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)

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).
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PMID:Discriminatory effects of protein kinase inhibitors and calcium ionophore on endothelial ICAM-1 induction. 134 98

There is growing evidence that keratinocyte (KC) intercellular adhesion molecule-I (ICAM-I) expression is involved in the epidermal trafficking of T lymphocytes. To further characterize the molecular basis of KC ICAM-I expression, the detailed kinetics of induction by gamma interferon (IFN-gamma), as well as the phorbol ester, 12-O tetradecanoylphorbol-13-acetate (TPA), were studied. This study reports that KCs express both the class II major histocompatibility antigen (HLA-DR) and ICAM-I in response to IFN-gamma, although the response is distinctive for each molecule. Also, TPA induces ICAM-I, but not HLA-DR expression, whilst the protein kinase inhibitor, H7, blocks the TPA, but not the IFN-gamma-mediated response. The results provide a molecular basis whereby non-cytokine-mediated stimuli (e.g. TPA) alter KC signal transduction events involving protein kinase-C (PK-C) and thereby generate such immunologically relevant events as ICAM-I expression. Thus, KCs may be targets for both T-cell derived cytokines (e.g. IFN-gamma), and non-cytokine TPA-like molecules which stimulate PK-C. Induction of ICAM-I by either mechanism would be capable of instigating intraepidermal T-cell trafficking.
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PMID:Differential modulation of keratinocyte intercellular adhesion molecule-I expression by gamma interferon and phorbol ester: evidence for involvement of protein kinase C signal transduction. 196 46

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.
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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.
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PMID:Identification of two protein kinases that phosphorylate the neural cell-adhesion molecule, N-CAM. 254 81

Leukocyte recruitment is a key step in the inflammatory reaction. Several changes in the cell morphology take place during lymphocyte activation and migration: spheric-shaped resting T cells become polarized during activation, developing a well defined cytoplasmic projection designated as cellular uropod. We found that the chemotactic and proinflammatory chemokines RANTES, MCP-1, and, to a lower extent, MIP-1 alpha, MIP-1 beta, and IL-8, were able to induce uropod formation and ICAM-3 redistribution in T lymphoblasts adhered to ICAM-1 or VCAM-1. A similar chemokine-mediated effect was observed during T cells binding to the fibronectin fragments of 38- and 80-kD, that contain the binding sites for the integrins VLA-4 and VLA-5, respectively. The uropod structure concentrated the ICAM-3 adhesion molecule (a ligand for LFA-1), and emerged to the outer milieu from the area of contact between lymphocyte and protein ligands. In addition, we found that other adhesion molecules such as ICAM-1, CD43, and CD44, also redistributed to the lymphocyte uropod upon RANTES stimulation, whereas a wide number of other cell surface receptors did not redistribute. Chemokines displayed a selective effect among different T cell subsets; MIP-1 beta had more potent action on CD8+ T cells and tumor infiltrating lymphocytes (TIL), whereas RANTES and MIP-1 alpha targeted selectively CD4+ T cells. We have also examined the involvement of cAMP signaling pathway in uropod formation. Interestingly, several cAMP agonists were able to induce uropod formation and ICAM-3 redistribution, whereas H-89, a specific inhibitor of the cAMP-dependent protein kinase, abrogated the chemokine-mediated uropod formation, thus pointing out a role for cAMP-dependent signaling in the development of this cytoplasmic projection. Since the lymphocyte uropod induced by chemokines was completely abrogated by Bordetella pertussis toxin, the formation of this membrane projection appears to be dependent on G proteins signaling pathways. In addition, the involvement of myosin-based cytoskeleton in uropod formation and ICAM-3 redistribution in response to chemokines was suggested by the prevention of this phenomenon with the myosin-disrupting agent butanedione monoxime. Interestingly, this agent also inhibited the ICAM-3-mediated cell aggregation, but not the cell adhesion to substrata. Altogether, these results demonstrate that uropod formation and adhesion receptor redistribution is a novel function mediated by chemokines; this phenomenon may represent a mechanism that significantly contributes to the recruitment of circulating leukocytes to inflammatory foci.
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PMID:Chemokines regulate cellular polarization and adhesion receptor redistribution during lymphocyte interaction with endothelium and extracellular matrix. Involvement of cAMP signaling pathway. 759 74

