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

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of tumor necrosis factor (TNF)-alpha signaling is unknown. TNF-alpha signaling may involve sphingomyelin hydrolysis to ceramide by a sphingomyelinase and stimulation of a ceramide-activated protein kinase. In a cell-free system, TNF-alpha induced a rapid reduction in membrane sphingomyelin content and a quantitative elevation in ceramide concentrations. Ceramide-activated protein kinase activity also increased. Kinase activation was mimicked by addition of sphingomyelinase but not by phospholipases A2, C, or D. Reconstitution of this cascade in a cell-free system demonstrates tight coupling to the receptor, suggesting this is a signal transduction pathway for TNF-alpha.
...
PMID:Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. 131 89

We investigated the relationship of polymorphonuclear leukocyte (PMN) candicidal activity, matrix proteins, and lipopolysaccharide (LPS) to determine how LPS modulates the normal enhancing effect of matrix proteins on PMN candicidal activity. LPS reduced PMN candicidal activity when PMN were adhered in the presence of either fibronectin or laminin. In the presence of fibronectin or laminin, LPS reduced CD11b/CD18 expression (the fibronectin receptor) as assessed using sheep erythrocytes coated with C3bi. Experiments with 125I-fibronectin and 125I-RGDS (Arg-Gly-Asp-Ser) demonstrated that LPS reduced both the binding of fibronectin and the bioavailability of the binding epitope on the PMN surface. Stimulating the PMN oxidative burst with PMA but not FMLP also reduced fibronectin and RGDS binding. Incubation of LPS-treated PMN with staurosporine blocked the decrease in fibronectin and RGDS binding. Exposure of PMN to LPS plus low-dose TNF-alpha restored both fibronectin and RGDS binding with a concomitant increase in CD11b/CD18 surface expression. Low-dose TNF-alpha restored PMN candicidal activity in the presence of LPS and was most effective if PMN were preadhered to fibronectin. These results demonstrate that: (1) matrix proteins enhance normal PMN candicidal activity, (2) LPS reduces PMN candicidal activity in the presence of matrix proteins, (3) stimulation of the PMN oxidative burst in particular via protein kinase c activation reduces the bioavailability of the fibronectin receptor, and (4) low-dose TNF-alpha may restore PMN candicidal activity in part by upregulating the surface receptor for fibronectin binding.
...
PMID:Endotoxin suppresses matrix protein-induced upregulation of PMN candicidal activity: an effect reversed by low-dose TNF-alpha. 161 18

This study analyzes the expression of monocyte chemoattractant protein-1 (MCP-1) by inflamed synovial tissue and defines its regulation in cultured synoviocytes. Synoviocytes from patients with rheumatoid arthritis and osteoarthritis express the 0.7-kb MCP-1 mRNA. Stimulation of synoviocytes with IL-1, TNF-alpha, LPS, platelet-derived growth factor, and transforming growth factor-beta-1, but not with basic fibroblast growth factor causes a marked increase in MCP-1 mRNA levels. Expression of the MCP-1 gene is inducible by activators of the protein kinase A (cAMP) and C (PMA) signal transduction pathways and is differentially regulated by the steroids dexamethasone and retinoic acid. Cultured synoviocytes de novo synthesize 12-, 15-, and 15.2-kDa MCP-1 proteins, which increase after stimulation with IL-1. Synovial tissues from donors without joint disease and from patients with rheumatoid or osteoarthritis were analyzed for MCP-1 mRNA expression by in situ hybridization. In these samples MCP-1 mRNA expressing cells were predominantly found in the sublining cell layers, whereas specimens of normal synovial tissue contained only few positive cells. These results identify synoviocytes as a source of MCP-1. Its expression is controlled by peptide regulatory factors that are known to be present in arthritic joints. Detection of cells producing MCP-1 mRNA in synovial tissues from patients with arthritis shows that this gene is expressed in vivo and suggests that MCP-1 can play a role in recruiting monocytes in joint inflammation.
...
PMID:Production of monocyte chemoattractant protein-1 by inflamed synovial tissue and cultured synoviocytes. 162 9

