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)

Intercellular adhesion molecule 1 (ICAM-1) is a proinflammatory adhesion glycoprotein induced by cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) as well as lipopolysaccharide (LPS). Little is known, however, concerning the intracellular regulatory mechanisms that modulate ICAM-1 expression in endothelial cells. We probed the involvement of protein kinase function and intracellular calcium ion upon ICAM-1 expression of human umbilical vein endothelial cells activated alternatively by TNF-alpha, IL-1 beta, LPS, or phorbol 12-myristate 13-acetate (PMA). Methodologies for the detection of ICAM-1 included both enzyme-linked immunosorbent assay and immunoprecipitation from biosynthetically labeled cells. The protein kinase inhibitor H-7 blocked induction of ICAM-1 by all of the activators; nonlinear regression analysis revealed 50% inhibitory concentration (IC50) values of 6-10 microM. Another kinase inhibitor, HA1004, did not block expression of the adhesion molecule at concentrations up to 50 microM. In contrast, the kinase inhibitor staurosporine dose dependently inhibited ICAM-1 expression triggered by PMA (IC50 67 +/- 4 nM) but, at similar concentrations, did not inhibit ICAM-1 expression induced by the other inflammatory stimuli. The divalent cation ionophore ionomycin (0.5 microM) interacted synergistically with PMA but not with cytokines or LPS in upregulating ICAM-1. We conclude from these data that although PMA-induced ICAM-1 expression may be triggered through activation of protein kinase C, ICAM-1 induction by IL-1 beta, TNF-alpha, or LPS may involve distinct regulatory pathway(s).
 ...
PMID:Discriminatory effects of protein kinase inhibitors and calcium ionophore on endothelial ICAM-1 induction. 134 98

Keratinocyte intercellular adhesion molecule (ICAM)-I expression is induced by interferon (IFN)-gamma. It has been previously reported that IFN-beta suppresses IFN-gamma-induced ICAM-I expression in A431 cells, a human squamous cell carcinoma cell line. In this study, the suppression mechanisms were investigated at the post second messenger level. Both 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium ionophore (A23187) induce ICAM-I expression in A431 cells. ICAM-I expression induced by either was not suppressed with cotreatment with IFN-beta. Furthermore, IFN-beta did not inhibit the translocation of protein kinase C (PKC) by TPA. It appears that the pathways involved in ICAM-I expression induced by activation of PKC or increased in intracellular Ca++ are not affected by IFN-beta.
 ...
PMID:The effects of interferon-beta on phorbol ester or calcium ionophore-induced intercellular adhesion molecule-I expression in epidermal carcinoma cells. 135 13

Directed migration of lymphocytes from blood into lymph nodes and gut-associated lymphatic tissue, also referred to as homing, is subject to change following activation. Lymphocyte migration into lymphoid organs in vivo and binding to high endothelial venules in vitro is largely suppressed after short-term stimulation with phorbol esters. The observed functional alterations were correlated with changes in the expression of three putative homing receptors, LECAM-1 (MEL-14 antigen), LPAM-1/2 (alpha 4-integrin) and the murine CD44 (Pgp-1, H-CAM, Hermes-antigen equivalent) upon different modes of cellular activation. Expression of LECAM-1 (gp90 MEL-14), a lymphocyte adhesion molecule implicated in targeting extravasation into lymph nodes, was found to be lost almost completely within minutes after protein kinase C activation. LECAM-1 re-expression occurred within less than 24 h. Rapid loss of LECAM-1 was also observed after calcium ionophores whereas anti-CD3 or concanavalin A elicited a gradual and heterogeneous loss of LECAM-1 becoming detectable after several hours only. A number of cytokines tested were not able to induce alterations in LECAM-1 expression. In contrast, expression of LPAM-1/2 (alpha 4-integrin) and CD44 (Pgp-1, H-CAM), two adhesion molecules supposed to direct extravasation into Peyer's patches, remained stable for hours after every stimulus tested; CD44 expression gradually increased 24 h after mitogenic activation, whereas a small reduction only was observed for the expression of the alpha 4-chain under certain conditions. Thus, reduced extravasation of lymphocytes into Peyer's patches after activation is not due to a decline in the surface density of LPAM-1/2 alpha-chain or CD44 whereas alterations in migration into lymph nodes parallel the expression of LECAM-1.
 ...
PMID:Lymphocyte activation and regulation of three adhesion molecules with supposed function in homing: LECAM-1 (MEL-14 antigen), LPAM-1/2 (alpha 4-integrin) and CD44 (Pgp-1). 137 Aug 69

