Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines are known to be important regulators of normal hemopoiesis, acting in concert with components of the bone marrow microenvironment. Interactions with this microenvironment are known to regulate the proliferation, differentiation, and homing of hemopoietic progenitor (CD34+) cells. Adhesive interactions with the extracellular matrix retain CD34+ cells in close proximity to cytokines, but may also provide important costimulatory signals. Thus, the functional states of adhesion receptors are critical properties of CD34+ cells, but the physiological mechanisms responsible for regulating functional properties of cell adhesion receptors on primitive hemopoietic cells are still unknown. We confirm that the integrins very late antigen (VLA)-4 and VLA-5 are expressed on the CD34+ cell lines MO7e, TF1, and on normal bone marrow CD34+ progenitor cells, but in a low affinity state, conferring on them a weak adhesive phenotype on fibronectin (Fn). Herein, we show that the cytokines interleukin (IL)-3, granulocyte-macrophage CSF (GM-CSF), and KIT ligand (KL) are physiological activators of VLA-4 and VLA-5 expressed by MO7e, TF1, and normal bone marrow CD34+ progenitor cells. Cytokine-stimulated adhesion on Fn is dose dependent and transient, reaching a maximum between 15 and 30 min and returning to basal levels after 2 h. This cytokine-dependent activation is specific for VLA-4 and VLA-5, since activation of other beta 1 integrins was not observed. The addition of second messenger antagonists staurosporine and W7 abolished all cytokine-stimulated adhesion to Fn. In contrast, genistein inhibited KL-stimulated adhesion, but failed to inhibit GM-CSF- and IL-3-stimulated adhesion. Our data suggest that cytokines GM-CSF and IL-3 specifically stimulate beta 1 integrin function via an "inside-out" mechanism involving protein kinase activity, while KL stimulates integrin activity through a similar, but initially distinct, pathway via the KIT tyrosine-kinase. Thus, in addition to promoting the survival, proliferation, and development of hemopoietic progenitors, cytokines also regulate adhesive interactions between progenitor cells and the bone marrow microenvironment by modifying the functional states of specific integrins. These data are of importance in understanding the fundamental processes of beta 1 integrin activation and cellular response to mitogenic cytokines as well as on the clinical setting where cytokines induce therapeutic mobilization of hematopoietic progenitors.
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PMID:Cytokines increase human hemopoietic cell adhesiveness by activation of very late antigen (VLA)-4 and VLA-5 integrins. 753 95

An established megakaryoblastic cell line, MEG-01s, was used to study receptor expression and receptor-mediated responses to factors known to affect megakaryocytopoiesis. In addition, the antigenic characteristics of this cell line were further defined. MEG-01s cells were CD34+CD33+CD38 +/- HLA-DR- and expressed erythroid and granulocytic differentiation antigens as well as many megakaryocytic lineage-restricted antigens. These cells also expressed receptors for interleukin-3 (IL-3), IL-6, and stem cell factor (SCF), as measured by flow cytometry and/or RNA expression. MEG-01s cell proliferation or survival was only marginally influenced by these factors and their combinations. c-kit, the receptor for SCF, was downmodulated by its ligand. This modulation was time-dependent, appeared to involve receptor conformational changes, and became concentration-dependent by day 3. Northern blot analysis indicated that amounts of c-kit RNA increased as downmodulation proceeded. IL-3 induced IL-6 secretion in these cells, which was augmented by a protein kinase-C (PKC) inhibitor, H7, and reduced by a tyrosine kinase inhibitor, genistein. Evidence for autocrine regulation of this cell line by IL-6 was demonstrated by the inhibitory effects of an antisense oligonucleotide on 3H-thymidine (3H-TdR) incorporation. These cells should prove useful for studies of the early signal transduction mechanisms involved in cytokine function.
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PMID:MEG-01s cells have receptors for and respond to IL-3, IL-6, and SCF. 753 84