High resolution two-dimensional gel electrophoresis was used to analyze the signal transduction pathways of tumor necrosis factor (TNF-alpha) and interleukin 1 (IL-1 alpha and -beta) in human fibroblasts. Approximately 450 discrete radioactive spots were electrophoretically resolved from cytosolic extracts of cells prelabeled with 32P. At least 63 of these polypeptides exhibited significant and concordant phosphorylation or dephosphorylation in response to TNF or IL-1, despite the fact that different receptors are involved. Most of these changes concerned serine/threonine residues although enhanced tyrosine phosphorylation of several polypeptides was also observed. Phosphorylation patterns induced by a number of other agonists were compared with the patterns induced by IL-1 and TNF. These included activators of protein kinases C and A, bradykinin (a stimulator of inositol phospholipid hydrolysis), epidermal growth factor, heatshock, and mellitin (an activator of phospholipase A2). Although each of these agonists induced changes resulting in a distinct pattern of protein phosphorylation, none of these patterns had significant homology with that induced by IL-1 and TNF. Other assays were performed to verify the involvement of specific kinases. Collectively, these data indicate that IL-1 and TNF activate multiple protein kinases viz. a kinase(s) which activates microtubule-associated protein 2 (MAP-2) kinase, a kinase that phosphorylates the cap-binding protein, and a possibly novel serine/threonine protein kinase.
...
PMID:Interleukin 1 and tumor necrosis factor activate common multiple protein kinases in human fibroblasts. 165 Mar 57

Medium conditioned by mouse peritoneal macrophages, activated by muramyl dipeptide (MDP), was used as a possible source of p185neu-specific ligand. MDP-activated macrophage-conditioned medium (MDP-CM) was shown to induce p185neu down-regulation in NEU-expressing NIH3T3 cells in a dose-dependent and temperature-sensitive manner. To exclude the possibility of an indirect action of proteins/metabolites present in MDP-CM on p185neu turnover, a ligand-trapping approach was used. Secreted NEU protein possessing only the extracellular domain but lacking transmembrane and protein kinase domains was expressed in HeLa cells and then purified from conditioned medium, using affinity chromatography on WGA-Sepharose. Co-incubation of the truncated, soluble NEU protein preparation with MDP-CM abolished MDP-CM-induced p185neu down-regulation and reduced self-phosphorylation. It is concluded that a putative p185neu-specific ligand is produced by macrophages activated by MDP. Using MDP-CM, the presence of a 25 kDa polypeptide distinct from EGF, PDGF, FGF, IGF, TGF-alpha and TGF-beta and TNF-alpha, could be demonstrated by decorating a Western blot with soluble NEU and anti-NEU antibodies. Thus, a 25 kDa (non-reduced) p185neu ligand has been described.
...
PMID:A 25 kDa polypeptide is the ligand for p185neu and is secreted by activated macrophages. 168 16

Nuclear factor kappa-B (NF-kappa B) has been shown to play an important role in LPS-mediated induction of several genes in macrophages. Several studies have implicated protein kinase C (PKC) or cAMP-dependent protein kinase in the regulation of NF-kappa B activity. In this study we have investigated the mechanism of NF-kappa B induction in murine macrophages. A chloramphenicol acetyl transferase (CAT) expression vector containing multiple copies of the TNF-alpha NF-kappa B element was transfected into the RAW264 macrophage-like cell line and assessed for inducible CAT activity. LPS treatment of the transfected cells resulted in a significant induction of CAT activity. CAT activity was not induced by treatment with phorbol myristate acetate (PMA) or the cAMP analogue 8-bromo cAMP. To further study NF-kappa B induction, nuclear extracts were prepared from RAW264 cells. Extracts from RAW264 cells that were treated from 30 min to 2 hr with LPS had a significant increase in NF-kappa B binding activity as determined by the electrophoresis mobility shift assay (EMSA). Treatment of these cells from 30 min to 2 hr with PMA did not result in such binding activity. U.V. crosslinking analysis of the DNA-binding activity confirmed these results and indicated that LPS induced a 55 KD DNA-binding protein. Induction of this NF-kappa B binding activity was not inhibited by pretreatment with the PKC inhibitor H-7. H-7 did inhibit induction of TPA responsive element binding by either LPS or PMA. Prolonged exposure to phorbol ester, a treatment which down-regulates PKC, had no effect on LPS induction of NF-kappa B activity in these cells. These results suggest that the induction of NF-kappa B in macrophages by LPS is independent of PKC.
...
PMID:Regulation of NF-kappa B activity in murine macrophages: effect of bacterial lipopolysaccharide and phorbol ester. 173 Jul 83

