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)

Alcohol consumption has multiple effects in the central nervous system (CNS). Whereas, alcohol is an immunosuppressive drug the effect of alcohol on the neuroimmune system, remains unclear. In cultured astrocytes, prolactin (PRL) induces mitogenesis and the expression of inflammatory cytokines, including tumor necrosis factor-alpha (TNF alpha). We have recently shown that whereas ethanol does not inhibit PRL receptor binding, it markedly inhibits PRL-induced mitogenesis and TNF alpha secretion in cultured astrocytes. It is clear that PRL activates the tyrosine phosphorylation of several proteins, including members of a novel family of protein tyrosine kinases, the Janus Kinases (JAKs). The aims of this study were to characterize PRL-induced activation of the JAK/STAT (signal transducers and activators of transcription) pathway, and to determine if ethanol affects JAK/STAT activation in cultured astrocytes. We found that PRL specifically increases the tyrosine phosphorylation of JAK2, but not JAK1, JAK3, or Tyk2, and the subsequent phosphorylation of STAT1 alpha, STAT5a, and STAT5b. Preincubation of astrocytes with ethanol markedly inhibited phosphorylation of JAK2, STAT1 alpha, STAT5a, and STAT5b. In PRL-stimulated astrocytes, ethanol inhibited binding of nuclear proteins to oligonucleotides corresponding to the gamma-interferon activated sequence (GAS). Further, ethanol blocked PRL-induced increases in interferon regulatory factor-1 (IRF-1) mRNA, a PRL/cytokine inducible transcription factor involved in the regulation of a number of cytokine inducible genes. The inhibition of tyrosine phosphorylation by ethanol was not a general effect, however, as we found that ethanol increased basal and NGF-induced tyrosine phosphorylation of extracellular signal-activated protein kinase-1 (ERK-1). These data indicate that ethanol inhibits PRL-induced tyrosine phosphorylation of the JAK/STAT pathway resulting in decreased nuclear GAS DNA binding and inhibition of the PRL inducible gene, IRF-1. Thus, suggesting that ethanol-induced inhibition of JAK2 phosphorylation may be one mechanism though which ethanol could after the brain's response to injury or infection.
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PMID:Ethanol inhibits prolactin-induced activation of the JAK/STAT pathway in cultured astrocytes. 1040 96

IkappaB kinases (IKK)-1 and -2 are related kinases that are induced by stimuli such as TNF or IL-1 to phosphorylate serines 32 and 36 of IkappaBalpha, the regulatory subunit of the transcription factor NF-kappaB. A procedure for an IKK protein kinase assay is described that uses an in vivo biotinylated IkappaB protein substrate, [gamma-(33)P]ATP, and capture onto a streptavidin membrane. Residues 1-54 of the IkappaBalpha substrate were expressed as a fusion with glutathione S-transferase (GST) and a short (22 amino acid) biotinylation sequence that allowed modification during bacterial expression. Using the streptavidin capture assay the phosphorylation activities of recombinant IKK-1 and -2 were characterized. The assay provided a convenient way to compare IKK protein and peptide substrate preferences; biotinylated GST-IkappaBalpha(1-54) was more readily phosphorylated by both IKK-1 and IKK-2 compared to biotinylated myelin basic protein or a 20-mer biotinylated peptide containing serines 32 and 36 of IkappaBalpha. IKK-1 had 83-fold less activity than IKK-2, and the IKK-1+2 complex had approximately 2-fold more activity than IKK-2. IKK-1+2 and IKK-2 had similar K(m) values for ATP and GST-biotin-IkappaB(1-54) and were similarly inhibited by staurosporine and two of its analogues K252a and K252b, suggesting that most of the IkappaBalpha kinase activity in the IKK-1+2 complex may be attributed to IKK-2. Several features of the assay including the broad linear binding range of the streptavidin membranes for the protein substrate GST-biotin-IkappaB(1-54) (1-4000 pmol of protein/cm(2)), the low background, and its capacity for both biotinylated peptides and proteins make it a useful tool for quantitating IKK activity. These factors and the ease of expressing in vivo biotinylated GST fusions will make this assay approach suitable for a wide variety of protein kinases.
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PMID:Assay for IkappaB kinases using an in vivo biotinylated IkappaB protein substrate. 1052 19

