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)

Sublethal concentrations of reactive oxygen intermediates including H2O2 can alter human T cell function and inhibit proliferative responses but relatively little is known about the effects of low levels of oxidant stress on signaling pathways. In the present study, we investigated whether the exposure of Jurkat T cells to micromolar concentrations of H2O2 might influence the activity of certain serine/threonine kinases and protein phosphatases important for T cell signaling as well as initiation of nuclear events. Jurkat cells treated with 100-200 microM H2O2 exhibited rapid increases in cytosolic protein kinase C (PKC) activity without detectable translocation of PKC to the membrane/particulate compartment. The stimulation of PKC activity by H2O2 was associated with an increase in the activation of kinases phosphorylating myelin basic protein (MBP), a substrate for mitogen-activated protein (MAP) kinase and RRLSSLRA (S6 peptide; a substrate for the approximately 90-kDa ribosomal S6 kinases). Optimal activation of MAP kinase in cells treated with H2O2 was preceded by increases in protein tyrosine phosphorylations and occurred at sublethal concentrations of H2O2 which did not markedly deplete intracellular ATP. Pretreatment of cells with the PKC inhibitors sangivamycin and H7 suppressed but did not block the stimulation of MAP kinase activity in response to H2O2 or phytohemagglutinin. The activities of both protein tyrosine phosphatase (PTP) and protein phosphatase 2A (PP2A) were reduced after H2O2 treatment of intact cells. Furthermore, kinetic studies showed that H2O2 was capable of suppressing the activities of PTP and PP2A before inducing optimal increases in MAP kinase activity. These results demonstrate that the exposure of T cells to sublethal levels of oxidant stress acutely stimulates the MAP kinase cascade and suggest that this activation may involve PKC-dependent and -independent pathways as well as inhibition of certain protein phosphatases.
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PMID:Sublethal levels of oxidant stress stimulate multiple serine/threonine kinases and suppress protein phosphatases in Jurkat T cells. 777 89

SH-PTP1 is a protein tyrosine phosphatase (PTP) predominantly expressed in haematopoietic cells and containing two src homology-2 (SH2) domains. Here we report that SH-PTP1 is phosphorylated on both serine and tyrosine residues in response to thrombin or phorbol myristate acetate (PMA), which increased by 60 and 40%, respectively, SH-PTP1 activity. Thrombin-induced phosphorylation of SH-PTP1 is an early signalling event (maximal within 10 s) involving neither integrin signalling, nor calcium, nor release of ADP or thromboxane A2. Moreover, in contrast with PMA, the effect of thrombin on the tyrosine phosphorylation of SH-PTP1 was hardly affected by GF109203X, a specific protein kinase C (PKC) inhibitor. Finally, phosphorylation of SH-PTP1 could be provoked in permeabilized platelets by thrombin or GTP gamma S. This was abolished by pertussis toxin, the specificity of this effect being verified with the megakaryocytic cell line Dami cell. Our data thus identify SH-PTP1 as an in vivo substrate of a putative protein tyrosine kinase linked to the thrombin receptor by a Gi protein. This might offer some clue to unravel the mechanism of thrombin not only in platelets but also in nucleated cells, where its mitogenic effect is known to involve pertussis toxin-sensitive G-proteins, tyrosine phosphorylation and the ras pathway.
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PMID:Tyrosine phosphorylation of an SH2-containing protein tyrosine phosphatase is coupled to platelet thrombin receptor via a pertussis toxin-sensitive heterotrimeric G-protein. 778 4

Using the yeast two-hybrid system, complementary DNA clones were isolated from a HeLa cell library encoding proteins that interacted with p52shc. One of these clones encoded the non-catalytic, COOH-terminal half of the cytosolic protein tyrosine phosphatase PTP-PEST. Expression of truncated forms of p52shc in the two-hybrid system revealed that the amino-terminal half of p52shc was sufficient for interaction with PTP-PEST. The p52 and p66 forms of Shc, but not the p46 form, bound to a glutathione S-transferase fusion protein containing the region of PTP-PEST isolated from the two-hybrid screen. Similarly, when HeLa cell lysates were immunoprecipitated with PTP-PEST antiserum, p52shc and p66shc proteins, but not p46shc, co-precipitated. Shc-PTP-PEST complex formation was stimulated 6-8-fold by the protein kinase C activator phorbol 12-myristate 13-acetate, while epidermal growth factor and serum had no effect. Phorbol 12-myristate 13-acetate also stimulated phosphorylation of p52shc and p66shc. The muscarinic agonist carbachol (also an activator of protein kinase C) stimulated complex formation 3-5-fold in SH-SY5Y neuroblastoma cells. These results suggest a role for PTP-PEST in G protein receptor signaling and in cross-talk between G protein receptor and tyrosine kinase receptor pathways.
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PMID:Activators of protein kinase C stimulate association of Shc and the PEST tyrosine phosphatase. 792 14

