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)

We have studied the effect of activation of the c-erbB-2 receptor tyrosine kinase on protein kinase C (PKC) in cultured SKBR-3 human breast cancer cells. Treatment with the agonistic anti-receptor monoclonal antibody TAb 250 induces receptor autophosphorylation and stimulates phospholipase C-gamma 1 (L. K. Shawver et al. Cancer Res., 54: 1367-1373, 1994). TAb 250 induced a rapid and marked translocation of PKC histone phosphorylation activity to the particulate fraction of SKBR-3 cells. By immunoblot, however, this translocation was limited to specific PKC isozymes. beta PKC and zeta PKC translocated to the particulate fraction, whereas epsilon PKC underwent "partial reversed translocation" to the cell soluble fraction after receptor stimulation. Furthermore, beta PKC was rapidly degraded following TAb 250 treatment. By immunocytochemistry, beta IPKC translocated from the perinuclear area to the cytosol and into the nucleus, whereas zeta PKC translocated to the perinuclear region and into the nucleus. Consistent with the Western blot results, epsilon PKC translocated from the nucleus to the perinuclear area and the cytosol. These changes in the localization of PKC isozymes were not observed after addition of normal IgG1 or a nonagonistic anti-c-erbB-2 monoclonal antibody to SKBR-3 cells. alpha, beta II, or delta PKC present in these cells did not translocate following receptor stimulation. These data indicate that c-erbB-2 signal transduction may involve the activation of specific PKC isozymes. The biological role of these enzymes in the phenotype and cellular responses of c-erbB-2-overexpressing carcinoma cells remains to be studied.
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PMID:Distinct responses of protein kinase C isozymes to c-erbB-2 activation in SKBR-3 human breast carcinoma cells. 798 52

To study the signal transduction mechanisms by which ultraviolet B (UVB) leads to increased prostaglandin E2 (PGE2) synthesis, human epidermal cultures were irradiated with 30 mJ/cm2 UVB and assayed for 6-h cumulative PGE2. Supernatants from irradiated cultures showed a 4-fold increase in PGE2 synthesis (113.6 +/- 26.8 pg/mg protein) when compared to supernatants from sham-irradiated cultures (25.6 +/- 3.9 pg/mg protein). Pretreatment of irradiated cultures with genistein (10 micrograms/ml) or tyrphostin-23 (50 microM), inhibitors of tyrosine kinases, blocked UVB-stimulated PGE2 synthesis. Treatment of nonirradiated cultures with epidermal growth factor (EGF), which acts through the receptor tyrosine kinase EGF-R, produced a 4-fold increase in PGE2 synthesis. However, addition of EGF to irradiated cultures did not further enhance their PGE2 synthesis, indicating irradiation rendered them refractory to EGF stimulation. In contrast, irradiated cultures could still significantly increase their PGE2 synthesis in response to the calcium ionophore A23187 or the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate, suggesting that the lack of response to EGF was selective. Furthermore, anti-phosphotyrosine immunoblot analysis revealed UVB-induced phosphorylation of tyrosine residues of EGF-R, an indicator of receptor activation. Phosphorylation was maximal 30-60 min after irradiation and was blocked by the tyrosine kinase inhibitors, genistein and tyrphostin. The antioxidant N-acetylcysteine decreased UVB-induced EGF-R tyrosine phosphorylation and PGE2 synthesis to near-basal levels. Conversely, treatment of unirradiated cultures with the potent oxidant tert-butyl-hydroperoxide (100 microM) increased both PGE2 synthesis and EGF-R phosphorylation. Collectively, these data suggest that antioxidant depletion induced by UV results in tyrosine phosphorylation and activation of the EGF-R. This activation may subsequently activate epidermal phospholipase at early time points after UVB exposure.
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PMID:Ultraviolet B injury increases prostaglandin synthesis through a tyrosine kinase-dependent pathway. Evidence for UVB-induced epidermal growth factor receptor activation. 810 95

