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)

CD2, CD3, and MHC class II have been demonstrated to stimulate lymphocyte function-associated antigen (LFA)-1 (CD11a/CD18) mediated adhesion (Van Kooyk et al., 1989, Dustin and Springer, 1989; Mourad et al., 1990). Activation of LFA-1 may be mediated by different intracellular signals generated from these stimuli, since previous findings suggest that triggering of LFA-1 through CD2 or CD3 leads to sustained and transient cell adhesion respectively (Van Kooyk et al., 1989). We investigated the role of intracellular signalling pathways in more detail. The results demonstrate that, in addition to protein tyrosine kinase (PTK) and protein kinase C (PKC) mediated signalling, increase in cytosolic-free calcium ([Ca2+]i) levels play a major role in the activation of LFA-1. The calcium ionophore Ionomycin, which increases [Ca2+]i is capable of directly activating LFA-1. Furthermore, activation of LFA-1 by triggering through CD2, CD3 or MHC class II is associated with an increase in [Ca2+]i levels, with kinetics that directly correlate with cell adhesiveness. Moreover, entry of extracellular Ca2+ via Ca-channels is involved in both the CD3- and MHC class II, as well as part of the CD2 induced LFA-1 activation. Depletion of intracellular calcium results in unresponsiveness of LFA-1 to these stimuli, further demonstrating a regulatory role for [Ca2+]i in LFA-1 mediated adhesion.
 ...
PMID:Role of intracellular Ca2+ levels in the regulation of CD11a/CD18 mediated cell adhesion. 791 56

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.
 ...
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

Secretion of unique eosinophil granule constituents may play a role in allergic and parasitic reactions. Therefore we have investigated possible mechanisms for regulation of secretion in eosinophils. A hemolytic plaque assay and an enzyme-linked immunospot (ELISPOT) assay were developed for detection of secreted eosinophil cationic protein (ECP) from single adherent eosinophils. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA) induced release of ECP in a dose-dependent fashion but 4-alpha-PMA, an analogue that does not activate protein kinase C, did not cause degranulation. Staurosporine and K252a, inhibitors of protein kinase C, decreased PMA-induced ECP secretion. Low concentrations of cytochalasin B enhanced PMA-induced secretion but high concentrations had an inhibitory effect. The calcium ionophores A23187 and ionomycin were weaker secretagogues than PMA. Tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, interleukin-5, N-formylmethionyl-leucyl-phenylalanine, and lipopolysaccharide caused little or no degranulation in adherent eosinophils. Preincubation of eosinophils with antibodies to CD18, the common beta chain of leukocyte adhesion proteins, resulted in inhibition of PMA-induced ECP release from adherent cells. 1,2-Bis(O-aminophenyl)-ethane-ethane-N,N,N',N'-tetraacetic acid (BAPTA), an agent that acts intracellularly by chelation of calcium, also inhibited PMA-mediated ECP release. In conclusion, PMA induces release of ECP from single adherent eosinophils and the effect appears to be mediated via protein kinase C and, in contrast to that in neutrophils, to be dependent on CD11/CD18 leukocyte integrins.
 ...
PMID:Phorbol ester-induced degranulation in adherent human eosinophil granulocytes is dependent on CD11/CD18 leukocyte integrins. 809 65

Changes in adhesive properties play important regulatory roles in activation and differentiation of B-cells. To better understand the regulation of interactions between B-cells and other cells during the immune response, we have studied surface expression of the adhesion molecules LFA-1 (CD11a/CD18) and ICAM-1 (CD54). Both adhesion molecules were upregulated during B-cell activation. However, upon stimulation with anti-IgM and IL-4, ICAM-1 levels started to increase within 12 hr, while LFA-1 levels did not start to increase until after 36 hr. When B-cells were stimulated with the PKC activator PDB and a calcium ionophore, ICAM-1 levels, but not LFA-1 levels, increased. Only if these activators were removed after around 24 hr of activation and the cells were recultured in fresh medium was there an eightfold induction of LFA-1. Such reculturing in fresh medium led, however, to decreased ICAM-1 levels.
 ...
PMID:Differential regulation of LFA-1 and ICAM-1 on human primary B-lymphocytes. 809 39

