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)

The murine myeloid progenitor cell line 32D was recently shown to undergo monocytic differentiation when protein kinase C-delta (PKC-delta) was overexpressed and activated by 12-O-tetradecanoylphorbol-13-acetate (TPA) (H. Mischak, J.H. Pierce, J. Goodnight, M.G. Kazanietz, P.M. Blumberg, and J.F. Mushinski, J. Biol. Chem. 268:20110-20115, 1993). Tyrosine phosphorylation of PKC-delta occurred when PKC-delta-transfected 32D cells were stimulated by TPA (W. Li, H. Mischak, J.-C. Yu, L.-M. Wang, J.F. Mushinski, M.A. Heidaran, and J.H. Pierce, J. Biol. Chem. 269:2349-2352, 1994). In order to elucidate the role played by PKC-delta in response to activation of a receptor tyrosine kinase, we transfected platelet-derived growth factor beta receptor (PDGF-beta R) alone (32D/PDGF-beta R) or together with PKC-delta (32D/PDGF-beta R/PKC-delta) into 32D cells. NIH 3T3 cells which endogenously express both PDGF-alpha R and PDGF-beta R were also transfected with PKC-delta (NIH 3T3/PKC-delta). Like TPA treatment, PDGF-BB stimulation caused striking phosphorylation of PKC-delta in vivo and translocation of some PKC-delta from the cytosol fraction to the membrane fraction in both cell systems. Some of the phosphorylation induced by PDGF-BB treatment was found to be on a tyrosine residue(s). Tyrosine-phosphorylated PKC-delta was observed only for the membrane fraction after stimulation with PDGF-BB or TPA. The enzymatic activity of PKC-delta in the membrane fraction also increased after stimulation with TPA or PDGF, providing a positive correlation between PKC-delta tyrosine phosphorylation and its activation. Overnight treatment of 32D/PDGF-beta R/PKC-delta cells with PDGF-BB induced monocytic differentiation as judged by an increase in expression of cell surface macrophage differentiation markers. PDGF-BB had much weaker effects on 32D/PDGF-beta R cell differentiation, suggesting that increased PKC-delta expression enhanced monocytic differentiation. These results indicate that PKC-delta is a downstream molecule in the PDGFR signaling pathway and may play a pivotal role in PDGF-beta R-mediated cell differentiation.
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PMID:Stimulation of the platelet-derived growth factor beta receptor signaling pathway activates protein kinase C-delta. 793 92

Tyrosine phosphorylation of proteins is an essential component of high affinity IgE receptor (Fc epsilon RI) signaling and secretion. This signaling and secretion is also dependent on the organization of the cytoskeleton. Here we report that the aggregation of Fc epsilon RI on rat basophilic leukemia cells results in tyrosine phosphorylation of the cytoskeletal protein, paxillin. Tyrosine phosphorylation of paxillin is a relatively late event after Fc epsilon RI aggregation. Both the direct increase in intracellular Ca2+ with calcium ionophore and the activation of protein kinase C (PKC) with PMA induced tyrosine phosphorylation of paxillin. The optimal tyrosine phosphorylation of paxillin by Fc epsilon RI aggregation required PKC and extracellular Ca2+. However, there was also Fc epsilon RI-mediated tyrosine phosphorylation of paxillin independent of Ca2+ influx or PKC activation. By fluorescent microscopy, cell stimulation induced a redistribution of paxillin toward the periphery of the cells. Although Fc epsilon RI aggregation induced tyrosine phosphorylation of paxillin in nonadherent cells, adherence markedly enhanced this phosphorylation. Together, the data suggest a role for paxillin in Fc epsilon RI signaling.
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PMID:The aggregation of the high affinity IgE receptor induces tyrosine phosphorylation of paxillin, a focal adhesion protein. 796 37