Interleukin 1 (IL-1) and tumour necrosis factor (TNF) are primary inflammatory cytokines. They have highly similar diverse biological actions and act as local and systemic hormones to cause many features of inflammation. Results of studies in animals and humans indicate that blocking their production or action will have marked anti-inflammatory effects. They combine with distinct receptors at the cell surface and rapidly activate intracellular protein kinase cascades. The protein kinases then phosphorylate a variety of cellular protein substrates, including transcription factors, to produce the biological response. In cell culture IL-1 and TNF have the potential to activate all three MAP (Mitogen-Activated Protein) kinase cascades, as well as other less well characterized enzymes. The mechanism(s) by which the cytokine receptors activate the kinases is unknown. There is some evidence that IL-1 and TNF activate sphingomyelinase in the cell membrane to generate ceramide, which may have a signalling function.
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PMID:Intracellular signalling mechanisms of interleukin 1 and tumour necrosis factor: possible targets for therapy. 755 72

Cellular responses initiated by tumor necrosis factor (TNF) are mediated by two different cell surface receptors with respective molecular masses of 55 kDa (p55) and 75 kDa (p75). p55 is functional in almost every cell type and can independently transmit most biological activities of TNF. In contrast, TNF signaling via p75 seems so far largely restricted to cells of lymphoid origin, where it can induce proliferation, cytokine production, and/or apoptosis. The mechanisms that regulate TNF receptor activity are largely unknown. Here we report that the p75 of unstimulated p75-responsive PC60 T cells is phosphorylated on serine by a kinase activity present in p75 immune complexes. Several lines of evidence indicate that the latter kinase is casein kinase-1 (CK-1). Previous results have shown that the p75 TNF receptor is constitutively phosphorylated in vivo. Our data show that the latter in vivo phosphorylation is also at least partially due to CK-1. Pretreatment of cells with TNF had no detectable effect on p75 phosphorylation in vitro or in vivo. However, a specific CK-1 inhibitor potentiated TNF-induced apoptosis mediated by p75, suggesting an inhibitory role for phosphorylation by CK-1. Although in vivo p75 phosphorylation could be seen in both p75-unresponsive and p75-responsive cell lines, in vitro p75 phosphorylation in p75 coimmunoprecipitates could not be observed in cell lines that were biologically unresponsive to p75 stimulation. The latter observation further indicates a regulatory role for p75 phosphorylation in p75-mediated signaling. Taken together, our data demonstrate that the p75 TNF receptor is phosphorylated and associated with CK-1, which negatively regulates p75-mediated TNF signaling.
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PMID:Casein kinase-1 phosphorylates the p75 tumor necrosis factor receptor and negatively regulates tumor necrosis factor signaling for apoptosis. 755 83

Migration of astrocytes is thought to play a role in nerve regeneration and to be mediated, at least in part, by inflammation-associated cytokines. Plasminogen activators are secreted proteases that function in fibrinolysis and participate in cellular migration and invasion and, in some cases, are modulated by cytokines. Here, we show that two cytokines, tumor necrosis factor-alpha and interleukin-1 beta, can modulate plasminogen activation in astrocytes, each causing 90% reduction of total plasminogen activator activity. Direct and reverse zymography indicated that this reduction resulted from two simultaneous events, a pronounced decrease in tissue-type plasminogen activator activity and an induction of plasminogen activator inhibitor-1. Northern hybridization analysis indicated a 30-fold increase of the steady-state level of plasminogen activator inhibitor-1 mRNA following treatment with each of the two cytokines. Both of the cytokine-induced effects could be blocked by cycloheximide or actinomycin D. When signal transduction pathways were blocked, the results indicated the involvement of reduction in cyclic AMP levels, protein kinase activity, and arachidonic metabolites of the lipoxygenase pathway. The results thus show that the two cytokines reduce the ability of astrocytes to conduct fibrinolysis and extracellular proteolysis, and suggest that the effect of these cytokines on members of the plasminogen activation system is through a common signal transduction pathway.
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PMID:Components of the plasminogen activator system in astrocytes are modulated by tumor necrosis factor-alpha and interleukin-1 beta through similar signal transduction pathways. 756 46