Previously we have shown that reactive oxygen species (ROS) formation induced by phorbol ester in association with vanadate is essential for protein tyrosine phosphorylation and phospholipase A2 (PLA2) activation. Here we show that the interaction of beta-glucan particles (glucanp) or zymosan with complement receptor type 3 (CR3) leads, when associated with vanadate, to a cascade of reactions culminating in PLA2 activation. Vanadate + zymosan (or glucanp) markedly enhance protein tyrosine phosphorylation in bone marrow derived macrophages (BMMs), whereas neither of the agents alone has any effect. The enhancement was due to both sustained activation of protein tyrosine kinase (PTK) and inactivation of protein tyrosine phosphatase (PTP) as assessed in lysates of treated cells. Zymosan elevates membranal PKC, an effect that is potentiated by vanadate. Activation of both PTK and PKC leads to the activation of NADPH oxidase and to ROS formation. The formed ROS together with vanadate are potent inactivators of PTP leading to amplification of tyrosine phosphorylation and myelin basic protein kinase (MBP-K) activation. The activation of the cascade of protein kinases eventually leads to activation of PLA2. All the activation steps, i.e., activation of PTK, NADPH oxidase, MBP-K,PLA2 and the inactivation of PTP are sensitive to the NADPH oxidase inhibitor diphenyleneiodonium (DPI), to antioxidants and to PKC inhibitors. Thus, ROS formation (in the presence of vanadate) is critical for protein phosphorylation processes constituting the regulatory pathway of PLA2 activation by ligand-CR3 interaction.
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PMID:A role for reactive oxygen species in zymosan and beta-glucan induced protein tyrosine phosphorylation and phospholipase A2 activation in murine macrophages. 803 63

In HER14 cells, epidermal growth factor (EGF) induces tyrosine phosphorylation of several proteins, including its own receptor. The bee venom peptide, melittin, impaired EGF-dependent protein tyrosine phosphorylation in a calcium-dependent manner. The melittin effect was similarly reproduced by calcium ionophore A23187. The effect of melittin and calcium ionophore A23187 on EGF-dependent protein tyrosine phosphorylation was abolished by treatment of cells with the calcium chelator EGTA. Phorbol-myristate acetate (PMA) inhibited EGF-dependent protein tyrosine phosphorylation, and when compared to melittin or calcium ionophore A23187, only PMA potentiated the EGF-induced tyrosine phosphorylation of two proteins immunologically related to mitogen activated protein (MAP) kinases of 40 kDa and 44 kDa molecular mass. Unlike PMA, the effect of melittin and calcium ionophore A23187 on inhibition of EGF-dependent protein tyrosine phosphorylation was lost neither in protein kinase C-depleted cells nor in cells treated with the protein tyrosine phosphatase inhibitors NaF and Na3VO4. Melittin inhibited high affinity binding of EGF to its receptor in intact cells, but this effect was not prevented by EGTA. It is concluded that melittin and calcium ionophore A23187 differ from PMA in their inhibition of EGF-dependent protein tyrosine phosphorylation in vivo, by acting via a Ca(2+)-dependent pathway, that is independent of protein kinase C, protein tyrosine phosphatase activity and high affinity binding of EGF to its receptor.
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PMID:Melittin inhibits epidermal growth factor-induced protein tyrosine phosphorylation: comparison with phorbol myristate acetate and calcium ionophore A23187. 803 17