The role of protein kinase C (PKC) in TNF alpha-induced activation of endothelial adhesion molecules ICAM-1 and VCAM-1 was analysed. Phorbol myristate acetate, which is known to activate PKC, was able to mimic TNF alpha-induced up-regulation of ICAM-1 and partly also VCAM-1 expression. Similarly a PKC inhibitor, H7, but not another kinase inhibitor, HA1004, inhibited TNF alpha-induced enhancement of ICAM-1 expression at both the mRNA and the protein level. Moreover we were able to measure a transient PKC activation peak at 16 min after TNF alpha induction in endothelial cells analysed by phorbol-dibutyrate binding. These results indicate that the TNF alpha-induced effect on the regulation of endothelial adhesion molecule expression is at least partly mediated by PKC activation.
 ...
PMID:TNF alpha-induced expression of endothelial adhesion molecules, ICAM-1 and VCAM-1, is linked to protein kinase C activation. 138 Jan 76

Leukocyte adherence to endothelium is in part mediated by the transient expression of endothelial-leukocyte adhesion molecule 1 (ELAM-1) on endothelial surfaces stimulated by tumor necrosis factor alpha (TNF), interleukin (IL) 1, or bacterial lipopolysaccharide (LPS). The intracellular factors controlling induction of ELAM-1 mRNA and protein are unknown. In nuclear runoff experiments with cultured human umbilical vein endothelial cells (HUVEC), we demonstrate that transcriptional activation of the ELAM-1 gene occurs following stimulation with TNF. Sequence analysis of the 5' flanking region of the ELAM-1 gene reveals consensus DNA-binding sequences for two known transcription factors, NF-kappa B and AP-1. Gel mobility shift assays demonstrate that TNF, IL-1, or LPS (but not IL-2, IL-4, IL-6, interferon gamma, histamine, or transforming growth factor beta) induces activation of NF-kappa B-like DNA binding activity in HUVEC. In contrast, neither TNF, IL-1, nor LPS activates proteins that bind to an AP-1 consensus sequence under these experimental conditions. Phorbol 12-myristate 13-acetate, a known activator of protein kinase C (PKC), weakly induces NF-kappa B-like activity, ELAM-1 mRNA, and ELAM-1 surface expression in HUVEC. However, TNF, IL-1, and LPS do not activate PKC in HUVEC at doses that strongly induce NF-kappa B-like protein activation and ELAM-1 gene expression. PKC blockade with H7 does not inhibit activation of these NF-kappa B-like proteins but does inhibit ELAM-1 gene transcription. We conclude that PKC-independent activation of NF-kappa B in HUVEC with TNF, IL-1, or LPS is associated with, but not sufficient for, activation of ELAM-1 gene transcription.
 ...
PMID:Activation of endothelial-leukocyte adhesion molecule 1 (ELAM-1) gene transcription. 171 80

