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)

A correlation between changes in protein kinase C (PKC) activity and tumor metastasis has been reported previously with several murine tumor cell lines. Treatment of a human metastatic melanoma cell line, M24met, with phorbol ester, phorbol-12-myristate-13-acetate (PMA), followed by injection into the tail vein of scid mice doubled pulmonary metastasis. Adhesion of M24met cells exposed to PMA, was enhanced to collagens I and IV, but not to laminin or fibronectin, suggesting a change in specific adhesion receptors on the tumor cells. Treatment of M24met cells with PMA did not affect de novo synthesis of integrin subunits (alpha 2, alpha 3, beta 1) known to form collagen receptors. However, PMA stimulated the phosphorylation of integrin subunits alpha 3 and beta 1 on serine. Therefore, PMA effects on metastasis and cell adhesion may occur through PKC-mediated phosphorylation of integrins.
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PMID:Modulation of human melanoma cell metastasis and adhesion may involve integrin phosphorylation mediated through protein kinase C. 794 69

Hepatic fibrosis is an important morphological feature of alcohol-induced liver injury. We previously reported that acetaldehyde stimulates collagen I and fibronectin gene transcription in rat fat-storing cell (FSC) culture. We here evaluated whether acetaldehyde increases Col I and FN gene transcription through the induction of c-fos and c-jun proto-oncogenes and studied the possible role played by protein kinase C (PKC) and c-AMP. FSCs, isolated from rat liver on a Nycodenz density gradient, were exposed to acetaldehyde for 1/2, 1, 3, 6, 12, 24 hr and for 10, 20, 30, 45, 60, 90 min in the experiments for jun and fos expression, respectively. Acetaldehyde produced a rapid and transient induction of fos mRNA (undetectable at t = 0, peak at t = 45 and still evident at t = 90). Jun mRNA was weakly expressed in unstimulated FSCs; acetaldehyde induced a prolonged activation of jun expression up to 24 hr with a peak at 3 hr. To study the role of PKC were repeated the experiments in the presence of Staurosporine and H-7. These inhibitors of PKC activity blocked the stimulatory effect of acetaldehyde on fos and jun mRNA expression. Furthermore, they abolished the stimulatory effect of acetaldehyde on collagen I and fibronectin gene expression by FSCs. Acetaldehyde increased the cell membrane PKC activity in FSC cultures in a dose-dependent way. Intracellular cAMP levels were not significantly modified by acetaldehyde in the first 30 min of incubation. We conclude that acetaldehyde increases procollagen I and fibronectin gene transcription in FSCs, possibly through c-fos and c-jun expression, and that PKC may play a regulatory role in this chain of events.
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PMID:Acetaldehyde induces c-fos and c-jun proto-oncogenes in fat-storing cell cultures through protein kinase C activation. 794 71

Interaction of Entamoeba histolytica trophozoites with fibronectin (FN) induces reorganization of the actin cytoskeleton and an increase in proteolytic activities that results in the degradation of the bound protein. The binding is mediated by a 37-kDa FN "receptor" localized in the trophozoite surface and associated to the cytoskeleton. The intracellular signals triggered by the ligand-receptor interaction are not well understood but it is plausible that they drive the observed responses. To address this issue, the activation of protein kinase C (PKC) pathways by FN binding was explored. Stimulation with phorbol myristate acetate (PMA) or FN produced a rapid increase in the amebas adhesion to the substrate and local release of proteases. Two PKC inhibitors, H7 and staurosporine, reverted the PMA stimulus and inhibited the response induced by FN. Interaction with FN as well as treatment with PMA produced transient changes of F-actin levels susceptible to inhibition by H7. Furthermore, phosphorylation of amebic proteins was enhanced in response to FN binding and PMA, while the presence of the PKC inhibitor diminished their phosphorylation. Inositol triphosphate production was stimulated by the FN binding, and PKC activation and translation was registered in cell extracts obtained from the stimulated amebas. Our results suggest that PKC pathways are activated in amebas by information transduced as a result of trophozoite binding to FN.
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PMID:Entamoeba histolytica: PKC transduction pathway activation in the trophozoite-fibronectin interaction. 795 62