Monocyte adherence to the endothelium, their penetration to the subendothelial space and excessive lipid accumulation (foam cell formation) are the initial events in atherogenesis. Scavenger receptors have been reported to play an important role in foam cell formation, since modified low density lipoproteins can be taken up via scavenger receptors in a non-down-regulated fashion. In this study we demonstrate that stimulation of scavenger receptors in endothelial cells induces the expression of endothelial adhesion molecules. Polyinosinic acid (poly I), a known scavenger receptor ligand, significantly induced the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on human umbilical vein endothelial cells when compared with polycytidylic acid (poly C), a structurally related compound to poly I, which does not bind to the scavenger receptor. The effect of scavenger receptor ligands on the endothelial cell line EA hy. 926 was also tested. Poly I up-regulated ICAM-1 expression also on EA hy. 926 cells, while it had no effect on IL-1 beta or tumour necrosis factor-alpha (TNF-alpha) production on the same cell line. Poly I-induced ICAM-1 expression on EA hy. 926 cells could be inhibited by H7, a protein kinase C inhibitor, while HA 1004, a preferential protein kinase A inhibitor, had no effect on ICAM-1 expression. The role of protein kinase C in scavenger receptor-mediated adhesion molecule upregulation was confirmed by the ability of poly I to directly activate protein kinase C, when measured with 3H-phorbol dibutyrate binding to EA hy. 926 cells, while poly C again was ineffective.
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PMID:Regulation of endothelial adhesion molecules by ligands binding to the scavenger receptor. 768 91

IL-4 and TNF-alpha increase endothelial cell adhesiveness for PBL by promoting the expression of adhesion molecules. We investigated the intracellular cAMP involvement in the increased endothelial cell adhesivity induced by IL-4 or TNF-alpha. We showed that both IL-4 and TNF-alpha increased intracellular cAMP in endothelial cells (EC). Furthermore, dibutyryl-cAMP and forskolin (which increased intracellular cAMP) increased basic EC adhesivity for PBL. The co-stimulation of EC with cAMP elevating agents and TNF-alpha, but not IL-4, resulted in an additive increase in EC adhesiveness. 2',5' dideoxyadenosine, an inhibitor of adenylate cyclase, decreased PBL adhesion to IL-4- but not TNF-alpha-treated EC. Similarly, HA1004, a protein kinase A inhibitor, totally reversed the IL-4 but not TNF-alpha effect on EC adhesiveness, whereas H7, a protein kinase C inhibitor, did not antagonise cytokine-enhanced EC adhesivity. These results indicate that IL-4, but not TNF-alpha, uses a cAMP-dependent pathway to increase PBL adhesion. Furthermore, we showed that cAMP elevation in EC did not induce vascular cell adhesion molecule 1, the only identified adhesion molecule induced by IL-4, indicating that a rise in cAMP in EC promotes an as yet unidentified adhesion pathway. Our results show that IL-4 increases EC adhesiveness for PBL through activation of protein kinase A by promoting an unidentified adhesion pathway.
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PMID:IL-4, but not tumor necrosis factor-alpha, increases endothelial cell adhesiveness for lymphocytes by activating a cAMP-dependent pathway. 768 17