Angiotensin II has been demonstrated to act as a growth factor in rat cardiac fibroblasts. However, the signaling events that lead to fibroblast cell growth in response to angiotensin II remain to be elucidated. This study was designed to determine whether angiotensin II stimulated tyrosine phosphorylation of proteins in cardiac fibroblasts. Immunoblot analysis demonstrated rapid tyrosine phosphorylation of distinct substrates of 125, 95, 46-60, and 44 kDa in response to 10 nM angiotensin II. Tyrosine phosphorylation was maximal at 5 min and persisted for at least 180 min. Additional tyrosine-phosphorylated proteins of 185, 145, and 85 kDa were detected in response to 10 ng/ml platelet-derived growth factor BB. A cluster of 75-80-kDa proteins were phosphorylated in response to angiotensin II, phorbol ester, and platelet-derived growth factor. Angiotensin II-induced tyrosine phosphorylation was unaffected by phorbol ester-sensitive protein kinase C down-regulation and could be partially blocked by pertussis toxin pretreatment. Angiotensin II stimulation resulted in increased cytosolic tyrosine kinase activity which was recovered by immunoprecipitation. Immunoblot analysis demonstrated tyrosine phosphorylation of p44MAPK, and, in addition, we demonstrated for the first time tyrosine phosphorylation of p125FAK, p46SHC, and p56SHC in response to angiotensin II. The finding that angiotensin II and platelet-derived growth factor stimulated tyrosine phosphorylation of p46SHC and p56SHC suggested that this protein may serve as a common tyrosine kinase substrate in the mitogenic signaling cascade induced by G-protein-coupled receptors and growth factors and is consistent with the hypothesis that angiotensin II-induced tyrosine phosphorylation is involved in mitogenic signaling pathways in neonatal rat cardiac fibroblasts.
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PMID:Angiotensin II-induced protein tyrosine phosphorylation in neonatal rat cardiac fibroblasts. 803 31

The insulin receptor tyrosine kinase is required for insulin to elicit subsequent biological signalling. Recent studies have identified several endogenous substrates of the insulin receptor kinase, including one called insulin receptor substrate 1 (IRS-1). Tyrosine phosphorylation of this substrate results in its being bound by various proteins containing src homology 2 (SH2) sites, including a phosphatidylinositol 3-kinase and a ras activator complex containing GRB2 and son of sevenless (SOS) 1. Decreases in the insulin receptor tyrosine kinase activity have been observed in various insulin-resistant states, such as non-insulin-dependent diabetes mellitus. A model of insulin resistance has recently been described in which the insulin receptor is expressed in Chinese hamster ovary cells along with the phospholipid- and calcium-activated serine/threonine kinase called protein kinase C. In this model system, activation of protein kinase C is shown to interfere with insulin receptor signalling by inhibiting tyrosine phosphorylation of IRS-1 and its subsequent binding by phosphatidylinositol 3-kinase. Such a model system may be further utilized to determine the detailed biochemical basis for insulin resistance.
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PMID:Biochemical mechanisms of insulin resistance. 808 4

The Fc receptor on B lymphocytes, Fc gamma RIIB (beta 1 isoform), helps to modulate B-cell activation triggered by the surface immunoglobulin complex. Crosslinking of membrane immunoglobulin by antigen or anti-Ig F(ab')2 antibody induces a transient increase in cytosolic free Ca2+, a rise in inositol-3-phosphate, activation of protein kinase C, and enhanced protein tyrosine phosphorylation. Crosslinking Fc gamma RIIB with the surface immunoglobulin complex confers a dominant signal that prevents or aborts lymphocyte activation triggered through the ARH-1 motifs of the signal transduction subunits Ig-alpha and Ig-beta. Here we show that Fc gamma RIIB modulates membrane immunoglobulin-induced Ca2+ mobilization by inhibiting Ca2+ influx, without changing the pattern of tyrosine phosphorylation. A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB is both necessary and sufficient for this effect. Tyrosine at residue 309 in this motif is phosphorylated upon co-crosslinking with surface immunoglobulin; mutation of this residue aborts the inhibitory effect of Fc gamma RIIB. This inhibition is directly coupled to signalling mediated through Ig-alpha and Ig-beta as evidenced by chimaeric IgM/alpha and IgM/beta molecules. The 13-residue motif in Fc gamma RIIB controls lymphocyte activation by inhibiting a Ca2+ signalling pathway triggered through ARH-1 motifs as a result of recruitment of novel SH2-containing proteins that interact with this Fc gamma RIIB cytoplasmic motif.
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PMID:A 13-amino-acid motif in the cytoplasmic domain of Fc gamma RIIB modulates B-cell receptor signalling. 818 74

