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)

Raf-1 is a serine/threonine kinase that has been identified as a component of growth factor-activated signal transduction pathways, and is required for growth factor-induced proliferation of leukemic cell lines and colony formation of hematopoietic progenitors stimulated with single colony-stimulating factors, which promote the growth of committed hematopoietic progenitor cells. However, it is known that the most primitive progenitors in the bone marrow require stimulation with multiple cytokines to promote cell growth. We have determined that c-raf antisense oligonucleotides inhibit the growth of murine lineage-negative progenitors stimulated with two-, three- and four-factor combinations of growth factors, including GM-CSF + interleukin (IL)- 1, IL-3 + steel factor (SLF), IL-3 + IL-11 + SLF and IL-3 + IL-11 + SLF + G-CSF. In addition, c-raf antisense oligonucleotides inhibit the synergistic response of the MO7e human progenitor cell line induced to proliferate with IL-3 + SLF (99%) or GM-CSF + SLF (99%). In contrast, c-raf antisense oligonucleotides only partially inhibited day 14 colony formation of CD34+ human progenitors stimulated with IL-3 + SLF (50%) or GM-CSF + SLF (55%) but completely inhibited day 7 colony formation. However, pulsing CD34+ cells with additional oligonucleotides on day 7 of the colony assay further inhibited day 14 colony formation (70%-80%). Furthermore, a comparison of the effect of c-raf antisense oligonucleotides on the synergistic response of normal human fetal liver cells in [3H]thymidine incorporation assays and colony assays showed strong inhibition in short-term proliferation assays and partial inhibition in 14-day colony assays. Taken together, these results demonstrate that partial inhibition of colony formation of primitive human progenitors stimulated with multiple growth factors is a result of the length (14 days) of the human colony assay and does not represent a differential requirement of primitive progenitors for Raf-1. Thus Raf-1 is required for the proliferation and differentiation of primitive hematopoietic progenitor cells stimulated with synergistic combinations of cytokines.
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PMID:Raf-1 protein is required for growth factor-induced proliferation of primitive hematopoietic progenitors stimulated with synergistic combinations of cytokines. 900 24

The cAMP analogue 8-bromo-cAMP (8BrcAMP) inhibits granulocyte-colony-stimulating factor (G-CSF)-stimulated DNA synthesis in myeloid NFS-60 cells. We examined the effect of 8BrcAMP addition on the G-CSF-stimulated extracellular signal-related protein kinase 1 (Erk-1), p21ras and Raf-1 activation. The Erk-1 activity was not down-regulated by the increase in intracellular cAMP levels, whereas p21ras and Raf-1 activities were, suggesting that Erk-1 activity might not be dependent on upstream p21ras and/or Raf-1 activity in this system. To explore this possibility further, we sought to determine whether there were downstream substrates of Raf-1 that were distinguishable from those of Erk-1 by using two-dimensional SDS/PAGE analysis of the protein phosphorylation patterns of NFS-60 cell cytosolic extracts treated with exogenous Raf-1 or Erk-1 in the presence of [gamma-32P]ATP. The two phosphorylation patterns were found to have many differences. To gain further insights into the possible relevance of these phosphorylation patterns and as an approach to exploring in more detail the inhibitory effect of 8BrcAMP, two-dimensional SDS/PAGE analysis was performed on the cytosolic extracts of 32P-labelled NFS-60 cells treated with G-CSF, in the absence or presence of 8BrcAMP. It was found that the phosphorylated proteins whose appearance was specific to the action of exogenous Raf-1 were sensitive to the action of 8BrcAMP in vivo, whereas those whose appearance was specific to the action of exogenous Erk-1 alone, or common to the actions of Raf-1 and Erk-1, were 8BrcAMP-insensitive. The results are consistent with a Raf-1-independent pathway for Erk-1 activation in G-CSF treated myeloid cells, and a number of potential downstream substrates of these kinases have been identified for further characterization.
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PMID:cAMP suppresses p21ras and Raf-1 responses but not the Erk-1 response to granulocyte-colony-stimulating factor: possible Raf-1-independent activation of Erk-1. 907 46