We have examined the role of cell adhesion molecules in the homotypic aggregation of rat alveolar macrophages after exposure to wool and grain dusts. Molecules such as bacterial lipopolysaccharide (LPS) and phorbol myristate acetate (PMA) can upregulate adhesion molecules, resulting in aggregation of lymphocytes. In rats treated intratracheally with an inspirable sample of wool dust collected from the air of British wool textile mills, and sieved grain dust, aggregates of macrophages were present in the bronchoalveolar lavage (BAL). Our hypothesis was that substances present on the dust surface could activate and upregulate adhesion molecules of the CD11/CD18 complex on the BAL cells and account for the aggregates. Macrophages from untreated rats form aggregates in vitro, which averaged 19 cells/aggregate; when treated with both wool and grain dusts, this rose to 25 and 24 cells/aggregate, respectively. LPS, PMA, and the proinflammatory cytokine tumor necrosis factor (TNF) also caused increases in aggregate size. Staurosporine, an inhibitor of protein kinase C (PKC), reduced the number of cells per aggregate from 35 cells/aggregate in LPS- and PMA-treated macrophages to 18 cells/aggregate, the same as untreated. In contrast, staurosporine had no effect in reducing the size of aggregates produced by the organic dusts. Removal of divalent cations, which are essential for maintaining integrin stability and PKC activity, resulted in complete abolition of aggregate formation. Treatment with monoclonal antibodies to lymphocyte function-associated antigen-1 (LFA-1) alpha and beta and intercellular adhesion molecule-1 (ICAM-1) resulted in the inhibition of aggregate formation in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:LFA-1 and ICAM-1 in homotypic aggregation of rat alveolar macrophages: organic dust-mediated aggregation by a non-protein kinase C-dependent pathway. 810 15

The kinase inhibitors H7 and staurosporin dose-dependently stimulate adhesion U-937 cells to plastic but fail to inhibit the CD11b/CD18-dependent adhesion of U-937 cells induced by phorbol ester. The protein kinase C activity of U-937 cells, measured as phorbol ester-stimulated phosphorylation of pep epsilon in streptolysin-O permeabilized cells, is strongly inhibited by the kinase inhibitors. H7 and staurosporin efficiently overcome the inhibitory effect of phorbol-12,13-dibutyrate (PDBu) on leukotriene D4-induced increase in intracellular Ca2+. The results suggest that U-937 cell adhesion may be controlled by a protein kinase C isoform not sensitive to the inhibitors. In addition, the data indicate that selective pharmacological interference with different protein kinase C-mediated processes is achievable.
 ...
PMID:Selective inhibition by H7 and staurosporin of phorbol ester responses in U-937 cells. 810 41

Antigen-independent adhesion of CD4+ T lymphocytes to Epstein-Barr virus transformed B cells is mainly mediated by LFA-1 (CD11a/CD18) and CD2 molecules. Low-affinity binding of resting T cells can be transiently upregulated by cross-linking of CD3-TCR (T cell receptor) complexes. This inside-out signaling influences integrin (beta 1 and beta 2) adhesion capacity. Studies using the nonspecific inhibitor staurosporine have suggested that this phenomenon is dependent on protein kinase C activation. We found that the upregulation of anti-CD3-activated CD4+ T cell adhesion was inhibited strongly and in a concentration-dependent manner by GF109203X, a compound described as a potent and selective inhibitor of PKC. Comparative studies showed that GF109203X and staurosporine had similar inhibitory effects on the upregulation of activated CD4+ T cell adhesion. However, staurosporine is a nonselective kinase inhibitor. PMA-activated CD4+ T cell adhesion was also inhibited by GF109203X. In contrast, passive enhancement of adhesion by treatment with the CD11a-specific antibody NKI-L16 was unaffected by GF109203X. Taken together, these results show that PKC is involved in upregulating the adhesion of CD4+ T cells to B cells following activation of the former by CD3 cross-linking. PKC-dependent upregulation of CD4+ T cell adhesion to B cells is exclusively LFA-1-dependent, as GF109203X had no additional inhibitory effect on anti-LFA-1 antibody-pretreated T cells activated by the anti-CD3 antibody OKT3 and had no effect on the adhesion of LFA-1(-) CD4+ T cells. Finally, PKC inhibition did not alter CD2-mediated adhesion. This points to a limited participation of CD2 in T-B cell interactions after TCR/CD3 cross-linking.
 ...
PMID:GF109203X, a specific PKC inhibitor, abrogates anti-CD3 antibody-induced upregulation of CD4+ T cell adhesion to B cells. 810 10