Focal adhesion formation in fibroblasts results from complex transmembrane signaling processes initiated by extracellular matrix molecules. Although a role for integrins with attendant tyrosine kinases has been established, there is evidence that cell surface heparan sulfate proteoglycans (HSPGs) are also involved with an associated role of protein kinase C. The identity of the proteoglycan has remained elusive, but we now report that syndecan 4 (ryudocan/amphiglycan) is present in focal adhesions of a number of cell types. Affinity-purified antibodies raised against a unique portion of the cytoplasmic domain of syndecan 4 core protein recognized an HSPG of similar characteristics to those of syndecan 4. These antibodies stained focal adhesions only after cell permeabilization and recognized differing mammalian species. Syndecan 4 was associated with focal adhesions that contained either beta 1 or beta 3 integrin subunits and those that formed on substrates of fibronectin, laminin, vitronectin, or type I collagen. No focal adhesions were found that were vinculin-containing but lacked syndecan 4. In contrast, syndecan 2, whose cytoplasmic domain is closely homologous to syndecan 4, does not appear to be a focal adhesion component. Thus, syndecan 4 represents a new transmembrane focal adhesion component, probably involved in their assembly.
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PMID:Syndecan 4 heparan sulfate proteoglycan is a selectively enriched and widespread focal adhesion component. 801 4

Integrins are a family of cell surface heterodimers which mediate both cell-cell and cell-extracellular matrix interactions and affect cellular differentiation through their signal transduction capacity. Integrin expression is regulated during differentiation as well as by numerous growth factors and cytokines. We have analyzed the changes in p150,95 (CD11c/CD18 or alpha X/beta 2) and VLA-4 (CD49d/CD29 or alpha 4/beta 1) integrin subunits mRNA levels that take place during the myeloid differentiation of HL60 and U937 cells, and compared them to other integrins with similar functional activities. Northern blot analysis revealed that the monocytic differentiation of U937 and HL60 cells alters the alpha X and alpha 4 mRNA steady-state levels: alpha X mRNA is induced de novo whereas alpha 4 mRNA decreases to undetectable levels. Both changes were dependent on the activity of protein kinase C and were also observed upon granulocytic differentiation of HL60 cells. Parallel analysis of other integrin subunits mRNA (beta 1, alpha 5, beta 7) demonstrated that the mRNA levels for the alpha subunits of the fibronectin receptors alpha 4/beta 1 (VLA-4) and alpha 5/beta 1 (VLA-5) are differentially regulated during the monocytic differentiation of myeloid cell lines, and suggested that myeloid cells express a heterodimer formed by the association of beta 7 with an integrin alpha subunit distinct from alpha 4. Nuclear transcription assays and functional analysis of the alpha X and alpha 4 promoter regions demonstrated that the transcription rate of the alpha X gene is considerably elevated after phorbol 12-myristate 13-acetate treatment of U937 cells, while that of alpha 4 is almost unaffected, suggesting that post-transcriptional mechanisms are causing the extremely low alpha 4 mRNA levels observed in differentiated U937 cells.
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PMID:Regulated expression of p150,95 (CD11c/CD18; alpha X/beta 2) and VLA-4 (CD49d/CD29; alpha 4/beta 1) integrins during myeloid cell differentiation. 802 May 69

Previous work from our laboratory (Scheidl et al. (1992) Biochim. Biophys. Acta 1135, 295-300) has shown that sphingosine (Sph), a known inhibitor of protein kinase C (PKC) inhibited the release of fibronectin (FN) into the media of fibroblast cells in culture and that this effect was independent of PKC. We now report that the action of Sph was time dependent (maximum inhibition in 2 h), concentration dependent (0.5-10 microM, at which concentration Sph was not toxic), and rapidly reversible after removal of Sph. Incubating with [35S]methionine, we found Sph reduced FN release either by inhibition of FN synthesis or FN secretion. To distinguish between these two possibilities, cells were treated with monensin, an inhibitor of FN secretion, which together with Sph showed no additive effect on FN release. Cycloheximide also inhibited FN release, but this inhibition was additive to that with monensin. We concluded that Sph inhibited secretion of FN, not synthesis. Furthermore, intracellular FN declined less in Sph-treated than in untreated control cells. By cell-surface iodination with Na125I and lactoperoxidase, followed by immunoprecipitation with antibodies to FN and alpha 5 beta 1-integrin, we showed that labeled multimeric and dimeric cell-surface FN declined, whereas integrins remained unchanged upon Sph treatment. This result suggested that though the number of cell-surface receptors for FN was not affected by Sph, their affinity may be reduced. In addition, we found that either pre- or co-treatment for 30 min with Sph caused a robust inhibition of cell adhesion to FN-coated plastic. We conclude that Sph rapidly inhibits FN secretion, lowers cell-surface FN, and greatly reduces cell adhesion to a FN substratum.
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PMID:The effect of sphingosine on the release of fibronectin from human lung fibroblasts. 806 Oct 52