Recent data have indicated that resident mouse peritoneal macrophages (PMo) transcribed the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes in response to stimulation with the monocyte-macrophage colony-stimulating factor (CSF-1) but only Il6 mRNA was translated into secreted protein. In this paper, we extend these observations. It is shown that resident PMo incubated with protein kinase (PK)C inhibitors, staurosporine (SP) and its derivative GF109203-X, showed a several fold increase in the levels of Il6 mRNA in control and CSF-1-primed PMo and a parallel release of large amounts of protein. In contrast, SP was shown to have no effect on the release of GM-CSF from control or CSF-1-primed PMo, although it increased by approximately twofold the amount of Csfgm mRNA in CSF-1-primed Mo. When SP was added 4 h after CSF-1 priming to block CSF-1-induced protein kinase pathways, an increased amount of IL-6 release was again seen but without any increase in Il6 mRNA levels. Under these conditions, Csfgm gene expression was relatively unaffected. Activation of PKC by phorbol myristate acetate (PMA) also resulted in increased Il6 gene expression by control and CSF-1-primed PMo. PMA had no apparent effect on Csfgm transcription but appeared to influence translation at a low level, as measured by the release of small amounts of GM-CSF protein. The addition of lipopolysaccharide (LPS) to CSF-1-primed PMo resulted in a synergistic increase in the expression of both genes at the levels of transcription and protein release. The addition of SP to CSF-1-primed Mo before LPS, however, further enhanced IL-6 release but not GM-CSF release from the cells. The data indicate that CSF-1-priming drives a number of pathways involved in the regulation of expression of both genes and renders PMo highly susceptible to appropriate secondary stimulatory agents that transform the PMo into secretory inflammatory cells.
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PMID:Priming of mouse macrophages with the macrophage colony-stimulating factor (CSF-1) induces a variety of pathways that regulate expression of the interleukin 6 (Il6) and granulocyte-macrophage colony-stimulating factor (Csfgm) genes. 928 58

Activation of the respiratory burst imposes acute metabolic demands on phagocytic cells. These are met by mobilizing internal energy stores and by increasing the utilization of exogenous energy, including glucose in the circulation. To determine whether the increased glucose uptake that is known to be associated with the respiratory burst involves the regulation of glucose transporter molecules, the intrinsic transport properties of glucose transporters on the macrophage cell line RAW 264.7 were determined after activation with PMA, N-formyl-methionine-leucine-phenylalanine (fMLP) and the cytokines granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). Treatment with PMA resulted in a 2-fold increase in respiratory burst activity within 10 min; this was associated with a 30-50% increase in 2-deoxyglucose uptake and a 4-fold increase in transporter affinity for glucose. Similarly, fMLP, GM-CSF and IL-3 treatments stimulated 2-deoxyglucose uptake that was associated with a 3-4-fold increase in transporter affinity for glucose. To determine whether the changes observed in 2-deoxyglucose uptake in response to PMA, fMLP and growth factors were influenced by phosphorylation of the sugar, 3-O-methylglucose, which is not phosphorylated, was used. Increased 3-O-methylglucose uptake and increased transporter affinity for glucose were also observed after PMA, fMLP and GM-CSF treatments. Whereas both fMLP and GM-CSF stimulated superoxide production, IL-3 failed to activate respiratory burst activity. The protein kinase inhibitors genistein and staurosporine inhibited the increase in 2-deoxyglucose uptake observed with fMLP and GM-CSF, and partly reversed the affinity increase towards that of untreated control cells. In contrast, the phosphatidylinositol 3-kinase inhibitor wortmannin had little effect on 2-deoxyglucose uptake in response to these activators. Western blotting with subtype-specific antisera showed that Glut-3 was the predominant transporter on RAW 264.7 cells. These studies demonstrate that acute regulation of glucose transporters occurs in response to activators that promote respiratory burst activity, and show that this regulation involves both tyrosine kinases and protein kinase C activity.
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PMID:Acute regulation of glucose transport in a monocyte-macrophage cell line: Glut-3 affinity for glucose is enhanced during the respiratory burst. 935 3