The cytokine lymphotoxin (LT)alpha is known to play a role in B cell activation. As the engagement of the B cell antigen CD40 is known to lead to B cell proliferation and differentiation, we studied LT alpha expression in human B cells after CD40 ligation. We demonstrate that anti-CD40 monoclonal antibody (mAb) induces strong LT alpha mRNA and surface-expression in human tonsil B cells. Induction of LT alpha mRNA and surface expression by CD40 ligation is inhibited by the protein tyrosine kinase (PTK) inhibitors herbimycin and genistein in a dose-dependent manner. The protein kinase C (PKC)-specific inhibitors sphingosine and bis-indolylmaleimide caused negligible inhibition of anti-CD40-induced LT alpha mRNA and surface expression. No inhibition is observed with the protein kinase (PKA) inhibitors H89 and HA1004. Cross-linking of the transmembrane phosphatase CD45 to CD40 by using goat-anti-mouse F(ab')2 fragments strongly inhibits CD40-mediated LT alpha expression in human B cells, confirming the role of PTK activation in CD40-mediated induction of LT alpha expression. Inhibitors of the serine/threonine protein phosphatases PP1 and PP2A, okadaic acid and calyculin induce LT alpha mRNA expression. In contrast, cyclosporin A, an inhibitor of the serine/threonine phosphatase calcineurin has no effect on anti-CD40-induced LT alpha expression. These results suggest that induction of LT alpha expression in B cells following engagement of CD40 involves activation of protein tyrosine kinases.
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PMID:CD40-mediated lymphotoxin alpha expression in human B cells is tyrosine kinase dependent. 758 8

The effect of individual unsaturated fatty acids on the release of tumour necrosis factor (TNF) and interleukin 6 (IL6) was investigated in thioglycollate-induced rat peritoneal macrophages. The intracellular mechanisms associated with the changes of cytokine production in response to fatty acids were also studied. Incubation of macrophages with 100 microM docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) increased TNF (21% and 15% respectively) and IL6 (69% and 40% respectively) production. Linoleic acid (LA) diminished TNF production by 16%. At 100 microM oleic acid (OA), LA and EPA concentration an increase in macrophage adenylate cyclase activity (110%, 72% and 39% respectively) and a decrease (14%) in the presence of DHA was observed. PGE2 production in the presence of 100 microM DHA was reduced by 36%, whereas in the presence of 100 microM LA an increase (75%) was observed. Phospholipase A2 (PLA2) activity was also found to be modified in the presence of EPA and DHA at 50 microM (20% and 60% respectively) and 100 microM (34% and 62% respectively) concentrations. The activities of both protein kinase A (PKA) and protein kinase C (PKC) were effected by the different fatty acids. At 50 microM all fatty acids suppressed PKA activity except OA which enhanced PKA activity by 14%. At 100 microM fatty acid concentration, EPA suppressed PKA activity by 40%. PKC activity was enhanced by LA and OA, by 18% and 21% respectively. However, at 100 microM EPA and DHA, PKC activity was suppressed by 37% and 17% respectively, whereas PKC activity was enhanced by 146% in the presence of 100 microM LA. These results show for the first time that unsaturated fatty acids have an effect on macrophage PLA2 activity and that PGE2 may be a potent modulator of IL6 production. From these studies it is tempting to speculate that macrophage TNF and IL6 release may, in part, occur via a PKC and PKA independent pathway and that PLA2 activity and PGE2 concentration are inversely related to production of TNF and IL6.
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PMID:Influence of unsaturated fatty acids on the production of tumour necrosis factor and interleukin-6 by rat peritoneal macrophages. 759 52