We have shown that transferred lysophosphatidylcholine (lysoPC) from oxidized low-density lipoprotein (Ox-LDL) to endothelial surface membrane activates protein kinase C (PKC) in endothelial cells, suggesting that Ox-LDL could alter endothelial functions through PKC activation. The purposes of the present study were to examine whether the endothelial susceptibility to polymorphonuclear leukocytes (PMNs) may be altered in Ox-LDL-treated coronary arteries, which have properties closely resembling those observed in atherosclerotic arteries, and to determine the mechanism(s) by which Ox-LDL may affect the endothelial susceptibility to PMNs. Isolated porcine coronary arteries were cannulated and perfused with oxygenated culture medium with or without LDLs or lipids at a constant flow (37 degrees C, pH 7.4). The treatment of porcine coronary arteries with Ox-LDL increased endothelial adhesiveness to PMNs and augmented PMN-induced impairment of endothelium-dependent arterial relaxation (EDR). Furthermore, Ox-LDL stimulated the expression of intercellular adhesion molecule-1 (ICAM-1) in the porcine coronary arterial endothelium. These effects of Ox-LDL were not mediated by the scavenger-receptor-mediated process but were attributed to lysoPC in Ox-LDL. Blocking of the PMN adherence to endothelium by using anti-CD18 monoclonal antibody abolished the PMN-induced impairment of EDR. Coincubation with staurosporine or calphostin C, inhibitors of PKC, during treatment of the arteries with Ox-LDL or lysoPC attenuated the augmentative effects of Ox-LDL and lysoPC on endothelial ICAM-1 expression, endothelial adhesiveness to PMNs, and PMN-induced EDR impairment. Treatment of the arteries with phorbol 12-myristate 13-acetate, a potent stimulator of PKC, induced ICAM-1 expression and enhanced the endothelial adhesiveness to PMNs and PMN-induced EDR impairment, mimicking the effects of Ox-LDL. These results suggest that lysoPC in Ox-LDL induces endothelial ICAM-1 expression, which facilitates PMN adherence to endothelium and the subsequent augmentation of PMN-induced EDR impairment. PKC activation in endothelial cells by lysoPC in Ox-LDL may at least in part be involved in these effects of Ox-LDL. LysoPC in Ox-LDL increases endothelial susceptibility to PMN-induced endothelial dysfunction.
 ...
PMID:Lysophosphatidylcholine in oxidized low-density lipoprotein increases endothelial susceptibility to polymorphonuclear leukocyte-induced endothelial dysfunction in porcine coronary arteries. Role of protein kinase C. 813 94

Recent evidence suggests that phospholipase A2 (PLA2)-derived lipid mediators may regulate a number of neutrophil responses including degranulation and adhesion. In view of the potential role of PLA2 in stimulus-secretion coupling, we examined the relationship between PLA2 activation and the surface expression of CD11b/CD18 (MAC-1) in human polymorphonuclear leukocytes (hPMNL), including the functional consequences of PLA2 inactivation on MAC-1-dependent adhesion. The selective inhibition of PLA2 by the marine natural products manoalide (MLD) and scalaradial (SLD) blocks [3H]arachidonic acid (AA) release in calcium ionophore A23187-stimulated neutrophils, and also inhibits secretion of specific and azurophilic granule constituents. Additional studies demonstrate that MLD, SLD, and other less potent PLA2 inhibitors such as 4-bromophenacylbromide and nordihydroguiaretic acid inhibit the surface expression of MAC-1 (IC50: MLD, 0.33 microM; SLD, 0.23 microM; 4-bromophenacylbromide, 2.8 microM; NDGA, 3.5 microM) at concentrations similar to those at which they inhibit [3H]AA release. Inhibitors of cyclooxygenase, 5-lipoxygenase, protein kinase C, or calcium channel antagonists have no effect on MAC-1 expression. PLA2 inactivation also prevents MAC-1 up-regulation in hPMNL stimulated with FMLP, IL-8, TNF-alpha, PMA, or platelet activating factor. In FMLP-stimulated hPMNL, under conditions in which no secondary granule constituents are secreted, MAC-1 and alkaline phosphatase up-regulation from intracellular granules is inhibited by MLD and SLD. Functional assays also demonstrate that MLD and SLD block MAC-1-dependent adhesion of activated neutrophils to keyhole limpet hemocyanin at concentrations that block the surface expression of MAC-1. [3H]AA release and MAC-1 expression in MLD and SLD-treated hPMNL could be recovered in the presence of 1 mM hydroxylamine in a time-dependent fashion, consistent with reported data that MLD and SLD inactivate PLA2 through Schiff base formation. In summary, these data emphasize the role of PLA2 as a key regulator of MAC-1 expression in models of neutrophil adhesion.
 ...
PMID:Regulation of CD11b/CD18 expression in human neutrophils by phospholipase A2. 822 53

CD53 is a member of a novel family of molecules with four presumably membrane-spanning domains. The structure and functional characteristics of these molecules indicate that they may play an important role in transmembrane communication. We therefore investigated whether CD53 is involved in activation of human leukocytes. Cross-linking of cell-bound F(ab')2 fragments of two different anti-CD53 mAb with F(ab')2 anti-mouse Ig led to cytoplasmic calcium fluxes in B cells, monocytes, and granulocytes and activation of the monocyte oxidative burst. These responses were specific for CD53, as cross-linking of CD11a, CD18, CD35, CD43, CD44, CD45, or CDw50 did not induce leukocyte activation. Low concentrations of staurosporine (10 to 20 nM) completely inhibited PMA-mediated activation, but had no effect on CD53-mediated calcium fluxes and inhibited only partially CD53-mediated oxidative burst. This suggests that CD53-mediated signaling is largely independent of protein kinase C. CD53-mediated calcium fluxes were inhibited by high concentrations of staurosporine (300 to 500 nM) but not by ADP-ribosylating toxins, suggesting dependence on tyrosine kinases rather than GTP-binding proteins. The results indicate that CD53, like several other leukocyte Ag with four membrane-spanning regions, has the ability to mediate cell activation, and support the view that these molecules are involved in transmembrane communication.
 ...
PMID:CD53, a protein with four membrane-spanning domains, mediates signal transduction in human monocytes and B cells. 833 5


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>