Protein phosphorylation is central to multiple regulatory processes in cells. Tumor necrosis factor (TNF), a cytokine synthesized by macrophages, effects polymorphonuclear leukocyte (neutrophil) chemotaxis, induces superoxide anion generation, and mediates neutrophil adhesion to endothelial cells. Although protein phosphorylation is almost certainly involved in many TNF-mediated neutrophil functions, little is known about TNF's impact on neutrophil protein phosphorylation. Therefore, we studied human recombinant TNF-alpha-induced protein phosphorylation in human neutrophils. Neutrophils were preincubated with 32PO(4)2- and treated with a variety of stimulatory agents. One- and two-dimensional polyacrylamide gel electrophoresis was used to analyze phosphorylated proteins. Phosphoaminoacids were identified by two-dimensional thin layer chromatography electrophoresis. The findings were as follows: (1) TNF induces the phosphorylation of two 16-kD proteins (pI = 5.9 and 6.1) by 5- to 6-fold, and a 57-kD protein (pI = 5.8) by 3- to 4-fold compared with untreated neutrophils; (2) these proteins are phosphorylated as early as 15 min after stimulation with TNF, and phosphorylation is induced by concentrations of TNF as low as 1 ng/ml (10 U/ml); (3) TNF induces the phosphorylation of proteins at either serine or threonine residues and not at tyrosine; (4) TNF-stimulated neutrophils show a unique pattern of protein phosphorylation when compared to neutrophils treated with formylmethionylleucylphenylalanine; (5) lipopolysaccharide does not induce protein phosphorylation in neutrophils; (6) a 16-kD protein is phosphorylated in response to TNF in neutrophils but not in mononuclear cells; and (7) protein kinase inhibitors appear to have no effect on TNF-induced protein phosphorylation. Thus, the mechanism of action of TNF on neutrophils may involve protein phosphorylation.
...
PMID:Tumor necrosis factor-induced protein phosphorylation in human neutrophils. 191 Aug 14

Recent investigations have identified a signal-transduction system involving sphingomyelin and derivatives. In this paradigm, sphingomyelin hydrolysis by a sphingomyelinase generates ceramide, which may be converted to the protein kinase C inhibitor sphingosine or to ceramide 1-phosphate. Ceramide may have second-messenger function because it induces epidermal growth factor receptor phosphorylation, presumably on Thr-669 in A-431 cells. The present studies describe a kinase that may mediate ceramide action. With a 19-amino acid epidermal growth factor receptor peptide containing Thr-669, a membrane-bound activity that phosphorylated the peptide was detected in A-431 cells. Activity was linearly related to ATP (0.3-300 microM) and peptide concentration (0.02-1 mg/ml), possessed a physiologic pH optimum (pH 7.0-7.4), and was Mg(2+)-dependent. Other cations--Ca2+, Mn2+, and Zn(2+)--were ineffective. Natural and synthetic ceramide induced time- and concentration-dependent enhancement of kinase activity. Ceramide (0.5 microM) increased kinase activity 2-fold by 30 s, and activity remained elevated for at least 15 min. As little as 0.001 microM ceramide was effective, and 1 microM ceramide induced maximal phosphorylation. Sphingosine was similarly effective. Because tumor necrosis factor (TNF) alpha rapidly induces sphingomyelin hydrolysis to ceramide during monocytic differentiation of HL-60 cells, its effects on kinase activity were assessed. Kinase activity was increased 1.5-fold at 5 min and 2-fold at 2 hr in membranes derived from TNF-stimulated cells. The effective concentration range was 3 pM-30 nM TNF. Exogenous ceramide induced a similar effect. In sum, these studies demonstrate the existence of an unusual Mg(2+)-dependent ceramide-activated protein kinase that may mediate some aspects of TNF-alpha function.
...
PMID:Characterization of a ceramide-activated protein kinase: stimulation by tumor necrosis factor alpha. 194 18