Intracellular signaling events occurring downstream of receptor activation for the colony-stimulating factors GM-CSF and G-CSF and Steel factor the latter a member of the tyrosine kinase receptor family of hematopoietic growth factors, are discussed. Hematopoietic signaling pathways, including the Ras/Raf-1/MAP kinase cascade and the Jak-STAT pathway are defined and links existing between separate signaling pathways are discussed. Emphasis is given to exploring the relationships that exist between activation of receptor-associated proteins and signal transduction pathways, and the regulation of gene transcription, translation, and hematopoietic cell proliferation. A model system exploring the synergistic interaction between GM-CSF and Steel factor in the regulation of hematopoietic cell proliferation is presented.
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PMID:Advances in understanding the postreceptor mechanisms of action of GM-CSF, G-CSF, and Steel factor. 937 74

Exposure of neutrophils to inflammatory stimuli such as the chemoattractant FMLP leads to activation of responses including cell motility, the oxidative burst, and secretion of proteolytic enzymes. A signaling cascade involving sequential activation of Raf-1, mitogen-activated protein kinase (MEK), and extracellular signal regulated kinase (ERK) is also rapidly activated after agonist exposure. The temporal relationship between these events suggests that the kinases may be involved in triggering the effector functions, but direct evidence of a causal relationship is lacking. To assess the role of the MEK/ERK pathway in the activation of neutrophil responses, we studied the effects of PD098059, a potent and selective inhibitor of MEK. Preincubation of human neutrophils with 50 microM PD098059 almost completely (>90%) inhibited the FMLP-induced activation of MEK-1 and MEK-2, the isoforms expressed by neutrophils. This dose of PD098059 virtually abrogated chemoattractant-induced tyrosine phosphorylation and activation of ERK-1 and ERK-2, implying that MEKs are the predominant upstream activators of these mitogen-activated protein kinases. Pretreatment of neutrophils with the MEK antagonist inhibited the oxidative burst substantially and phagocytosis only moderately. In addition, PD098059 antagonized the delay of apoptosis induced by exposure to granulocyte-macrophage CSF. However, the effects of PD098059 were selective, as it failed to inhibit other responses, including chemoattractant-induced exocytosis of primary and secondary granules, polymerization of F-actin, chemotaxis, or activation of phospholipase A2. We conclude that MEK and ERK contribute to the activation of the oxidative burst and phagocytosis, and participate in cytokine regulation of apoptosis.
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PMID:Importance of MEK in neutrophil microbicidal responsiveness. 955 1

RAFTK, a novel nonreceptor protein kinase, has been shown to be involved in focal adhesion signal transduction pathways in neuronal PC12 cells, megakaryocytes, platelets, and T cells. Because focal adhesions may modulate cytoskeletal functions and thereby alter phagocytosis, cell migration, and adhesion in monocyte-macrophages, we investigated the role of RAFTK signaling in these cells. RAFTK was abundantly expressed in THP1 monocytic cells as well as in primary alveolar and peripheral blood-derived macrophages. Colony-stimulating factor-1 (CSF-1)/macrophage colony-stimulating factor (M-CSF) stimulation of THP1 cells increased the tyrosine phosphorylation of RAFTK; similar increases in phosphorylation were also detected after lipopolysaccharide stimulation. RAFTK was phosphorylated with similar kinetics in THP1 cells and peripheral blood-derived macrophages. Immunoprecipitation analysis showed associations between RAFTK and the signaling molecule phosphatidylinositol-3 (PI-3) kinase. PI-3 kinase enzyme activity also coprecipitated with the RAFTK antibody, further confirming this association. The CSF-1/M-CSF receptor c-fms and RAFTK appeared to associate in response to CSF-1/M-CSF treatment of THP1 cells. Inhibition of RAFTK by a dominant-negative kinase mutant reduced CSF-1/M-CSF-induced MAPK activity. These data indicate that RAFTK participates in signal transduction pathways mediated by CSF-1/M-CSF, a cytokine that regulates monocyte-macrophage growth and function.
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PMID:The related adhesion focal tyrosine kinase (RAFTK) is tyrosine phosphorylated and participates in colony-stimulating factor-1/macrophage colony-stimulating factor signaling in monocyte-macrophages. 957 36