To identify the novel receptor tyrosine kinases (RTKs) critical to the proliferation of hematopoietic stem cells, we performed polymerase chain reaction-based cloning from highly purified murine hematopoietic stem cells. Lineage marker-negative, c-KIT-positive, and Ly6A/E- or Sca-1-positive (Lin-c-KIT+Sca-1+) cells were sorted by a fluorescence-activated cell sorter. Two sets of degenerate oligonucleotide primers were directed to the conserved sequences of the catalytic domain, and were used to amplify cDNAs that encode protein tyrosine kinases (PTKs). One hundred cDNA clones were sequenced and 8 RTKs were identified, as well as 12 non-RTKs and 2 serine/threonine kinases. Sixteen cDNAs were identical to the known kinase genes (PKC beta, JAK-1, JAK-2, TYK-2, HCK, FGR, FYN, BLK, c-FES, FER, c-ABL, c-KIT, FLK-1, FLK-2, IGF1R, and ECK). Six novel cDNA sequences (stk series) were identified. However, three of them turned out to be BPK, RYK, and TEK. The remaining three showed high homology to S6 kinase II, JAK-2, and v-SEA/c-MET, respectively. Characterization of full-length cDNA sequence of the v-SEA/cMET-related gene showed that this was a novel RTK gene and we named this gene STK (stem cell-derived tyrosine kinase). We identified two distinct forms of STK cDNA; the short one encoded a putative truncated protein that lacked most of the extracellular domain. STK was expressed at various stages of hematopoietic cells, including stem cells, but we could not detect any apparent expression in other adult tissues. The expression of the truncated form of mRNA was more predominant than that of the complete form. STK was assigned by fluorescent in situ hybridization to the R-positive F1 band of chromosome 9, the same region to which hepatic growth factor-like protein has been assigned. Characterization of these PTKs, including STK, will be helpful to elucidate the molecular mechanism of the growth regulation of hematopoietic stem cells.
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PMID:Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells. 819 52

The feline sarcoma virus oncogene v-fms has significantly contributed to the dissection of peptide growth factor action since it encodes the transmembrane tyrosine kinase gp140v-fms, a transforming version of colony-stimulating factor 1 receptor, a member of the growth factor receptor tyrosine kinase family. In this study, the functional significance of structural differences between distinct tyrosine kinase types, in particular between cellular receptors and viral transforming proteins of distinct structural types, has been further investigated, and their functional compatibility has been addressed. For this purpose, major functional domains of three structurally distinct tyrosine kinases were combined into two chimeric receptors. The cytoplasmic gp140v-fms kinase domain and the kinase domain of Rous sarcoma virus pp60v-src were each fused to the extracellular ligand-binding domain of the epidermal growth factor (EGF) receptor to create chimeras EFR and ESR, respectively, which were studied upon stable expression in NIH 3T3 fibroblasts. Both chimeras were faithfully synthesized and routed to the cell surface, where they displayed EGF-specific, low-affinity ligand-binding domains in contrast to the high- and low-affinity EGF-binding sites of normal EGF receptors. While the EFR kinase was EGF controlled for autophosphorylation and substrate phosphorylation in vitro, in vivo, and in digitonin-treated cells, the ESR kinase was not responsive to EGF. While ESR appeared to recycle to the cell surface upon endocytosis, EGF induced efficient EFR internalization and degradation, and phorbol esters stimulated protein kinase C-mediated downmodulation of EFR. Despite its ligand-inducible kinase activity, EFR was partly EGF independent in mediating mitogenesis and cell transformation, while ESR appeared biologically inactive.
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PMID:Epidermal growth factor (EGF) modulation of feline sarcoma virus fms tyrosine kinase activity, internalization, degradation, and transforming potential in an EGF receptor/v-fms chimera. 825 51

Mitogenic stimulation of quiescent mammalian cells triggers an array of early events crucial for cell cycle progression. Here we show that the activity of the anoxic stress protein, lactate dehydrogenase 6/k, transiently increased after mitogenic stimulation of serum-starved HeLa cells. Regulation of lactate dehydrogenase 6/k activity in early G1 depended on the activity of a receptor tyrosine kinase and on protein and mRNA synthesis, but did not involve protein kinase C. The guanine analog, queuine, an ubiquitously occurring tRNA base of bacterial origin, suppressed the mitogen-induced protein synthesis and also the transient increase in lactate dehydrogenase 6/k activity. The results suggest that queuine relieves hypoxic stress resulting from mitogenic stimulation by suppressing protein synthesis during G0/G1 transition.
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PMID:Mitogenic stimulation of HeLa cells increases the activity of the anoxic stress protein, LDH 6/k: suppression by queuine. 828 Jan 49

