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)

We investigated the role of fyn kinase on the expression of macrophage colony-stimulating factor (M-CSF) receptors (M-CSFR) and macrophage differentiation using a human myelomonocytic leukemic cell line THP-1. Treatment of THP-1 cells with Bryostatin 1 (bryo 1), a potent protein kinase C (PKC) activator, caused a major fraction of them to become adherent (AD) with distinct monocyte/macrophage characteristics. The differentiation was associated with an enhanced expression of M-CSFR and fyn tyrosine kinase activity, occurring primarily on cells in the AD fraction. Scatchard plot analysis showed that the enhanced expression of M-CSFR binding activity was due to an increase in total receptor number per AD cell, rather than an increase in the binding affinity. Fyn antisense (AS) phosphorothioate oligonucleotides (s-oligos) inhibited the up-regulation of both M-CSFR and c-fms transcripts in bryo 1-treated THP-1 cells. In contrast, fyn sense s-oligos did not affect the up-regulation of either M-CSFR or c-fms mRNA in bryo 1-treated cells. In addition, fyn AS s-oligos blocked the expression of AD capacity in bryo 1-treated THP-1 cells. The efficacy of fyn AS s-oligos as macromolecular inhibitors was verified by their ability to lower fyn-associated tyrosine kinase and in vitro autophosphorylation activity in bryo 1-treated THP-1 cells. Taken together, our results show a strong correlation between M-CSFR expression and monocytic differentiation in THP-1 cells, and suggest a possible role of c-fyn tyrosine kinase in mediating these processes.
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PMID:Induction of macrophage colony-stimulating factor receptor up-regulation in THP-1 human leukemia cells is dependent on the activation of c-fyn protein tyrosine kinase. 927 65

Human U937 myeloid leukemia cells were treated with different concentrations of 12-O-tetradecanoylphorbol-13-acetate (TPA) to determine signals that contribute to growth arrest and differentiation. While 0.5 nM TPA had little if any effect, exposure of U937 cells to higher TPA concentrations (5-500 nM) revealed a complete growth arrest after 48 h. Cytosolic PKC activity decreased by 50% after exposure to 0.5 nM TPA and by 80 and 95% after stimulation with 5 nM and 50 nM TPA, respectively. Simultaneously, the PKC activity in the particulate fraction of U937 cells increased accordingly. These events were associated with induction of a differentiated monocytic phenotype. Expression of the c-myc gene was down-regulated and c-jun and c-fms transcripts increased following exposure to 5-500 nM TPA. In contrast, exposure to 0.5 nM TPA decreased c-myc expression and increased c-jun transcripts only transiently between 4 and 8 h while little if any effect was detectable on c-fms mRNA expression and subsequent differentiation. Taken together, these data suggest that a certain initial threshold of PKC activation is required for induction of a differentiated monocytic phenotype while beyond this threshold, a growth-arrested and differentiated state in these human leukemic cells can be maintained regardless of TPA concentrations.
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PMID:Differential effects of phorbol ester on signaling and gene expression in human leukemia cells. 930 78

PU.1 is a transcription factor found in macrophages, B cells, neutrophils, and hemopoietic stem cells. In macrophages PU.1 regulates a number of genes, including c-fms, CD11b, CD18, and FcgammaR1b. Previously, in primary macrophages PU.1 binding to the sequence GAGGAA was found to be induced by treatment with bacterial lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma). Here we investigated the role of protein kinase C (pKC) in the induction of PU.1 binding in macrophages. We report that pharmacological activation of pKC increases PU.1 binding, while inactivation of pKC inhibits the increases in PU.1 binding by agents which activate pKC in macrophages (LPS and tumor necrosis factor-alpha), but not by an agent which does not activate pKC (IFN-gamma). pKC activation may therefore be one pathway by which PU.1 binding may be increased in primary macrophages.
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PMID:Protein kinase C activation increases binding of transcription factor PU.1 in murine tissue macrophages. 992 Jul 60

