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)

The CD45 glycoprotein isoforms exhibit a receptor-like composition and display intracellular protein tyrosine phosphatase (PTPase) activity. The present study links CD45 to the regulation of L-selectin (CD62L), a leucocyte glycoprotein important for extravasation and homotypic aggregation. Monoclonal antibodies (MoAbs) IOL1b and AICD45.2, but not GAP8.3, all of which are directed against common CD45 epitopes, were found to elicit lymphocyte L-selectin down-regulation. Lymphocyte L-selectin down-regulation in response to anti-CD45 MoAbs was enhanced by high cell density and partially antagonized by the protein tyrosine kinase (PTK) inhibitor, herbimycin A. The MoAbs IOL1b, AICD45.2 and GAP8.3 recognized granulocyte-expressed CD45 but did not induce loss of L-selectin expression of granulocytes. In contrast, the CD45 PTPase inhibitor, vanadate, induced L-selectin down-regulation both in lymphocytes and granulocytes. The PTPase activation by nitric oxide (NO) or the NO-generating compound, sodium nitroprusside, did not affect L-selectin surface expression. Increased concentrations of soluble L-selectin were detected after anti-CD45 or vanadate-induced down-regulation of L-selectin surface expression. While activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) induces rapid L-selectin down-regulation of L-selectin surface expression in both lymphocytes and granulocytes, the PKC inhibitor, H 7, was also found to down-regulate lymphocyte and granulocyte L-selectin surface expression. The inhibitor H 7 synergized with vanadate in down-regulating lymphocyte L-selectin surface expression, but partially inhibited vanadate-induced granulocyte L-selectin down-regulation. The results suggest that in a cell type-specific fashion the PKC system and tyrosine phosphorylation and dephosphorylation cascades are involved in the regulation of L-selectin surface expression.
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PMID:CD45 engagement induces L-selectin down-regulation. 869 90

We recently reported a contraction of middle cerebral artery (MCA) preparations isolated from newborn lambs in response to tissue cooling. However, the mechanism(s) by which cold stimulus modifies the contractile properties of MCA is not known. We hypothesize that cold stimulus-triggered contraction may be mediated by a signal transduction pathway associated with protein tyrosine kinase (PTK)-dependent machinery. In the present study the tissue bath technique was used to evaluate the effect of select inhibitors of PTK and protein tyrosine phosphatase (PTP) on the temperature-dependent contractile behavior of isolated MCA from new-born lambs. Reduction of tissue bath temperature from 37 to 21 degrees C stimulated contraction (55 +/- 3% of the response to 120 mM KCl). Two distinct inhibitors of PTK, genistein and tyrphostin 47, completely reversed the cold-stimulated contraction, whereas staurosporine, an inhibitor of protein kinase C, was without effect. Sodium orthovanadate (50 microM) potentiated the cold-stimulated contraction, augmenting the slope of the temperature-force relationship over twofold. Two Ser/Thr phosphatase inhibitors (okadaic acid and calyculin A) had no effect on the temperature-force relationship. These results offer experimental evidence to support a novel hypothesis where PTK/PTP-dependent signal transduction pathways may be preferably targeted by cold stimulus and thus provide a biochemical basis for cold-stimulated modification of cerebral vascular contractile properties.
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PMID:Protein tyrosine kinase signaling in cold-stimulated contraction of newborn lamb cerebral arteries. 877 41