PTP2C, a widely distributed protein tyrosine phosphatase (PTP) containing two SH2 domains, was expressed as a recombinant enzyme in Escherichia coli and purified to near homogeneity. The purified enzyme and a truncated form lacking the SH2 domains (delta SH2-PTP2C) have been characterized with four commonly used substrates. Both forms showed pH optima of around neutrality for protein substrates but below 5.5 for a peptide substrate and para-nitrophenylphosphate. The dependence of the enzymes on ionic strength varied with the nature of the substrates involved. Like its analog PTP1C, PTP2C displayed a specific activity of less than 0.1% of that observed with other known PTPs toward protein substrates. Deletion of the SH2 domains increased its activity by 12-45-fold, depending on the substrates used. Limited trypsinolysis which cleaved about 4 kDa from the carboxyl terminus resulted in a 2-5-fold activation of the full-length enzyme but was essentially without effect on the truncated enzyme. Both forms showed similar responses to effectors including activators (e.g. anionic phospholipids) or inhibitors (e.g. vanadate, molybdate, or Zn2+). PTP2C and delta SH2-PTP2C were phosphorylated in vitro by mitogen-activated protein kinase, protein kinase C, and various protein tyrosine kinases; in the latter case, they underwent autodephosphorylation. No significant effect of the phosphorylation reactions on enzyme activity could be observed in vitro.
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PMID:Purification and characterization of PTP2C, a widely distributed protein tyrosine phosphatase containing two SH2 domains. 813 10

We attempted to study the role of protein tyrosine kinase (PTK) and protein kinase C (PKC) in the cascade of phosphorylation of ribosomal protein S6 during differentiation of leukemic cells (HL-60, THP-1, and RWLeu-4). Neither activation nor inhibition of colony stimulating factor-1 (CSF-1) receptor's PTK activity with CSF-1 or genistein respectively affected the phosphorylation of S6. However, vanadate which is a protein tyrosine phosphatase (PTP) inhibitor showed enhancement of S6 phosphorylation. Dimethylsulfoxide which does not affect either PTK or PKC demonstrated no change in S6 phosphorylation. PKC activation by acute 12-0-tetradecanoyl phorbol-13-acetate (TPA) treatment induced monocytic differentiation and S6 phosphorylation. Surprisingly, the more prominent phosphorylation of S6 protein was observed in PKC-depleted cells by prolonged TPA treatment. Our results suggest that PTK/PTP play a lesser role in S6 phosphorylation of HL-60 cells than PKC does. In addition, two different mechanisms seem to be involved in TPA-induced S6 phosphorylation during HL-60 differentiation: PKC activation by acute TPA treatment and PKC depletion which may lead to the synthesis of some endogenous protein responsible for the differentiation by chronic TPA treatment.
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PMID:Phosphorylation of ribosomal protein S6 and its regulation during differentiation of human leukemic cells. 817 29

Continuous infusion of a nonlethal dose of Escherichia coli lipopolysaccharide (LPS) into rats induced extravasation of mononuclear phagocytes into the liver and the priming of Kupffer cells for in vitro phorbol myristate acetate (PMA)-stimulated superoxide anion (O2-) release. The purpose of this investigation was to determine the role of protein kinase C (PKC), protein serine-threonine phosphatase(s) 1 and 2a, protein tyrosine kinase(s) and phosphatase(s), phospholipase A2 (PLA2), arachidonic acid (AA) and its cyclooxygenase (CO) and 5-lipoxygenase (5-LO) metabolites in the modulation of PMA-stimulated O2-generation in in vivo LPS-primed rat Kupffer cells. The following inhibitors blocked PMA-stimulated O2- generation in the absence (-AA) or presence of AA (+AA) (50 microM): 1) staurosporine, a putative PKC inhibitor (150 nM, 95% inhibition without AA, 88% inhibition with AA); 2) okadaic acid, a protein serine-threonine phosphatase inhibitor (2 microM, 65% inhibition with or without AA); 3) the marine PLA2 inhibitor manoalide (1 microM, 97.5% inhibition without AA, 75% with AA). In addition, it was observed that exogenously added AA enhanced PMA-stimulated O2- generation in a time- and dose-dependent manner (5-50 microM) and partially reversed the inhibitory effect of manoalide. The following inhibitors did not block PMA-stimulated O2- generation in the absence or presence of AA: 1) indomethacin, a CO inhibitor (1-100 microM) and WY-50,295M tromethamine, a novel 5-LO inhibitor (1-100 microM); 2) genistein, a protein tyrosine kinase inhibitor (1-100 microM); and 3) sodium orthovanadate (1-300 microM), a protein tyrosine phosphatase inhibitor. It was concluded that, in in vivo LPS-primed Kupffer cells, PMA-stimulated O2- generation is modulated by PKC, protein serine-threonine phosphatase(s), PLA2 and AA but not by protein tyrosine kinase(s) and phosphatase(s) and CO and 5-LO products. These findings could have implications on the design of novel therapeutic approaches for the modulation of enhanced O2- release by Kupffer cells in endotoxemia.
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PMID:Modulation of superoxide generation in in vivo lipopolysaccharide-primed Kupffer cells by staurosporine, okadaic acid, manoalide, arachidonic acid, genistein and sodium orthovanadate. 830 64