Monocytes-macrophages which serve as host immune cells to kill pathogens can often be "activated" after exposing to viruses, bacteria, cytokines as well as chemical substances, However, it is paradoxical that highly activated macrophages can be induced to become the suppressor ones by live microbes, microbial products, tumor, and autoimmune disease, although the mechanism remains unknown. Our previous experimental studies have shown that immuno-suppressor activities of suppressor macrophages on T, B and NK cells can be prevented by the treatment with LPS or supernatant in vitro from mitogen-stimulated lymphocytes, while, at the same time, the tumoricidal activities of those macrophages can be kept or even enhanced following the same treatment. This phenomenon was then termed as "immune modulation" For the understanding of its mechanism, we are now undertaking signal transduction in modulated macrophages. Since mitogen-activated protein kinase (MAPK) is an integration point of different signal transduction pathways, its cascade and regulation of activation are being investigated extensively by the assay of electrophoresis mobility shift. Recent results suggested that interaction of ligand-receptor triggers protein tyrosine kinase(PTK) activation leading to Ras-GTP binding with Raf-1 to phosphorylate MAPK kinase (MAPKK), the specific activator of MAPK. It is reported that PKC-alpha can directly phosphorylate or activate Raf-1 in NIH3 T3 cells. Raf-1 (74 KDa), with an intrinsic serine (Ser)-threonine (The) kinase activity, becomes hyperphosphorylated after activation which can be followed by gel mobility shift test. It has also been shown that a variety of extracellular factors stimulate a pair of MAPK p44 and MAPK p42 of MAPK family members. A significant property of activation of ERK 1 and ERK 2 is the requirement for the phosphorylation of both Thr-183 and Tyr-185 (at TEY motif) within in its protein kinase subdomain VIII. More recently, two other MAPK subtypes, p38 MAPK (mammalian equivalents of HOG1 in yeast) and JNK MAPK have been discovered. The requirement for activation of p38 MAPK for both Thr-180 and Tyr-182 (at TGY motif) has been shown. p38 MAPK is important in certain transcriptional regulatory pathways, since it can phosphorylate the following transcriptional factors: 1) Elk at Ser 383/389 for binding with SRE motif; 2). ATF 2 at Ser 69/71, forming a complex with Myc for DNA binding at CRE motif; 3) Max at Ser-62 to combine DNA of E-Box motif. p38 MAPK can be activated by LPS, inflammatory cytokines, such as TNF and IL-1, osmolarity. To examine the possibility that whether activation of Raf-1 and ERK 1, ERK2 and p38 MAPK can be regulated directly or/and differently by PKC and PKA pathways, herbimycin A (Ki = 0.9 mumol/L), a potent PTK inhibitor (J. Immunol. 155:3944-4003, 1995) at 2 mumol/L concentration was utilized to block Ras/Raf-1/MAPK cascade. After pre-incubation of macrophages with herbimycin A for 30 min or 90 min, cells were treated with LPS (10 micrograms/ml) and PMA (100 nmol/L) for 15 min. No inhibition of phosphorylation of Raf-1, MAPK p44 and MAPK p42 in response to LPS and PMA was observed (Fig. 1 and 3). However, forskolin, a cAMP inducer for protein kinase A (PKA) activation, inhibited the phosphorylation of LPS- and PMA-stimulated Raf-1, MAPK p44 and MAPK p42 (Fig. 2 and 4). Similarly, in agreement with a very recent report from David, M et al in NIH, in which they indicated that forskolin (30 mumol/L) inhibited IFN-beta-stimulated ERK activity by U 266 cells (J. Biol. Chem. 271: 4585-4588 1996), we found that the levels of phosphorylations of Raf-1 and ERK1 and ERK2 were declined when forskolin (30 mumol/L) was added to macrophages for 20 min at 37 degrees C prior to the stimulation by LPS and PMA. Interestingly, under the same condition, forskolin (30 mumol/L) stimulated the phosphorylation of LPS- and PMA-triggered p38 MAPK of murine peritoneal suppressor macrophages, suggesting that activatio
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PMID:[Studies on cell signaling immunomodulated murine peritoneal suppressor macrophages: LPS and PMA mediate the activation of RAF-1, MAPK p44 and MAPK p42 and p38 MAPK]. 1068 11