The receptor for hepatocyte growth factor/scatter factor (HGF/SF) is an alpha beta tyrosine kinase of 190 kDa which mediates growth and motility in several cell types. We have previously shown that tyrosine autophosphorylation enhances the receptor kinase activity, while serine phosphorylation by protein kinase C or other Ca(2+)-dependent kinase(s) is inhibitory. We now identify Ser985 as the major phosphorylation site for the protein kinases responsible for such inhibition. Both phorbol esters or Ca2+ ionophore treatment induces phosphorylation of the same tryptic phosphopeptide corresponding to the sequence Leu983-Arg987 located in the juxta-membrane domain of the receptor beta chain. Purified protein kinase C phosphorylates in vitro a synthetic peptide (V14S) including Ser985. Trypsin digestion of the phosphorylated V14S generates a single phosphopeptide comigrating in reverse-phase high performance liquid chromatography with the tryptic peptide phosphorylated in vivo. Phorbol ester treatment of cultured cells inhibits the ligand-induced tyrosine autophosphorylation of the receptor. In vitro, Ser985 phosphorylation inhibits the receptor tyrosine kinase activity on exogenous substrates. Substitution of Ser985 by site-directed mutagenesis results in increased tyrosine phosphorylation of the receptor and abolishes down-modulation by protein kinase C. These data show that phosphorylation of Ser985 is a key mechanism for the negative regulation of HGF/SF receptor.
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PMID:Phosphorylation of serine 985 negatively regulates the hepatocyte growth factor receptor kinase. 829 30

Human interleukin-3 binds to a high affinity receptor composed of alpha- and beta-subunits. The beta-subunit is responsible for signal transduction but does not contain any intrinsic tyrosine kinase activity or other consensus motifs related to intracellular signaling. Previous work using IL-3 dependent MO7E cells has suggested a major role only for non-receptor tyrosine kinase activation in IL-3 signal transduction. We have shown, however, that engagement of the human interleukin-3 receptor induces the translocation of protein kinase C from the cytosol to the cell membrane in MO7E cells. This translocation is accompanied by rapid (2-5 min) accumulation of 1'2'-diacylglycerol (twice control values) in the absence of an increase in intracellular Ca2+. Prelabeling cells with [3H]glycerol or [3H]-choline demonstrated rapid release of [3H]phosphorylcholine and a decrease in [3H]glycerol-labeled phosphatidylcholine in response to IL-3 stimulation. In addition, IL-3 did not induce phosphatidic acid accumulation, and the IL-3 induced diacylglycerol accumulation was blocked by p-bromophenacylbromide (a phospholipase C inhibitor). It is thus likely that interleukin-3 is activating a phosphatidylcholine specific phospholipase C rather than a phospholipase D. Finally, genistein and herbimycin, specific tyrosine kinase inhibitors, inhibited both IL-3 induced protein kinase C translocation and the accumulation of diacylglycerol. Thus, IL-3 induced tyrosine phosphorylation may result in activation of a phosphatidylcholine phospholipase C and protein kinase C.
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PMID:Human interleukin-3 stimulates a phosphatidylcholine specific phospholipase C and protein kinase C translocation. 830 41

Hepatocyte Growth Factor (HGF) and Scatter Factor (SF) are identical glycoproteins secreted by cells of mesodermal origin. The factor has several activities on epithelial cells, including mitogenesis, dissociation of epithelial sheets, stimulation of cell motility, and promotion of matrix invasion. HGF is the ligand for p190MET, the receptor tyrosine kinase encoded by the MET proto-oncogene. This was proved by HGF binding to immunopurified p190MET, chemical cross-linking of radiolabelled ligand, HGF-induced tyrosine phosphorylation of p190MET, and reconstitution of high-affinity binding sites for HGF into insect cells infected with a recombinant baculovirus carrying the human MET cDNA. p190MET is a 190 kDa heterodimer of two (alpha beta) disulfide-linked protein subunits. The alpha subunit is heavily glycosylated and extracellular. The beta subunit bears an extracellular portion involved in ligand binding, a membrane spanning segment and a cytoplasmic tyrosine kinase domain with phosphorylation sites regulating its activity. Both subunits originate from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. Alternative post-transcriptional processing originates two truncated Met proteins, endowed with ligand binding activity, lacking the cytoplasmic kinase domain of the beta subunit. One form is soluble and released from the cells. HGF binding triggers tyrosine autophosphorylation of the receptor beta subunit in intact cells. Autophosphorylation upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. The major phosphorylation site has been mapped to Tyr1235. Negative regulation of the receptor kinase activity occurs through distinguishable pathways involving protein kinase C activation or increase in the intracellular Ca2+ concentration. Both lead to the serine phosphorylation of a unique phosphopeptide of the receptor and to a decrease in its kinase activity. Receptor autophosphorylation also triggers the signal transduction pathways inside the target cells. The phosphorylated receptor associates ras GAP, phospholipase C-gamma, and src-related tyrosine kinase in vitro; Phosphatidylinositol 3-kinase, in vitro and in vivo, indicating that the generation of the D-3 phosphorylated inositol lipids is involved in effecting the motility and/or the growth response to HGF. The p190MET HGF receptor is expressed in several epithelial tissues and it is often overexpressed in neoplastic cells. In some tumors of the gastrointestinal tract the Met tyrosine kinase is constitutively activated, either by overexpression of the amplified MET oncogene or by lack of cleavage of the receptor precursor, due to defective post-translational processing.
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PMID:Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells. 838 Jul 35