Human erythroleukemia (HEL) cells grow in suspension, but after treatment with nM PMA the cells adhere and spread on glass or fibronectin [Jarvinen et al., 1987: Eur. J. Cell Biol. 44:238-246]. We observed an early (20-30 min) stage of spreading in which F-actin was organized into peripheral arcs near the spreading margin and vinculin was localised to the cell's periphery at the ends of these arcs. By 1 h the cells were well spread with straight actin bundles many of which ended at more central sites terminating on patches containing vinculin and talin; thus the cells assemble typical stress fibers but do not appear to polarize. The cells also spread on RGD polymer. DiC8 (1,2-dioctanoyl-sn-glycerol, C8:0, Sigma Chemical Co., St. Louis, MO) induced spreading but only if DAG kinase inhibitor and A-23187 were also present; in their absence cells adhered but did not spread. Spreading was approximately 85% inhibited by 100 nM staurosporine. PKC-beta was shown to be present in the cells by immunoblotting. In cells spread for 1 h with PMA, F-actin increased to 180% of control levels as measured by RP binding and the actin sequestering complex of G-actin-thymosin beta 4 decreased significantly. To determine whether the F-actin increase required adhesion, we inhibited cell attachment to the substratum by adding RGDS, by coating glass surfaces with hemoglobin, or by a combined treatment. Under these conditions PMA-treated suspended cells still increased their F-actin to 126-137% of controls, a significant increase over control levels. Staurosporine inhibited F-actin increases under all the conditions studied. Permeabilized cell suspensions, incubated with rhodamine labelled G-actin, incorporated the labelled actin along cell membranes at a low level. A few minutes preincubation with either diC8 plus DAG kinase inhibitor or with PMA strongly increased the incorporation. This increased incorporation was reduced to below control levels by either staurosporine (100 nM) or cytochalasin D (1 microM). We conclude that both suspended and spreading HEL cells can be stimulated to polymerize actin by a mechanism dependent on PKC or a PKC-like molecule. In suspended cells, the polymerization occurs along the membrane. When cells spread, F-actin increased to a significantly greater extent. This second step could involve additional polymerization, perhaps at the observed adhesion sites, decreased turnover of the actin bundles, or a combined effect of both mechanisms.
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PMID:Two-step mechanism for actin polymerization in human erythroleukemia cells induced by phorbol ester. 806 40

We have analysed the mechanism of PMA-induced adhesion of the MDS human leukemia cell line. Affinity to various matrix ligands indicated that PMA induced fibronectin adhesion of MDS cells. This interaction could not be inhibited by RGDS-peptide, therefore it was most probably not mediated by integrins. Rather, both the basal and PMA-induced fibronectin adhesion of MDS cells could be inhibited by heparin and much less efficiently by chondroitin sulphate, suggesting that glycosaminoglycans of proteoglycans may be responsible for the change in adhesive phenotype. PMA stimulation of MDS cells induced a significant increase in proteoglycan biosynthesis. Studies on the glycosaminoglycan pattern of the proteoglycans showed that PMA treatment initiated a shift in glycanation of the MDS-proteoglycans from the predominant chondroitin sulphate-proteoglycans in control cells to a predominant heparan sulphateproteoglycans in adherent cells. These data indicate that protein kinase C, the main target of PMA, may have a profound role in the regulation of glycanation pattern of proteoglycans. Furthermore, such alterations in the cellular proteoglycans may significantly affect the matrix adhesion potential of hematopoietic cells.
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PMID:PMA induces shift from chondroitin to heparan sulphate on proteoglycans correlating with fibronectin adhesion of MDS human leukemia cells. 807 77