Prorenin (Pro) is synthesized in a number of human utero-placental tissues, including chorion, decidua, villous placenta and probably mesenchymal cells. The release of Pro from these extra-renal tissues follows new protein synthesis and appears to utilize the constitutive secretory pathway. Unlike processing in the kidney, very little of the Pro is subsequently cleaved to the smaller product (active renin). Primary signals which regulate Pro include protein hormones and peptides (relaxin, endothelin, hCG), amines (epinephrine, norepinephrine, and related beta adrenergic agents), and eicosanoids. These agents increase the mRNA for prorenin at a time before peak secretory effects are noted. Other extracellular signals have negative regulatory effects. These include angiotensin, endotoxin and cytokines (TNF-alpha and interleukin-1 B). There is also evidence that glucocorticoid receptor activation has an inhibitory effects on Pro release in placenta. Second messengers involved in the regulation of Pro include cyclic AMP and protein kinase A (PKA), protein kinase C (PKC), and calcium. The possible biological effect(s) of the extracellular Pro are unknown but may be due to direct generation of angiotensin I. Since angiotensin-peptides have a number of trophic effect on both vascular and non-vascular tissues, regulation of utero-placental Pro by autocrine, paracrine or endocrine signalling may be critical in normal fetal and/or placental development.
...
PMID:Regulation of utero-placental prorenin. 748 44

One immune function of astrocytes is IL-6 production. Synthesis of IL-6 within the central nervous system (CNS) can produce several different responses, acting on glia, neurons, and lymphocytes infiltrating brain tissue, and some of these effects are associated with CNS autoimmune disease. IL-6 gene expression in astrocytes is regulated by cytokines, infectious agents, neuropeptides, and neurotransmitters, and most of these stimuli interact synergistically. To examine the integration of these diverse factors in the control of IL-6 production, we have studied the involvement of underlying signal transduction processes using neonatal rat astrocytes. We have focused on signal transduction related to the stimulation of IL-6 gene expression by IL-1 beta and TNF-alpha. Our results indicate that stimuli related to protein kinase C (PKC), such as PMA and calcium ionophore A23187, increase IL-6 expression, whereas pharmacologic inhibitors of PKC inhibit IL-6 induction by IL-1 beta and TNF-alpha. Furthermore, both IL-1 beta and TNF-alpha stimulate PKC activity in astrocytes. Stimulators of the cAMP pathway, such as cholera toxin, forskolin, and dibutyryl cAMP, also induced astrocyte IL-6 gene expression. However, inhibition of the cAMP pathway effector, protein kinase A, did not reduce the induction of astrocyte IL-6 gene expression in response to IL-1 beta or TNF-alpha, and an ELISA for cAMP detected only very small increases in cAMP synthesis in response to these cytokines. These data suggest that although cAMP does activate astrocyte IL-6 gene expression, it is the PKC pathway that plays a primary role in the stimulation of astrocyte IL-6 gene expression by IL-1 beta and TNF-alpha.
...
PMID:Signal transduction pathways mediating astrocyte IL-6 induction by IL-1 beta and tumor necrosis factor-alpha. 750 38


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

---