Exposure of cells to phorbol 12-myristate 13-acetate (PMA) has been reported to result in resistance to the acute biological effects of insulin and an associated reduction in insulin-receptor tyrosine kinase activity. To investigate the relationship of insulin receptor autophosphorylation with a longer-term action of insulin the effect of PMA on insulin-stimulated receptor down-regulation was examined in cultured human lymphocytes (IM-9). Lymphocytes bound [3H]phorbol dibutyrate specifically with characteristics typical of binding to protein kinase C (PKC). Acute exposure (30 min) to PMA resulted in a transient decrease of insulin binding which is consistent with a decrease in receptor number. Chronic (18 h) exposure to PMA (5 nM) resulted in inhibition of insulin-induced down-regulation of its cognate receptor. Sphingosine, an inhibitor of PKC, or chronic pre-exposure to a high concentration of PMA (1 microM), which is known to inactivate PKC, blocked the effect of PMA. PMA inhibited insulin-stimulated receptor internalization by 26% and receptor degradation by 82%. Exposure of intact cells to PMA followed by insulin treatment inhibited insulin-receptor autophosphorylation subsequently assayed in vitro, as well as beta-subunit tyrosine phosphorylation in situ. In summary, PMA inhibited insulin-stimulated receptor down-regulation via activation of PKC. This was associated with an inhibition of both receptor internalization and receptor degradation. There was a concomitant inhibition of receptor tyrosine autophosphorylation consistent with a requirement of receptor kinase activation for both short-term and long-term biological effects of insulin.
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PMID:Phorbol esters inhibit insulin-induced receptor down-regulation in cultured human lymphocytes: association with diminished insulin receptor autophosphorylation. 838 76

Epidermal growth factor (EGF) receptor tyrosine kinase activity is down-regulated by a number of growth-modulating agents that activate protein kinase C and/or mitogen-activated protein (MAP) kinases. Although the mechanism is unclear, it has been hypothesized that phosphorylation of specific threonine residues leads to inhibition of the EGF receptor tyrosine kinase. Two sites phosphorylated on the EGF receptor in response to phorbol esters are possible mediators of this effect: threonine 654, the target of protein kinase C, and threonine 669, the target of MAP kinase and the major site of phosphorylation on the EGF receptor. In order to investigate the role of these residues in receptor regulation, we substituted glutamic acid to mimic the negative charge introduced by phosphorylation at these sites. The wild-type and mutant receptor cDNAs were then transfected into CHO cells that lack endogenous EGF receptor. The EGF binding properties of the mutant receptors were similar to those of the wild-type EGF receptors. EGF stimulated tyrosine kinase activity and DNA synthesis in cells expressing both mutant receptors, indicating that the mutant EGF receptors are biologically active. Treatment of cells with phorbol esters inhibited the high affinity EGF binding and tyrosine kinase activities of both mutant and wild-type EGF receptors. These results indicate that acidic residues at either the Thr-654 or Thr-669 site modulate but do not block EGF receptor signalling. Furthermore, this data demonstrates that the mutant EGF receptors are still a target for inhibition by phorbol esters. Thus, events other than phosphorylation of Thr-654 or Thr-669 appear to be required for receptor down-regulation by protein kinase C or MAP kinase.
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PMID:Role of threonine residues in regulation of the epidermal growth factor receptor by protein kinase C and mitogen-activated protein kinase. 839 47


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