1. Endothelial cells can be stimulated by the pro-inflammatory cytokines interleukin (IL)-1 alpha and tumour necrosis factor (TNF) alpha to express the leukocyte adhesion molecules E-selectin, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 but the intracellular signalling mechanisms leading to this expression are incompletely understood. We have investigated the role of protein tyrosine kinases (PTK) in adhesion molecule expression by cytokine-activated human umbilical vein endothelial cells (HUVEC) using the PTK inhibitors genistein and herbimycin A, and the protein tyrosine phosphatase (PTP) inhibitor sodium orthovanadate. 2. Maximal E-selectin expression induced by incubation of HUVEC for 4 h with IL-1 alpha (100 u ml-1) and TNF alpha (100 u ml-1) was dose-dependently inhibited by genistein and herbimycin A. Although similar effects were seen on phorbol 12-myristate, 13-acetate (PMA)-induced expression, this was not due to inhibition of protein kinase C (PKC) activity as the selective inhibitors of PKC, bisindolylmaleimide (BIM), Ro31-7549 or Ro31-8220 did not affect IL-1 alpha- or TNF alpha-induced E-selectin expression at concentrations which maximally inhibited PMA-induced expression. 3. Genistein inhibited VCAM-1 expression induced by incubation of HUVEC for 24 h with TNF alpha or IL-1 alpha whereas it did not affect ICAM-1 expression induced by 24 h incubation with either of these cytokines. Herbimycin A inhibited both VCAM-1 and ICAM-1 expression induced by TNF alpha. 4. Basal expression of E-selectin, VCAM-1 and ICAM-1 was dose-dependently enhanced by sodium orthovanadate. In contrast, vanadate differentially affected TNF alpha-induced expression of these molecules with maximal E-selectin and ICAM-1 expression being slightly enhanced and VCAM-1 expression dose-dependently reduced. 5. We also studied the effects of PTK and PTP inhibitors on adhesion of the human pre-myeloid cell line U937 to TNF alpha-stimulated HUVEC. Adhesion of U937 cells to HUVEC pretreated for 4 or 24 h with TNF alpha was dose-dependently inhibited by genistein and herbimycin A but unaffected by daidzein. Adhesion of U937 cells after 4 h was partially inhibited by blocking antibodies against both E-selectin and VCAM-1 but after 24 h was only inhibited by anti-VCAM-1. 6. Sodium orthovanadate had no effect on TNF alpha-induced U937 adhesion but dose-dependently enhanced adhesion to unstimulated HUVEC. Vanadate-induced adhesion was inhibited by an antibody against VCAM-1. 7. These results demonstrate that PTK-mediated phosphorylation events are important for the regulation of adhesion molecule expression by human endothelial cells, and additionally show that PTK inhibitors differentially affect upregulation of different adhesion molecules, implicating divergent regulatory pathways for cytokine-induced adhesion molecule expression.
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PMID:Effects of protein tyrosine kinase inhibitors on cytokine-induced adhesion molecule expression by human umbilical vein endothelial cells. 884 42

Oxidant-induced activation of phospholipase D (PLD) in bovine pulmonary artery endothelial cells (BPAEC) is independent of protein kinase C and calcium. In the present study, the effects of tyrosine kinase and protein tyrosine phosphatase (PTPase) inhibitors on hydrogen peroxide (H2O2)-induced PLD activation and protein tyrosine phosphorylation were examined in BPAEC. Pretreatment of BPAEC with putative tyrosine kinase inhibitors genistein, tyrphostin, and herbimycin attenuated H2O2 (1 mM)-induced PLD activation. The inhibitory effect of the tyrosine kinase inhibitors was highly specific for H2O2-induced modulation and showed no effect on PLD activation mediated by 12-O-tetradecanoylphorbol 13-acetate or bradykinin. Furthermore, addition of H2O2 increased in a time-dependent manner tyrosine phosphorylation of several proteins (17-200 kDa), as determined by immunoblot analysis with antiphosphotyrosine antibodies. H2O2-mediated protein tyrosine phosphorylation preceded PLD activation, and a good correlation was observed on the effect of genistein in H2O2-induced PLD activation and protein tyrosine phosphorylation. Addition of vanadate, a phosphotyrosine phosphatase inhibitor, synergistically increased both PLD activation and protein tyrosine phosphorylation mediated by H2O2. Moreover, vanadate by itself had minimal effect on basal PLD activity in BPAEC; however, at 10 microM vanadate, an increase in protein tyrosine phosphorylation was observed. In addition to vanadate, phenylarsine oxide and diamide potentiated H2O2-induced PLD activation. These results suggest that tyrosine kinase activation may be involved in H2O2-induced PLD activation in vascular endothelial cells.
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PMID:Role of protein tyrosine phosphorylation in H2O2-induced activation of endothelial cell phospholipase D. 884 88

Thiol depleting agents phenylarsine oxide and N-ethylmaleimide significantly inhibited the phorbol ester induced protein kinase C activation in vascular smooth muscle cells. Phenylarsine oxide is a good protein tyrosine phosphatase inhibitor. Sodium orthovanadate, also a protein tyrosine phosphatase inhibitor, neither activated nor inhibited protein kinase C in vascular smooth muscle cells. Phenylarsine oxide, N-ethylmaleimide, orthovanadate, hydrogen peroxide and pervanadate [sodium orthovanadate + hydrogen peroxide] all significantly induced mitogen activated protein kinase in vascular smooth muscle cells. Phorbol ester and platelet derived growth factor induced mitogen activated protein kinase was inhibited by phenylarsine oxide pretreatment to vascular smooth muscle cells. However, hydrogen peroxide/pervanadate induced mitogen activated protein kinase was not prevented by phenylarsine oxide. These results suggest that oxidation of the cellular thiols inhibits the protein kinase C and activates mitogen activated protein kinase in vascular smooth muscle cells. In addition, peroxides induced, the activation of mitogen activated protein kinase in vascular smooth muscle cells which is independent of protein kinase C.
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PMID:Redox regulation of signal transduction in smooth muscle cells: protein kinase C inhibition by thiol agents. 888 82