The characteristics of homotypic neutrophil aggregation, mediated by the adhesion molecule CD11b/CD18, differ according to whether activation takes place via intracellular protein kinase C(PKC) inducers or chemoattractants. In response to diacylglycerol (DAG) analogues such as PMA and 1,2-dioctanoyl-sn-glycerol, a prolonged cellular aggregation occurs that is associated with intense phosphorylation of the CD18 beta-chain. In response to the chemoattractant FMLP, a more transient aggregation event results that is associated with minimal beta-chain phosphorylation. By using the PKC inhibitor staurosporine, we now show that these differences are likely to reflect two different pathways of activation. Both aggregation and phosphorylation induced by DAG analogues are completely abolished by staurosporine in a parallel dose-dependent manner. Conversely, FMLP-induced aggregation is enhanced and prolonged by staurosporine whereas the associated minimal phosphorylation event is further diminished by staurosporine. Accordingly, activation of neutrophil aggregation by DAG analogues is associated with and presumably due to phosphorylation of the CD18 beta-chain. This intense phosphorylation occurs via a staurosporine-sensitive kinase such as PKC. FMLP, on the other hand, appears to activate CD11b/CD18 by a distinct mechanism. This latter mechanism does not seem to be dependent on what may be a minor PKC-induced phosphorylation of the beta-chain, and indeed is enhanced by inhibition of PKC. Of note, staurosporine was also found to cause selective release of specific granules with concomitant increase in surface display of CD11b/CD18. These data further support previous observations that up-regulation of this adhesive molecule is not the primary event in the induction of cellular adhesiveness.
 ...
PMID:Two pathways of CD11b/CD18-mediated neutrophil aggregation with different involvement of protein kinase C-dependent phosphorylation. 197 98

ICAM-1 (CD54) is expressed on endothelial cells and serves as an important ligand for the white cell adhesion molecule CD11a/CD18 (LFA-1). Many studies have demonstrated that increased numbers of white cells binding to endothelial cells correlate with the level of ICAM-1 expression on endothelial cells. Several cytokines, including IFN-gamma, increase ICAM-1 expression in cultured human endothelial cells. We have analysed the second intracellular messenger pathways involved in IFN-gamma-induced up-regulation of ICAM-1 expression in endothelial cells. IFN-gamma induced a rapid activation of phospholipase C, leading to a breakdown of phosphoinositoldiphosphate (PIP2) into diacyglycerol (DAG) and inositoltriphosphate (IP3). DAG is a natural activator of the protein kinase C pathway. We were able to show that the effect induced by IFN-gamma could be inhibited by a protein kinase C inhibitor, H7, in a dose-dependent manner and mimicked by PMA, which stimulates protein kinase C. IFN-gamma induced a 5-fold translocation (activation) of protein kinase C from the cytosol into the endothelial cell membrane. Elevation of the IP3 levels led to activation of the calcium-dependent pathway. An inhibitor of calcium calmodulin, W7, decreased the IFN-gamma induced ICAM-1 expression, and addition of calcium ionophore to endothelial cells could replace IFN-gamma in the up-regulation of ICAM-1. Finally, IFN-gamma caused a significant increase in the calcium flux of endothelial cells. cAMP and cGMP had no effect on the regulation of ICAM-1 expression on cultured human endothelial cells.
 ...
PMID:Activation of protein kinase C is crucial in the regulation of ICAM-1 expression on endothelial cells by interferon-gamma. 198 67

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) increases neutrophil surface expression of the cellular adhesion molecule CD11b and primes the respiratory burst stimulated by the bacterial peptide f-met-leuphe (FMLP). We have examined the effects of the isoquinolinesulfonamide protein kinase inhibitors H7 and H8 on these functions of GM-CSF using whole blood assays. Concentrations of H7 and H8 that inhibited the 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulated upregulation of CD11b expression and activation of the respiratory burst, both augmented the effects of GM-CSF. H7 and H8 enhanced the GM-CSF-stimulated increase in CD11b expression to 215% +/- 10% (P less than .05) and 233% +/- 45% (P less than .05), respectively, of the value obtained with GM-CSF alone. The GM-CSF priming of the FMLP-stimulated oxidative burst was increased to 190% +/- 44% (P less than .01) by preincubation with H7 and to 172% +/- 25% (P less than .01) with H8. Preincubation with H8 did not affect overall binding of 125I-GM-CSF to neutrophils, but inhibited GM-CSF receptor internalization after ligand binding (P less than .05). These data indicate that the effects of GM-CSF are not mediated by protein kinase C and that a phosphorylation event down-modulates the neutrophil response to GM-CSF. It suggests that internalization of the receptor-ligand complex is not a rate-limiting step in signal transduction, and that regulation of the rate of internalization may be an important level of control of the activity of GM-CSF.
 ...
PMID:Isoquinolinesulfonamide protein kinase inhibitors H7 and H8 enhance the effects of granulocyte-macrophage colony-stimulating factor (GM-CSE) on neutrophil function and inhibit GM-CSF receptor internalization. 216 26