Tyrosine phosphorylation plays a critical role in Fc gamma RIIA signaling. In a mouse macrophage cell line transfected with human Fc gamma RIIA, cross-linking Fc gamma RIIA led to the transient generation of inositol 1, 4, 5-trisphosphate (IP3), [Ca2+]i flux, and rapid tyrosine phosphorylation of cellular substrates, including Shc, PLC-gamma 1, and a tyrosine kinase p72syk. In addition, tyrosine phosphorylated Fc gamma RIIA was co-precipitated with activated PLC-gamma 1. In contrast, no tyrosine phosphorylation of Shc or PLC-gamma 1 was detected in cells transfected with mutant receptors that failed to trigger [Ca2+]i flux. PMA inhibits both tyrosine phosphorylation of Shc and IP3 production leading to [Ca2+]i flux. However, PMA does not affect tyrosine phosphorylation of PLC-gamma 1 and p72syk. These results suggest that tyrosine phosphorylation of Shc and PLC-gamma 1 is important for the initiation of [Ca2+]i flux, and that activation of protein kinase C may modulate the activity of PLC-gamma 1 through serine/threonine phosphorylation.
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PMID:Correlations among tyrosine phosphorylation of Shc, p72syk, PLC-gamma 1, and [Ca2+]i flux in Fc gamma RIIA signaling. 814

In murine keratinocytes, Ca(++)-induced terminal differentiation is accompanied by a rapid and sustained increase of inositol phosphates and diacylglycerol. Based on Western blotting analysis, basal keratinocytes cultured in 0.05 mM Ca++ medium express phospholipase C (PLC)-gamma 1 predominantly and no detectable PLC-beta 1. Differentiating keratinocytes cultured in 1.4 mM Ca++ express two- to threefold more PLC-gamma 1 protein and PLC-delta 1, but no detectable PLC-beta 1. Although the amount of PLC-gamma 1 and -delta 1 protein increased, PLC-gamma 1 and -delta 1 mRNA decreased in differentiating cells. Thus the sustained rise of PLC activity induced by Ca++ in differentiating keratinocytes may be associated with higher amounts of both PLC-gamma 1 and -delta 1 in maturing cells, determined by a posttranscriptional mechanism. Tyrosine phosphate content in PLC-gamma 1 was low in basal cells and did not change in cells exposed to 1.4 mM Ca++. However, genistein inhibited the increase in PLC activity induced by 1.4 mM Ca++. In contrast, transforming growth factor (TGF)alpha, which stimulates both PLC activity and growth in basal keratinocytes, increased tyrosine phosphorylation of PLC-gamma 1. These results suggest that tyrosine phosphorylation of PLC-gamma 1 by the epidermal growth factor (EGF) receptor is linked to stimulated proliferation, whereas stimulation of PLC activity by Ca++ is linked to keratinocyte differentiation and involves the action of a tyrosine kinase but not tyrosine phosphorylation of PLC-gamma 1. Based on studies using the intracellular free Ca++ chelator BAPTA, a rise in intracellular free Ca++ was not required for stimulation of PLC activity by raising extracellular Ca++. Phorbol esters inhibited PLC stimulation by 1.4 mM Ca++ medium and increased serine phosphorylation of PLC-gamma 1. Exogenous phosphatidylinositol-specific and phosphatidylcholine-specific bacterial PLC also inhibited endogenous inositol phosphate formation and increased endogenous diacylglycerol (DAG). Thus, direct serine phosphorylation of PLC-gamma 1 by protein kinase C is associated with the inhibition of Ca(++)-mediated PLC stimulation. These results show that keratinocytes have multiple mechanisms to regulate PLC activity in response to a specific signal.
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PMID:Keratinocyte differentiation is associated with changes in the expression and regulation of phospholipase C isoenzymes. 822 34