Human platelets possess a specific membrane-bound leukotriene (LT) C4 synthase, which catalyzes the conversion of LTA4 to LTC4. Stimulation of the receptors for thrombin, collagen or thromboxane A2 provoked inhibition of this enzyme, as judged by suppressed transformation of exogenous LTA4 to LTC4. Similarly, direct activation of protein kinase (PK) C with nanomolar concentrations of 4 beta-phorbol 12-myristate 13-acetate (PMA) inhibited the production of LTC4. Kinetic studies demonstrated that the inhibition induced by thrombin and PMA was non-competitive. Elevation of intracellular cAMP levels with carbacyclin did not affect basal LTC4 formation, but abolished the attenuation of platelet LTC4 synthase activity induced by the thromboxane receptor agonist U-46619. The unselective protein kinase inhibitor staurosporine prevented both receptor-mediated and PMA-induced suppression of LTC4 formation. In contrast, two selective PKC inhibitors, Ro 31-8220 and GF 109203X, reversed the inhibitory effect provoked by PMA, but failed to prevent thrombin-induced inhibition. Furthermore, the protein tyrosine phosphatase inhibitor, sodium orthovanadate, induced dose-dependent inhibition of LTC4 production in platelet sonicates. In conclusion, receptor-mediated activation of human platelets leads to decreased LTC4 synthase activity via phosphoregulation. Although the present results demonstrate that platelet LTC4 synthase can be regulated via PKC-dependent events, alternative mechanisms appears to be involved in the physiological regulation of this enzyme. The findings suggest the possible importance of protein tyrosine phosphorylations in this process.
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PMID:Receptor-mediated regulation of leukotriene C4 synthase activity in human platelets. 853 97

Teleost nonspecific cytotoxic cells (NCC) initiate various cell triggering responses following receptor-target cell interactions. A putative receptor protein on NCC may alternatively initiate signalling processes following crosslinkage by homologous anti-receptor mab 5C6. In the present study, we demonstrated that binding to this receptor by mab 5C6 produced increased levels of expression of cytoplasmic src family proto-oncogene kinases lck, fyn and src. The phosphorylated isoforms of each kinase were approximately the same molecular weight (p60). Unlike their mammalian T-cell and natural killer (NK) cell counterparts, NCC p56lck did not autophosphorylate on tyrosine residues. This was determined by a lack of Western blot reactivity of teleost p56lck with anti-phosphotyrosine specific antibodies PT-66 or 4G10. Additional evidence for this lack of tyrosine phosphorylation was shown by experiments treating mab 5C6 activated NCC with sodium orthovanadate. This protein tyrosine phosphatase inhibitor did not affect levels of p56lck autophosphorylation. Mab 5C6 activated NCC were also examined to determine if levels of protein kinase C (PKC) expression were affected during triggering responses. Maximum increased PKC levels occurred 5-10 min following binding. The NCC receptor-activated PKC consisted of a 60,000 M(r) isoform and a 30,000 M(r) homologue equivalent to the mammalian PKC catalytic subunit. Not all kinases examined, however, were affected by mab 5C6 binding. Levels of expression of c-myc and cdc2p34 did not change following NCC activation. This is the first study of NK-like cells in cold-blooded vertebrates regarding the expression of these vital intermediary transducing kinases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Monoclonal antibody binding to a receptor on nonspecific cytotoxic cells (NCC) increases the expression of proto-oncogene kinases and protein kinase C. 856 7


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