The neural cell-adhesion molecule (N-CAM) is detected as at least 3 related polypeptides generated by alternative splicing of a single gene. In vivo the 2 larger polypeptides are phosphorylated, but the smallest polypeptide, which lacks a cytoplasmic domain, is not. We have found that the 2 larger polypeptides are phosphorylated in vivo on several common phosphorylation sites. Furthermore, the largest polypeptide has additional sites, suggesting that some phosphorylation occurs in that portion of the intracellular region unique to it. In vitro N-CAM is not a substrate for cyclic AMP-dependent protein kinase, cyclic GMP-dependent protein kinase, calcium/calmodulin-dependent protein kinase I, II, or III, protein kinase C, or casein kinase II. However, we have isolated 2 protein kinases from mammalian and avian brain that phosphorylate rodent and chicken N-CAM. On the basis of their chromatographic behavior and substrate specificity, the 2 kinases are glycogen synthase kinase 3 (GSK-3) and casein kinase I (CK I). The 2 kinases phosphorylate N-CAM rapidly, to a high stoichiometry and with a low Km for N-CAM, suggesting that the phosphorylation of N-CAM by these kinases is physiologically relevant. Both enzymes phosphorylate the 2 larger N-CAM polypeptides in vitro in the cytoplasmic domain on threonyl residues that are phosphorylated to a low level in vivo. In addition, the threonyl residues are close to seryl residues phosphorylated to a high level in vivo. Prior phosphorylation at the in vivo sites appears to be a prerequisite for phosphorylation by GSK-3 and CK I. Taken together, the results suggest that N-CAM may be physiologically phosphorylated on 2 sets of interrelated sites, one demonstrable in vivo and one in vitro. Phosphorylation on the "in vivo" sites is resistant to dephosphorylation and may be constitutive, while phosphorylation on the "in vitro" sites is much more labile.
 ...
PMID:Identification of two protein kinases that phosphorylate the neural cell-adhesion molecule, N-CAM. 254 81

Treatment of U-937 GTB cells with tumor-promoting phorbol esters induced adherence of the cells to plastic, with a t1/2 of 20 min. The ED50 was determined to 3.3 nM for phorbol-12,13-dibutyrate and 0.3 nM for 12-O-tetradecanoyl-4 beta-phorbol-13-acetate, whereas the non-tumor-promoting analogue 12-O-tetradecanoyl-4 alpha-phorbol-13-acetate was ineffective at concentrations up to 100 nM. The adherence process showed characteristics typical of leucocyte adhesion and was inhibited by a monoclonal antibody to the leucocyte adhesion molecule CD18. The sublines of U-937, RES and RESREV made resistant to the action of low doses of phorbol ester regarding inhibition of DNA synthesis and containing lower levels of protein kinase C compared to U-937 GTB, were desensitized with respect to the adhesion response. Translocation of protein kinase C from cytosol to the particulate fraction occurred at about 10-fold higher concentrations of phorbol ester than the adhesion response in U-937 GTB cells, under otherwise similar conditions, whereas no difference in sensitivity was observed between the sublines. Also phorbol ester stimulation of choline incorporation into lipids exhibited lower sensitivity compared to the adhesion response with no difference observed between the various cell lines. The results indicate that CD18-dependent adhesion, like DNA synthesis, is controlled by phorbol esters in a manner unrelated to the translocation of protein kinase C and that the control mechanism might involve forms of protein kinase C which are subject to stable down-modulation following TPA adaption of the cells.
 ...
PMID:Evidence for separate control by phorbol esters of CD18-dependent adhesion and translocation of protein kinase C in U-937 cells. 316 72


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