Cell morphogenesis is a fundamental phenomenon that involves understanding a number of biological processes including the developmental program, polarity and cell division. Fission yeast sts5 mutant cells are round rather than cylindrical with cortical actin randomly dispersed. Genetic analyses demonstrate that the sts5+ gene is required for maintenance of cell shape during interphase when the cell normally exhibits polarised growth. The sts5 mutant is not defective in cell wall integrity. Deletion of ppe1+, which encodes a type 2A-like protein phosphatase, shows similar phenotypes to the sts5 mutant and these two mutations are synthetically lethal. Multicopy plasmids containing either the protein kinase C-like gene pck1+ or the protein tyrosine phosphatase pyp1+, an inhibitor of an osmosensing Sty1/Spc1 MAP-kinase, are capable of suppressing the sts5 mutation. Consistent with this, we have found that the wis1 mutation, which is defective in a MAP-kinase kinase of the pathway, suppresses the sts5 mutation. The predicted sts5+ gene product exhibits sequence similarity to two yeast proteins, Dis3 and Ssd1 and a nematode protein, F46E8.6, where the former two yeast proteins have been shown to be involved in cell cycle control and cell morphogenesis. The sts5+ gene is not essential for cell viability, but is absolutely required for polarised growth as the gene disruption showed the same phenotypes as those of the original mutants. Overexpression of the sts5+ gene resulted in altered cell morphology and, cortical actin in these overproducing cells was also abnormal, fainter and often dispersed. Anti-Sts5 antibody specifically detected a 130 kDa protein by western blotting. A green fluorescent protein-Sts5 fusion protein localised in the cytoplasm with a discrete punctate pattern, suggesting that the Sts5 protein is a component of a novel structure. These results have indicated that the Sts5 protein is a crucial determinant of polarised growth and that it functionally interacts with the serine/threonine phosphatase, protein kinase C, and an osmosensing MAP-kinase to maintain cell morphology.
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PMID:The fission yeast sts5+ gene is required for maintenance of growth polarity and functionally interacts with protein kinase C and an osmosensing MAP-kinase pathway. 888 83

CD45 consists of a major family of membrane glycoproteins which have protein tyrosine phosphatase activity and regulate early activation events, progression and maturation signals in leucocytes. Various isoforms of CD45 (Mr 180-240 kDa) regulate sets of intermolecular associations between different surface receptors, and appear to be differentially expressed on B and T cells (namely CD45RA, B or CD45RO). We describe a novel IgG2a mAb directed against restricted and unique CD45R modified epitopes expressed preferentially on peripheral blood T cells. This anti-CD45R antibody (I(2)4c) at concentrations of 50 and 200 ng/mL inhibited mitogenic T cell lectin and anti-CD3-stimulated lymphocyte proliferation and blocked associated IL-2 secretion in vitro. Phorbol ester-stimulated mitogenesis was unaltered suggesting that the inhibition occurs independent of protein kinase C-mediated pathways. Western blotting and immunoprecipitation of purified cell lysates reveals that I(2)4c preferentially binds the higher Mr bands of CD45 expressed on T cells. Following T cell activation in vitro, the 190 kDa band became more predominant and an additional 130 kDa protein, possibly a proteolytic fragment was recognized. I(2)4c may inhibit T cell mitogenesis by direct effects on CD45R alone or by preventing interaction with other membrane-associated proteins and hence adhesive interactions with monocytes. Such interactions may however inhibit the initiation of signal transduction and, as a consequence, alter cellular activation by mitogenic lectins and anti-CD3 in vitro.
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PMID:Inhibition of T cell mitogenesis by a novel anti-CD45R monoclonal antibody. 893 56

This study was performed to evaluate the effect of human recombinant basic fibroblast growth factor on arachidonic acid release from rat pancreatic acini and to determine the cellular mechanism involved. From enzymatic assays, basic fibroblast growth factor did not significantly stimulate phospholipase A2 activity, whereas it significantly increased diacylglycerol lipase activity. Validity of phospholipase A2 or diacylglycerol lipase inhibitors was confirmed by their ability to inhibit phospholipase A2 or diacylglycerol lipase activities. Basic fibroblast growth factor increased intracellular accumulation and extracellular release of arachidonic acid from metabolically labelled acinar cells in a concentration- and time-dependent manner. This effect was maximal with 50 pM basic fibroblast growth factor and became significant after a 5-min incubation period. The protein tyrosine kinase inhibitor, 0.5 mM genistein, inhibited arachidonic acid release in basic fibroblast growth factor-stimulated acini, whereas 100 microM vanadate, a protein tyrosine phosphatase inhibitor, enhanced arachidonic acid release. Two phospholipase A2 inhibitors, mepacrine and aristolochic acid, failed to attenuate basic fibroblast growth factor-stimulated arachidonic acid release. A diacylglycerol lipase inhibitor RHC 80267 at 150 microM and 50 microM completely inhibited 50 pM basic fibroblast growth factor-induced intracellular accumulation and extracellular release of arachidonic acid, respectively. Furthermore, basic fibroblast growth factor stimulated arachidonic acid release was also inhibited by 10 microM U73122 and by 100 nM staurosporine, phospholipase C and protein kinase C respective inhibitors. Wortmannin, an inhibitor of basic fibroblast growth factor-stimulated phospholipase D, did not affect arachidonic acid release. 100 nM 4 beta-phorbol 12-myristate 13-acetate also increased arachidonic acid release, an effect also inhibited by staurosporine. Taken together, these data demonstrate activation of diacylglycerol lipase and arachidonic acid release in pancreatic acini upon stimulation by basic fibroblast growth factor, and strongly indicate that arachidonic acid release in response to basic fibroblast growth factor depends upon the sequential action of tyrosine kinase, phospholipase C, protein kinase C and diacylglycerol lipase but not from phospholipase A2 not phospholipase D activation.
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PMID:Basic fibroblast growth factor-stimulated arachidonic acid release in rat pancreatic acini: sequential action of tyrosine kinase, phospholipase C, protein kinase C and diacylglycerol lipase. 902 13