Both bombesin and epidermal growth factor (EGF) are potent mitogens in Swiss 3T3 cells that nonetheless have dissimilar receptor structures. To explore possible common intracellular events involved in the stimulation of cellular growth by these two peptides, we have evaluated the regulation of the mitogen-activated protein (MAP) kinase. Exposure of Swiss 3T3 cells to bombesin, EGF or the protein kinase C activator phorbol 12-myristate 13-acetate (PMA) causes the rapid and transient stimulation of the enzyme activity. Pretreatment of cells with the protein kinase inhibitor H-7, or down-regulation of cellular protein kinase C by prolonged exposure to PMA, causes a decrease of over 90% in the activation of MAP kinase by bombesin. In contrast, these treatments have no effect on the stimulation of MAP kinase by EGF. The stimulation of MAP kinase activity by bombesin is dose-dependent, occurring over a narrow concentration range of the peptide. Both EGF and bombesin stimulate the phosphorylation of an immunoprecipitable MAP kinase protein migrating at 42 kDa on SDS/PAGE. Phosphoamino acid analysis of this phosphorylated protein reveals that EGF and bombesin stimulate phosphorylation on tyrosine, threonine and serine residues. Tyrosine phosphorylation of the enzyme, as evaluated by antiphosphotyrosine blotting of the immunoprecipitated protein, reveals that the time course of phosphorylation by both mitogens correlates with stimulation of enzyme activity. These results provide further evidence for the convergence of discrete pathways emanating from tyrosine kinase and G-protein-linked receptors in the regulation of MAP kinase.
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PMID:Bombesin and epidermal growth factor stimulate the mitogen-activated protein kinase through different pathways in Swiss 3T3 cells. 838 Sep 87

Treatment of Swiss 3T3 cells with recombinant Pasteurella multocida toxin (rPMT), a potent intracellularly acting mitogen, stimulated tyrosine phosphorylation of multiple substrates including bands of M(r) 110,000-130,000 and M(r) 70,000-80,000. Tyrosine phosphorylation induced by rPMT occurred after a pronounced lag period (1 h) and was blocked by either lysosomotrophic agents or incubation at 22 degrees C. Focal adhesion kinase (p125FAK) and paxillin are prominent substrates for rPMT-stimulated tyrosine phosphorylation. Tyrosine phosphorylation by rPMT could be dissociated from both protein kinase C activation and the mobilization of calcium from intracellular stores. rPMT stimulated striking actin stress fiber formation and focal adhesion assembly in Swiss 3T3 cells. Cytochalasin D, which disrupts the actin cytoskeleton, completely inhibited rPMT-induced tyrosine phosphorylation. In addition, tyrosine phosphorylation of p125FAK and paxillin in response to rPMT was completely abolished when cells were subsequently treated with platelet-derived growth factor at a concentration (30 ng/ml) that disrupted the actin cytoskeleton. Our results demonstrate for the first time that rPMT, a bacterial toxin, induces tyrosine phosphorylation of p125FAK and paxillin and promotes actin stress fiber formation and focal adhesion assembly in Swiss 3T3 cells.
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PMID:Pasteurella multocida toxin, a potent intracellularly acting mitogen, induces p125FAK and paxillin tyrosine phosphorylation, actin stress fiber formation, and focal contact assembly in Swiss 3T3 cells. 855 Jun

Tyrosine kinases are involved in cell signalling of growth factors such as insulin and insulin-like growth factor (IGF-I) and others. Insulin and IGF-I receptors which possibly feedback on insulin release are established in insulin-secreting cells. The role of tyrosine kinase in insulin secretion is controversial. Both the tyrosine kinase inhibitors tyrphostin 25 (TYR) and genistein (GEN), but not its structurally similar albeit biologically inactive analogue daidzein, increase insulin release at 16.7 mM glucose in INS-1 cells, an insulin secreting cell line. Tyrosine kinase activity is inhibited by GEN, but not diadzein. The inhibitory effects of either insulin or IGF-I on insulin release are abolished by 10(-4) M GEN but not by daidzein indicating an involvement of tyrosine kinase in the inhibitory effect of both insulin and IGF-I on insulin release. Since GEN was argued not to be specific for tyrosine kinase, several second messengers were investigated. cAMP is not influenced. The insulinotropic effect of acutely administered TPA is not influenced by GEN while in protein kinase C (PKC)-downregulated cells the insulinotropic effect of GEN is preserved: both indicate no involvement of PKC in GEN effect. Since pertussis toxin (PT) pretreatment has no effect on the inhibitory effects of IGF-I on insulin release, a PT-sensitive G-protein is not likely to be involved. The data indicate that tyrosine kinase is involved in the inhibitory effects of insulin and IGF on insulin release in INS-1 cells, possibly mediating the negative feedback effect.
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PMID:Role of tyrosine kinase in insulin release in an insulin secreting cell line (INS-1). 856 11


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