FMRFamide evokes long-term inhibition of the sensorimotor connection of Aplysia that includes structural alterations in the presynaptic sensory cell. FMRFamide also evokes a down-regulation of the adhesion molecule apCAM from the surface of the postsynaptic motor cell L7. We examined the second messenger pathways mediating the long-term actions of FMRFamide on both the pre- and postsynaptic cells and determined whether the activation of each pathway is required for the expression of long-term functional and structural plasticity. Inhibition of the lipoxygenase pathway of arachidonic acid metabolism, but not the cyclooxygenase pathway, blocks the long-term changes in the presynaptic sensory cell evoked by FMRFamide. The down-regulation of apCAM in L7 appears to be mediated by cAMP-dependent activation of protein kinase A. Blocking the cAMP-dependent changes also blocks FMRFamide-induced long-term functional and structural changes. These results suggest that the expression of long-term heterosynaptic inhibition in Aplysia may require concomitant presynaptic and postsynaptic changes, each transduced by specific second messenger systems.
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PMID:Pre- and postsynaptic changes mediated by two second messengers contribute to expression of Aplysia long-term heterosynaptic inhibition. 790 29

The effect of angiopeptin, a stable analogue of somatostatin, was studied on basal and interleukin-1-beta-induced endothelial cell adhesiveness for mononuclear cells, and compared to the effect of somatostatin. Angiopeptin and somatostatin decreased basal and interleukin-1-beta-induced endothelial cell adhesiveness for mononuclear cells. The decreased mononuclear cells adhesion to endothelial cells exposed to angiopeptin and somatostatin is not due to modulation of the expression of intrecellular adhesion molecule-1 because neither angiopeptin nor somatostatin decreased basal and interleukin-1-beta-induced expression of this adhesion molecule. The effect of angiopeptin in inhibiting endothelial cell adhesiveness for mononuclear cells was abolished by addition of dibutyryl-cyclic AMP. Angiopeptin induced a transient decrease in basal and interleukin-1-beta-induced cyclic AMP levels in endothelial cells. Exposure of unstimulated and interleukin-1-beta-activated endothelial cells to KT5720, a specific inhibitor of cyclic AMP-dependent protein kinase, decreased endothelial cell adhesiveness for mononuclear cells. Thus, angiopeptin most likely diminishes endothelial adhesiveness for mononuclear cells by affecting the cyclic AMP-dependent protein kinase signal transduction pathway. The findings suggest that angiopeptin and somatostatin may modify the development of the immune response by attenuating endothelial cell adhesiveness for mononuclear cells. Angiopeptin may have a potential clinical application as a modulator of some aspects of the immune response due to its long half-life and prolonged inhibitory effect on interleukin-1-beta induced endothelial adhesiveness for mononuclear cells.
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PMID:Angiopeptin, the octapeptide analogue of somatostatin, decreases rat heart endothelial cell adhesiveness for mononuclear cells. 809 98

Rat lymphocytes were found to aggregate in response to monoclonal antibodies to the glycosyl phosphatidylinositol (GPI)-anchored surface antigen CD48. This clustering required bivalent antibodies but was not Fc mediated. It was blocked by inhibitors of cellular metabolism and cytoskeletal function but not by antibodies to leucocyte function-associated antigen-1 (LFA-1) or intracellular adhesion molecule-1 (ICAM-1). The clusters were found to be due to homotypic adhesion of B cells, with T cells showing no response despite expressing equal levels of CD48. In addition, thymocytes, which are known to cluster in response to cross-linking of Thy-1, another GPI-anchored molecule, were found not to respond to cross-linking of CD48. These results suggest that specific signalling through CD48 in B cells, but not T cells, and through Thy-1, but not CD48, in thymocytes, lead to cell adhesion events. This differential signalling is interesting as neither CD48 nor Thy-1 have transmembrane or intracellular domains. Levels of CD48-associated protein kinase activity were very low in both B and T cells, and no difference in the susceptibility to cleavage with phosphatidylinositol-specific phospholipase C was detected between B- and T-cell CD48.
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PMID:Homotypic adhesion of rat B cells, but not T cells, in response to cross-linking of CD48. 813 6


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