Phorbol esters increase scavenger-receptor mRNA expression and receptor activity in smooth muscle cells (SMCs). Our present results demonstrate that activation of protein kinase C (PKC) mediates this increase in receptor expression. This conclusion is based on the findings that (1) phorbol esters induced translocation of PKC-alpha from the cytosol to the membrane fraction; (2) PKC inhibitors blocked the effect of phorbol esters on receptor expression; (3) diacylglycerol, a physiological PKC agonist, enhanced scavenger-receptor activity; and (4) in cotransfected human SMCs, constitutively active PKC-alpha stimulated the expression of a reporter gene under control of the scavenger-receptor promoter. Phorbol ester treatment of SMCs increased intracellular reactive oxygen, and the increase in receptor activity was reduced 30% by the antioxidant N-acetyl cysteine (NAC), suggesting a role for reactive oxygen in phorbol ester-mediated receptor regulation. Furthermore, direct treatment of SMCs with reactive oxygen species increased scavenger-receptor activity. In rabbit SMCs, 100 micromol/L H2O2 alone slightly increased scavenger-receptor mRNA and protein expression. In combination, 100 micromol/L H2O2 and 10 micromol/L vanadate, which promotes formation of OH and enhances the inhibition of protein tyrosine phosphatase by H2O2, increased scavenger-receptor mRNA expression 25-fold in rabbit SMCs and 8-fold in human SMCs. NAC reduced the effect of H2O2 and vanadate by 93%. The increase in SMC scavenger-receptor expression occurs at the level of gene transcription. Receptor mRNA half-life was unchanged after treatment with either phorbol esters or reactive oxygen (approximately 14.5 hours), and induction by phorbol esters increased SMC scavenger-receptor mRNA transcription, as determined by nuclear run-on assay. Multiple cytokines and growth factors that contribute to the generation of reactive oxygen species are present in atherosclerotic lesions. These factors may all contribute to the upregulation of SMC scavenger-receptor activity and therefore to the formation of smooth muscle foam cells.
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PMID:Regulation of scavenger receptor expression in smooth muscle cells by protein kinase C: a role for oxidative stress. 915 63

Activation of protein kinase C (PKC) has been reported to inhibit Fas (APO-1, CD95)-mediated apoptosis in different cellular systems. Human Jurkat leukemic T cells express the Fas antigen in the cell membrane and undergo apoptosis upon cross-linking by anti-Fas monoclonal antibodies (mAb). Cleavage of the apoptosis-associated protease CPP32 and its substrate poly(ADP-ribose)polymerase are observed after the engagement of Fas antigen with mAb. In this report, we show that all these effects are substantially inhibited by the activation of PKC with a phorbol ester. Bisindolylmaleimide, an inhibitor of PKC, prevents phorbol ester-induced down-regulation of Fas signaling. Inhibition of Fas-mediated cell death by phorbol ester is also observed in other human leukemic T cell lines. Cross-linking of Fas antigen by mAb results in the rapid increase in tyrosine phosphorylation of several protein substrates which is further elevated in the presence of the protein tyrosine phosphatase inhibitor, orthovanadate. Furthermore, orthovanadate markedly enhances the cell death response to Fas mAb in different human leukemic T cell lines and human T cell blasts. These effects of orthovanadate on early tyrosine phosphorylation and cell death are clearly diminished by PKC activation. These results strongly suggest that tyrosine phosphorylation is involved in Fas signaling in apoptosis and that PKC plays a negative role in Fas-mediated apoptosis by counteracting at a very early stage the signals generated following cross-linking of this receptor.
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PMID:Activation of protein kinase C attenuates early signals in Fas-mediated apoptosis. 920 97


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