The phosphatidylinositol 3-kinase (PI3K)-signaling pathway has emerged as an important component of cytokine-mediated survival of hemopoietic cells. Recently, the protein kinase PKB/akt (referred to here as PKB) has been identified as a downstream target of PI3K necessary for survival. PKB has also been implicated in the phosphorylation of Bad, potentially linking the survival effects of cytokines with the Bcl-2 family. We have shown that granulocyte/macrophage colony-stimulating factor (GM-CSF) maintains survival in the absence of PI3K activity, and we now show that when PKB activation is also completely blocked, GM-CSF is still able to stimulate phosphorylation of Bad. Interleukin 3 (IL-3), on the other hand, requires PI3K for survival, and blocking PI3K partially inhibited Bad phosphorylation. IL-4, unique among the cytokines in that it lacks the ability to activate the p21ras-mitogen-activated protein kinase (MAPK) cascade, was found to activate PKB and promote cell survival, but it did not stimulate Bad phosphorylation. Finally, although our data suggest that the MAPK pathway is not required for inhibition of apoptosis, we provide evidence that phosphorylation of Bad may be occurring via a MAPK/ERK kinase (MEK)-dependent pathway. Together, these results demonstrate that although PI3K may contribute to phosphorylation of Bad in some instances, there is at least one other PI3K-independent pathway involved, possibly via activation of MEK. Our data also suggest that although phosphorylation of Bad may be one means by which cytokines can inhibit apoptosis, it may be neither sufficient nor necessary for the survival effect.
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PMID:Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation. 963 68

Cytokines are important regulators of hematopoiesis. They exert their actions by binding to specific receptors on the cell surface. Interleukin-5 (IL-5) is a critical cytokine that regulates the growth, activation, and survival of eosinophils. Because eosinophils play a seminal role in the pathogenesis of asthma and allergic diseases, an understanding of the signal transduction mechanism of IL-5 is of paramount importance. The IL-5 receptor is a heterodimer of alpha- and beta-subunits. The alpha-subunit is specific, whereas the beta-subunit is common to IL-3, IL-5, and granulocyte/macrophage colony-stimulating factor (GM-CSF) receptors and is crucial for signal transduction. It has been shown that there are two major signaling pathways of IL-5 in eosinophils. IL-5 activates Lyn, Syk, and JAK2 and propagates signals through the Ras-MAPK and JAK-STAT pathways. Studies suggest that Lyn, Syk, and JAK2 tyrosine kinases and SHP-2 tyrosine phosphatase are important for eosinophil survival. In contrast to their survival-promoting activity, Lyn and JAK2 appear to have no role in eosinophil degranulation or expression of surface adhesion molecules. Raf-1 kinase, on the other hand, is critical for eosinophil degranulation and adhesion molecule expression. Btk is involved in IL-5 stimulation of B cell function. However, it does not appear to be important for eosinophil function. Thus a clear segregation of signaling molecules based on their functional importance is emerging. This review describes the signal transduction mechanism of the IL-3/GM-CSF/IL-5 receptor system and compares and contrasts IL-5 signaling between eosinophils and B cells.
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PMID:The mechanism of IL-5 signal transduction. 973 Sep 44

Increased numbers of activated eosinophils in bronchial tissue is a feature of asthma and may, in part, be attributed to the prolonged cytokine-dependent survival of eosinophils within the inflamed microenvironment. Low-dose oral theophylline was previously shown to reduce the number of activated eosinophils within the sub-mucosa following allergen exposure. A number of inhibitory actions of theophylline have been described which relate to eosinophil recruitment and activation, including inhibition of cell migration and release of granule basic proteins. In this study we investigated the ability of theophylline to inhibit the release of preformed GM-CSF and IL-8 from eosinophils in vitro, as these cytokines may serve an autocrine function in eosinophil survival in vivo. Eosinophils rapidly released GM-CSF and IL-8 spontaneously, and release was further enhanced in response to sIgA-coated beads. Theophylline inhibited the stimulated, but not the spontaneous, release of both cytokines. We previously reported the role of protein kinase A in inhibition of arachidonic acid mobilization and LTC4 synthesis. Therefore we speculate that cAMP-dependent activation of protein kinase A following theophylline treatment of eosinophils resulted in inhibition of Raf-1 and MAPK/MAPKK dependent activation of phospholipase A2 and consequently inhibition of degranulation and cytokine release.
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PMID:Theophylline inhibits the release of eosinophil survival cytokines--is Raf-1 the protein kinase A target? 975 86


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