Macrophage colony-stimulating factor (CSF-1) binds to a receptor (CSF-1R) encoded by the c-fms proto-oncogene and activates transcription of the urokinase plasminogen activator (uPA) gene in murine bone-marrow-derived macrophages. This article demonstrates that the murine macrophage cell line RAW264 responds to CSF-1 with inducible phosphorylation of cytoplasmic proteins on tyrosine residues but fails to induce transcription of uPA. The defect was correlated with a selective failure to maintain CSF-1Rs on the cell surface, whereas all RAW264 cells contained abundant CSF-1Rs within the presumptive Golgi/endoplasmic reticulum compartment. Transfection with a CSF-1R expression plasmid permitted CSF-1-dependent activation of the signalling pathway targeting an Ets/AP1 (activator protein 1) element in the uPA promoter that has been shown previously to be a target of oncogenic ras and protein kinase C pathways. Mutation of the expressed CSF-1R at either Y807 or Y559, sites of receptor tyrosine phosphorylation implicated in signal transduction, reduced but did not abolish uPA promoter activation by CSF-1. Activation by mutant CSF-1R plasmids was additive; there was no evidence of mutual complementation. The results indicate that maintenance of elevated uPA transcription by CSF-1 requires new receptors emerging continuously on the cell surface. Parallel, partly redundant, signalling pathways arising from phosphorylated tyrosines on the CSF-1R activate multiple cis-acting elements on the complex uPA promoter.
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PMID:Regulation of urokinase plasminogen activator gene transcription in the RAW264 murine macrophage cell line by macrophage colony-stimulating factor (CSF-1) is dependent upon the level of cell-surface receptor. 1072 33

Membrane-bound macrophage colony-stimulating factor (m-M-CSF) is the membrane form M-CSF by alternative splicing. J6-1 leukemic cell line spontaneously forms cell clusters, whose growth depends on the auto-juxtacrine mediated by m-M-CSF and its receptor (M-CSFR). In this study, M-CSFR isolated from J6-1 cells and recombinant human M-CSF soluble receptor (rh-M-CSFsR) were used to study their effects on J6-1 cells. Both receptors inhibited cell proliferation. Use of M-CSFR monoclonal antibodies, M-CSFR or rh-M-CSFsR to block either M-CSFR or m-M-CSF on cell surface inhibited the cluster forming process, while both receptors stimulated cells adhering to culture plate. Furthermore, M-CSFR and/or rh-M-CSFsR caused multiple cellular changes including cytoplasmic pH, multinuclear cell ratio, antigen expression and cell diameter. A [Ca(2+)] rise was induced within 90 s by both receptors. Western blot experiments showed that rh-M-CSFsR caused tyrosine phosphorylation on multiple cytoplasmic proteins of 45 kDa and 55-90 kDa, which could be blocked by H7. These observations suggested that m-M-CSF and M-CSFR mediate J6-1 cell intercellular adhesion with bi-directional signal transduction, and Ca(2+), protein tyrosine kinases, PKC and/or other H7 sensitive kinase(s) involve in the counter-directional signal transduction.
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PMID:Membrane-bound macrophage colony-stimulating factor and its receptor play adhesion molecule-like roles in leukemic cells. 1078 59