In this work, we demonstrate the signal-transducing mechanism of TGF-beta 1 for gene expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 (MCP-1) in clonal osteoblastic MC3T3-E1 cells. TGF-beta 1-induced JE/MCP-1 gene expression in the cells was inhibited markedly by H-7 (1-(5-isoguinolinesulfonyl)-2-O-methylpiperazine-dihydrochloride) and staurosporine, potent inhibitors of protein kinase. TGF-beta 1-induced expression of both early proto-oncogenes c-fos and c-jun in the cells was also inhibited by H-7 and staurosporine. Antisense oligonucleotides to c-fos and c-jun genes inhibited significantly the cytokine-induced JE/MCP-1 gene expression. Curcumin, a specific inhibitor of c-jun/AP-1, inhibited the cytokine-induced c-jun gene expression in a dose-dependent manner, though the c-fos gene expression was not affected. TGF-beta 1 stimulated transcriptionally the JE/MCP-1 gene expression, and this stimulation was inhibited significantly by curcumin. Curcumin-induced inhibition of the JE/MCP-1 gene product was also evidenced by both an assay involving immunoprecipitation with antiserum specific for JE/MCP-1 and an assay for monocyte chemotaxis. Curcumin markedly inhibited AP-1 binding activity to 12-tetradecanoyl phorbol-13-acetate-responsive element (TRE) in the cytokine-treated cells. Furthermore, H-7 and staurosporine also inhibited the binding activity to TRE in the cells treated by the cytokine. These results demonstrate that TGF-beta 1 induces expression of monocyte chemoattractant JE/MCP-1 via the transcriptional factor AP-1 induced by protein kinase in the osteoblastic cells.
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PMID:TGF-beta induces expression of monocyte chemoattractant JE/monocyte chemoattractant protein 1 via transcriptional factor AP-1 induced by protein kinase in osteoblastic cells. 760 15

Increased synthesis of insulin-like growth factor I (IGF-I), a fibroblast growth factor, is induced in murine macrophages by TNF-alpha. TNF-alpha also induces macrophages to express cytocidal activity, but only during costimulation with IFNs. Since prostaglandin E2 (PGE2) is known to inhibit macrophage cytocidal activity, its possible reciprocal enhancement of IGF-I synthesis was examined. PGE2 or dibutyryl cyclic AMP (dbcAMP) stimulated the synthesis of IGF-I similarly to TNF-alpha in magnitude and time course. TNF-alpha did not increase IGF-I synthesis by first inducing PGE2 synthesis, because indomethacin was unable to block the effect of TNF-alpha. PGE2 did not stimulate IGF-I synthesis by first inducing TNF-alpha production, because 1) anti-TNF-alpha Ab did not block PGE2-induced IGF-I synthesis, and 2) PGE2 down-regulated TNF-alpha mRNA levels and did not affect levels of the cytokine in supernatants. Moreover, the difference in the induction of IGF-I was observed at the level of signal transduction, in that PGE2 and dbcAMP increased cAMP-dependent protein kinase (PKA) activity, whereas TNF-alpha stimulated the mitogen-activated protein (MAP) kinase pathway. Divergence between the two pathways was also noted in the regulation of IGF-I at the mRNA level, and an additive effect on IGF-I synthesis was observed when cells were incubated with the combination of TNF-alpha plus PGE2 or dbcAMP. Collectively, these data suggest that TNF-alpha and PGE2 stimulate IGF-I synthesis in macrophages by two separate pathways, and that PGE2 acts as a positive stimulus for IGF-I synthesis through a cyclic AMP/PKA pathway.
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PMID:Divergence in macrophage insulin-like growth factor-I (IGF-I) synthesis induced by TNF-alpha and prostaglandin E2. 763 60

Differences in levels of specific enzymes utilized in intracellular signalling could be a factor in the distinct signalling properties observed in memory and naive T cells. We have studied the expression of both classical and non-classical protein kinase of C (PKC) isoenzymes in CD45RA and CD45RO cells using a combination of Western blot and flow cytometric analysis. These data indicate that CD45RA cells express higher levels of PKC alpha, PKC beta and PKC delta than CD45RO cells. In addition, CD45RA+ cells show greater proliferative activity when stimulated with phorbol myristate acetate (PMA) and calcium ionophore than their CD45RO+ counterparts. Variations in the levels of these isoenzymes could be implicated in functional differences, such as proliferation and cytokine production, in these cell subsets.
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PMID:Protein kinase C isoform expression in CD45RA+ and CD45RO+ T lymphocytes. 764 20


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