Previous studies have shown that fibronectin (Fn) enhances phagocytosis and killing of antibody-coated bacteria by neutrophils and macrophages. In an attempt to understand the mechanism of this enhancement, we have investigated the effects of Fn on phagocytosis-related actin organization as well as respiratory burst activity in neutrophils, monocytes and culture-derived macrophages. Employing an NBD-phallacidin flow cytometric analysis of filamentous actin formation, we found that Fn promotes rapid actin polymerization within 30 seconds in neutrophils, monocytes, and macrophages, but not lymphocytes. Enhancement of actin polymerization by Fn was concentration-dependent and mediated by a pertussis toxin- but not cholera toxin-sensitive G protein. Inhibition of protein kinase C by sphingosine (20 microM), calcium influx by verapamil (0.1 mM), or intracellular calcium mobilization by 8-(N,N-diethyl-amino) octyl-3,4,5-trimethoxybenzoate HCl (TMB-8; 0.1 mM) did not block Fn-enhanced actin polymerization in phagocytes. Incubation of neutrophils and macrophages on microtiter plates precoated with Fn suppressed superoxide (O2-) production induced by IgG- and IgA- opsonized group B streptococci. In contrast, Fn significantly enhanced IgA- and IgG-mediated O2- production by freshly isolated monocytes. These data suggest that Fn enhances phagocytosis, presumably through G protein-coupled cytoskeleton reorganization and augments O2- production by circulating monocytes. In contrast, it appears to suppress O2- production by the active phagocytic cells, neutrophils and macrophages. This may result in enhanced phagocytosis and intracellular killing of microorganisms without damaging interstitial tissues.
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PMID:Effects of fibronectin on actin organization and respiratory burst activity in neutrophils, monocytes, and macrophages. 810 71

Intracellular Ca2+ responses to extracellular matrix molecules were studied in suspensions of pancreatic acinar cells loaded with Fura-2. Collagen type I, laminin, fibrinogen and fibronectin were unable to raise cytosolic free Ca2+ concentration ([Ca2+]i), whereas collagen type IV, at concentrations from 5 to 50 micrograms/ml, significantly increased it. The effect of collagen type IV was not due to possible contamination with type-I transforming growth factor beta or plasminogen, as neither of these agents was able to increase [Ca2+]i. Using highly specific mass assays, concentrations of inositol lipids, 1,2-diacylglycerol (DAG) and Ins(1,4,5) P3 were measured in pancreatic acinar cells stimulated with collagen type IV. A decrease in the concentrations of PtdIns(4,5) P2 and PtdIns4 P with a concomitant increase in the concentrations of DAG and InsP3 mass were observed, showing that collagen type IV increases [Ca2+]i by activation of phospholipase C. The observed [Ca2+]i signals had two components, the first resulting from Ca2+ release from the intracellular stores, and the second resulting from Ca2+ flux from the extracellular medium through the verapamil-insensitive channels. A tyrosine kinase inhibitor (tyrphostine) was able to block inositol lipid signalling caused by collagen type IV, which together with the insensitivity of this pathway to cholera toxin and pertussis toxin or to preactivation of protein kinase C, the longer duration of the increase in [Ca2+]i and a longer lag period needed for observation of increases in DAG and InsP3 concentration with collagen type IV than with carbachol (50 mM) suggest that activation of phospholipase C by collagen type IV is caused by tyrosine kinase activation. Inositol lipid signalling and increases in [Ca2+]i were also observed with Arg-Gly-Asp (RGD)-containing peptide but not with Arg-Asp-Gly (RDG)-containing peptide. Collagen type IV and RGD-containing peptide, but not carbachol, competed in increasing [Ca2+]i and DAG concentration, suggesting that the binding site of collagen type IV responsible for phospholipase C activation contains the RGD sequence. Together the present results suggest that, in pancreatic acinar cells, RGD sequence(s) within collagen type IV molecules cause activation of tyrosine kinase, probably through one of the integrin receptors, which then stimulates phospholipase C and increases [Ca2+]i.
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PMID:Collagen type IV stimulates an increase in intracellular Ca2+ in pancreatic acinar cells via activation of phospholipase C. 819 49


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