF receptor. The EGF receptor is a transmembrane protein tyrosine kinase. Binding of EGF to the receptor causes activation of the kinase and subsequently receptor autophosphorylation. The autophosphorylation is essential for the interaction of the receptor with its substrates. These bind to the receptor by the so-called SH2 domains. The signal transduction pathways activated by EGF include the phosphatidylinositol pathway, leading to activation of protein kinase C and to increase in the intracellular Ca2+ concentration, and to the ras pathway leading to MAP kinase activation. Recently the cytoplasm has been implicated as playing an important role in EGF induced signal transduction. The EGF receptor has been demonstrated to be an actin-binding protein. In addition EGF causes a rapid actin depolymerisation and the formation of membrane ruffles. In particular these membrane ruffles have been shown to act as the first site of signal transduction after EGF binding, and thus may be considered as signal transduction structures. Finally evidence has been presented suggesting a positive role for EGF and/or the receptor in the nucleus.
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PMID:The epidermal growth factor. 764 Jun 57

The proteinase thrombin, known to act via heptahelical G-protein-coupled receptors, is a mitogenic agent for different cell types, including the mouse muscle cell line BC3H1. In this study, the effect of thrombin on tyrosine phosphorylation was examined using anti-phosphotyrosine antibodies. Thrombin was found to induce phosphorylation of 65-70 and 110-120 kDa proteins in BC3H1 cells. The effect of thrombin was concentration-dependent, being half-maximal and maximal at concentrations of 0.03 and 1 unit/ml respectively. The thrombin-induced increase in phosphorylation was rapid (< or = 10 s) and transient, with a peak response after about 1-2 min. The effect of thrombin could be mimicked by the thrombin receptor agonist peptide SFLLRN-NH2. Preincubation of cells with pertussis toxin (PT) had no effect on thrombin-induced tyrosine phosphorylation. Epidermal growth factor, platelet-derived growth factor and insulin stimulated tyrosine phosphorylation of different proteins, among which were 65-70 and 110-120 kDa proteins. The phorbol ester 12-myristate 13-acetate (PMA) as well as the Ca2+ ionophore A23187 both stimulated tyrosine phosphorylation of proteins identical to those phosphorylated by thrombin, suggesting that activation of protein kinase C (PKC) and elevation of the cytosolic Ca2+ concentration alone are sufficient to induce tyrosine phosphorylation. However, calphostin C and other PKC inhibitors, which completely inhibited tyrosine phosphorylation induced by PMA, had no influence on the effect of thrombin, whereas loading of cells with the intracellular Ca2+ chelator bis-(O-aminophenoxy)ethane-NNN'N'-tetra-acetic acid totally blocked thrombin-stimulated tyrosine phosphorylation. Thus tyrosine phosphorylation stimulated by thrombin is an early PT-insensitive cellular response which is either directly mediated by elevation of cytosolic Ca2+ concentration or by a presently unknown mechanism that requires an elevated cytosolic Ca2+ concentration.
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PMID:Thrombin Ca(2+)-dependently stimulates protein tyrosine phosphorylation in BC3H1 muscle cells. 767 96

delta-Iodolactone (6-iodo-8,11,14-eicosatrienoic delta-lactone, delta-IL), an iodinated derivative of arachidonic acid, has been shown to be synthesized in thyroid tissue and to inhibit thyroid cell proliferation. It is discussed as a potential mediator of the autoregulatory pathway of iodide in cyclic adenosine-3',5'-monophosphate (cAMP)- and thyrotropin (TSH)-independent growth. We therefore further localized the action of iodide and of delta-IL in isolated porcine thyroid follicles. Epidermal growth factor (EGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) dose dependently stimulated thyroid cell proliferation, which could be inhibited by staurosporin (0.1-10 nmol/l). Iodide (2.5-40 mumol/l) as well as delta-IL (0.5-2 mumol/l) also dose dependently inhibited EGF- and TPA-induced proliferation. As the calcium ionophor A23187 (100 pmol/l) completely abolished the inhibitory effects of iodide and of delta-IL, this may indicate a mechanism of delta-IL at or proximal to the calcium-dependent activation of protein kinase C. The growth inhibitory effect was restricted to delta-iodolactones when delta-IL was compared to 6-iodo-8,11,14,17-eicosatetraenoic delta-lactone and 5-iodo-7,10,13,16,19-docosapentaenoic gamma-lactone. It could not be prevented with propylthiouracil and therefore deiodination and a different iodide action is unlikely. Inositol-1,4,5-trisphosphate (IP3) and cAMP were measured in extracts from isolated porcine thyroid follicles stimulated with EGF (10 ng/ml) or TSH (1.0 U/l) revealing comparable kinetics in IP3 generation, while cAMP formation was only stimulated by TSH. delta-Iodolactone (2 mumol/l) only decreased EGF-induced IP3 formation, whereas TSH-induced IP3 and cAMP formation was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:delta-Iodolactones decrease epidermal growth factor-induced proliferation and inositol-1,4,5-trisphosphate generation in porcine thyroid follicles--a possible mechanism of growth inhibition by iodide. 778 15

Epidermal growth factor (EGF) induces a rapid increase in the phosphorylation of extracellular signal-regulated kinases (ERKs) in the human osteosarcoma osteoblastic cell line G292 and in primary cultures of rat osteoblastic cells. This phosphorylation is transient and time-dependent. Maximal stimulation is attained within 1 min in G292 and within 5 min in rat osteoblastic cells. Enzymatic activity in G292 cells is also induced rapidly after EGF stimulation. Western blot analysis revealed that enhancement of the phosphorylation of ERKs in the EGF-stimulated cells is not due to an increase in ERK protein, since EGF-treatment does not lead to an increase in the absolute amount of ERKs present even after 2 days of stimulation. The pattern of expression of the ERKs observed in the two cell types differs in the apparent molecular weights observed. The most slowly migrating immunoreactive protein (approximately 45 kDa) in normal rat osteoblastic cells is ERK1, identified by an ERK1-selective antiserum. The same antiserum reacts only weakly with one of the ERK proteins (44 kDa) blotted from the human osteosarcoma cell line G292. Phorbol 12-myristate 13-acetate (PMA) is also capable of inducing ERK phosphorylation, albeit to a lasser degree. The combination of PMA and EGF does not produce a greater response than EGF alone. The role of protein kinase C (PKC) in the EGF-stimulated ERK signaling pathway was further examined by inhibition of PKC with the staurosporine analog, CGP41251, and by down-regulation of PKC via chronic treatment with PMA. Chronic PMA treatment results in a partial inhibition of the EGF-mediated phosphorylation. CGP41251 completely abolishes the increased ERK activity produced by PMA, but the effect of EGF in this regard is potentiated. We conclude that PKC and EGF act through parallel pathways to stimulate ERK phosphorylation and activity. The inhibitor studies, in addition, indicate that activation of PKC may moderate the actions of the EGF pathway via a tonic inhibitory feedback.
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PMID:EGF-mediated phosphorylation of extracellular signal-regulated kinases in osteoblastic cells. 786 Jun 43


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