We previously reported that macrophage activators such as LPS, IL-2, and IL-4 down-modulate the M-CSFR via a mechanism involving protein kinase C and phospholipase C. In this study, we showed that M-CSFR is shed from macrophage surface and identified the protease responsible for M-CSFR cleavage and down-modulation. The shedding of M-CSFR elicited by phorbol esters (tetradecanoylphorbol myristate acetate (TPA)) or LPS in murine BAC.1-2F5 macrophages was prevented by cation chelators, as well as hydroxamate-based competitive inhibitors of metalloproteases. We found that the protease cleaving M-CSFR is a transmembrane enzyme and that its expression is controlled by furin-like serine endoproteases, which selectively process transmembrane metalloproteases. M-CSFR down-modulation was inhibited by treating cells in vivo, before TPA stimulation, with an Ab raised against the extracellular, catalytic domain of proTNF-converting enzyme (TACE). TACE expression was confirmed in BAC.1-2F5 cells and found inhibited after blocking furin-dependent processing. Using TACE-negative murine Dexter-ras-myc cell monocytes, we found that in these cells TPA is unable to down-modulate M-CSFR expression. These data indicated that TACE is required for the TPA-induced M-CSFR cleavage. The possibility that the cleavage is indirectly driven by TACE via the release of TNF was excluded by treating cells in vivo with anti-TNF Ab. Thus, we concluded that TACE is the protease responsible for M-CSFR shedding and down-modulation in mononuclear phagocytes undergoing activation. The possible physiological relevance of this mechanism is discussed.
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PMID:TNF-alpha-converting enzyme cleaves the macrophage colony-stimulating factor receptor in macrophages undergoing activation. 1116 Jan 99

In multiple myeloma (MM), migration is necessary for the homing of tumor cells to bone marrow (BM), for expansion within the BM microenvironment, and for egress into the peripheral blood. In the present study we characterize the role of vascular endothelial growth factor (VEGF) and beta(1) integrin (CD29) in MM cell migration. We show that protein kinase C (PKC) alpha is translocated to the plasma membrane and activated by adhesion of MM cells to fibronectin and VEGF. We identify beta(1) integrin modulating VEGF-triggered MM cell migration on fibronectin. We show that transient enhancement of MM cell adhesion to fibronectin triggered by VEGF is dependent on the activity of both PKC and beta(1) integrin. Moreover, we demonstrate that PKC alpha is constitutively associated with beta(1) integrin. These data are consistent with PKC alpha-dependent exocytosis of activated beta(1) integrin to the plasma membrane, where its increased surface expression mediates binding to fibronectin; conversely, catalytically active PKC alpha-driven internalization of beta(1) integrin results in MM cell de-adhesion. We show that the regulatory subunit of phosphatidylinositol (PI) 3-kinase (p85) is constitutively associated with FMS-like tyrosine kinase-1 (Flt-1). VEGF stimulates activation of PI 3-kinase, and both MM cell adhesion and migration are PI 3-kinase-dependent. Moreover, both VEGF-induced PI 3-kinase activation and beta(1) integrin-mediated binding to fibronectin are required for the recruitment and activation of PKC alpha. Time-lapse phase contrast video microscopy (TLVM) studies confirm the importance of these signaling components in VEGF-triggered MM cell migration on fibronectin.
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PMID:Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation. 1175 5

CD80 and CD86, expressed on the antigen-presenting cells (APCs) provide costimulatory signals for T lymphocytes. Recently, defective expression of CD80 has been reported in systemic lupus erythematosus (SLE) although its mechanism is unclear. Here, expression of the B7 antigens induced by interferon-gamma, interleukin-4 or granulocyte-macrophage stimulating-factor (GM-CSF) along the differentiation process of APCs was investigated. In contrast to CD86, expression of CD80 on the CD14+ cells induced by GM-CSF was reduced in SLE. GM-CSF receptor (GM-CSFR) was down-regulated by GM-CSF or phorbol 12-myristate 13-acetate in both of the normal controls and SLE patients, while this change was more remarkable in the latter. In the presence of 1-(5-isoquinolinsulfonyl)-2-methylpiperazine, an inhibitor of protein kinase C, the PMA-induced down-regulation of GM-CSFR was reversed in the normal controls but not in SLE. These data suggest that dysregulation of the GM-CSFR might be associated with the defective expression of CD80, leading to dysfunction of the APCs in SLE.
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PMID:Dysregulation of the granulocyte-macrophage colony-stimulating factor receptor is one of the causes of defective expression of CD80 antigen in systemic lupus erythematosus. 1209 May 68

A variety of hematopoietic factors including granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin 3 (IL-3) and thrombopoietin (TPO) induce a rapid increase of intracellular reactive oxygen species (ROS). ROS induces the activation of many signaling molecules, including Shc, Lck, syk, PKC, MAPK, STAT3, through inhibition of protein phosphatase. Each growth factor has a specific cell-surface receptor, which activates both unique and shared signal transduction pathways. The processes of signal transduction linking cell-surface receptor to the formation of intracellular ROS have not been elucidated fully. Ferritins are composed of two subunit types, H and L, and made of 24 subunits that sequester up to 4500 atoms of iron. When the stored iron atoms are released from H-ferritin, through iron-catalyzed reaction, they have the capacity to promote the formation of ROS. Here, the interaction of G-CSFR and H-ferritin was confirmed by yeast two-hybrid screen, mammalian two-hybrid assays, glutathione-S-transferase (GST) pull-down experiments and immunoprecipitation studies in vitro and in vivo. Additional immunofluorescence assay showed that the two proteins colocalized along the plasma membrane and partly in the cytoplasm. The binding site for H-ferritin was demonstrated to locate to the box3 motif on the C-terminal region of granulocyte colony-stimulating factor receptor (G-CSFR). Furthermore, we found the interaction of full-length G-CSFR with H-ferritin was dissociated at 30 minutes after G-CSF induction and then began to assemble at 45 minutes. The labile iron pool (LIP) is a pool of redox-active iron complexes, which is regulated tightly by the expression of H-ferritin. Experiments showed that the level of LIP increased significantly at 30 minutes after G-CSF stimulation and intracellular ROS formation changed in a pattern similar to LIP response to G-CSF in bone-marrow hematopoietic cells. G-CSF-induced changes in the level of LIP and ROS formation could be blocked by pretreatment with iron chelators that repressed the expression of H-ferritin. In addition, the phosphorylation of STAT3 induced by G-CSF was decreased in iron chelator-treated hematopoietic cells. These data suggested that LIP may be released from the dissociated H-ferritin, and then induce intracellular ROS formation in the bone-marrow hematopoietic cells. ROS, acting as a second messenger, might take part in G-CSF receptor signal transduction. So, here, a new G-CSFR-H-ferritin-LIP-ROS pathway is proposed for regulation of intracellular ROS formation in bone-marrow hematopoietic cells.
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PMID:Regulation of LIP level and ROS formation through interaction of H-ferritin with G-CSF receptor. 1512 26

Macrophage colony-stimulating factor (M-CSF or CSF-1) and its cognate receptor, the tyrosine kinase c-fms, are essential for monocyte and macrophage development. We have recently identified an Fms-interacting protein (FMIP) that binds transiently to the cytoplasmic domain of activated Fms molecules and is phosphorylated on tyrosine by Fms tyrosine kinase. FMIP is a substrate not only for Fms but also for protein kinase C (PKC). Mutagenesis reveals that this occurs on serines 5 and 6. Adjacent to these sites is a nuclear localization signal (NLS). We show that this NLS is essential for the predominantly nuclear localization of FMIP. Generation of phosphomimetic substitutions on serine residues 5 and 6 confirms that PKC-mediated phosphorylation on this site leads to translocation of FMIP to the cytosol. Furthermore, the mutant FMIP (FMIPSS5,6AA) was detected abundantly in the nucleus even in the presence of activated PKCalpha. Wild-type FMIP and FMIPSS5,6AA inhibited M-CSF-mediated survival signaling, while FMIPSS5,6EE-expressing cells survived and differentiated into macrophages more efficiently than wild-type cells in the presence of M-CSF or TPA. We conclude M-CSF-mediated activation of PKCalpha can potentiate FMIP action to initiate survival/differentiation signaling.
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PMID:The M-CSF receptor substrate and interacting protein FMIP is governed in its subcellular localization by protein kinase C-mediated phosphorylation, and thereby potentiates M-CSF-mediated differentiation. 1522 Oct 8


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