The presence of protein kinase activity and its phosphorylated products has been demonstrated on the outer surface of the plasma membrane of endothelial cells. Extracellular phosphorylation was detected by incubation of primary endothelial cells (HUVEC's) and endothelial cell line EA.hy 926 with [gamma-32P]ATP. The reaction products were subjected to SDS/PAGE, autoradiography and scanning densitometry. Under the experimental conditions, five proteins with apparent molecular masses of 19, 23, 55, 88, and 110 kDa were prominently phosphorylated in both types of cells. Phosphorylation of the 19 kDa protein was the most rapid reaching maximum after 60 s and then the protein became dephosphorylated. Ecto-protein kinases responsible for the surface labeling of membrane proteins were characterized by using (a) protein kinase C inhibitors: K-252b, chelerythrine chloride, and [Ala113] myelin basic protein (104-118), (b) protein kinase A inhibitor Kemptide 8334, and (c) casein kinase II inhibitor 5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole (DRB). Stimulation of endothelial cells with tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) is associated with 20-80% reduction of extracellular phosphorylation of all membrane proteins. IFN gamma bound to membrane receptors becomes rapidly phosphorylated. Only in the case of IFN gamma it was associated with the appearance of a strongly phosphorylated band of 17 kDa corresponding to IFN gamma itself. Phosphorylation of this 17 kDa exogenous substrate was prevented by an ecto-kinase inhibitor K-252b. The existence of ecto-phosphoprotein phosphatase activity in endothelial cells was evidenced by testing the effect of microcystin LR--a membrane impermeable reagent that inhibits both PP-1 and PP-2a phosphoprotein phosphatases. The extent of phosphorylation of 19 kDa and 110 kDa phosphoproteins significantly increased in the presence of microcystin. Our results suggest the presence of at least two ecto-kinase activities on endothelial cells that may play a significant role(s) in the regulation of cytokines function.
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PMID:Interferon gamma bound to endothelial cells is phosphorylated by ecto-protein kinases. 1069 77

Apoptosis is a form of cell death that involves discrete genetic and molecular programs, de novo protein expression and a unique cellular phenotype. Evidence for the existence of apoptosis in the human heart has been reported in various cardiac diseases, including ischemic and non-ischemic heart failure, myocardial infarction and arrhythmias. Among the most potent stimuli that elicit cardiomyocyte apoptosis are: oxygen radicals (including NO), cytokines (FAS/TNF alpha-receptor signaling), stress conditions (chemical or physical, e.g., radiation), sphingolipid metabolites (ceramide) and autocoids, e.g., angiotensin II. Apoptosis of cardiac myocytes may contribute to progressive pump-failure, arrhythmias and cardiac remodeling. The recognition of numerous molecular targets associated with cardiomyocyte apoptosis may provide novel therapeutic strategies for diverse cardiac ailments, as recently suggested by pharmacologic studies in experimental animals. This review paper is aimed to highlight the role of protein kinase signaling pathways in apoptosis with special attention to the stress-activated protein kinases (SAPK) and mitogen-activated protein kinases (MAPK) systems.
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PMID:Apoptosis in cardiac diseases: stress- and mitogen-activated signaling pathways. 1072 77

The cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA) signal pathway regulates cell proliferation, differentiation and cell death. It may also regulate the multidrug resistance (MDR) phenotype in leukaemic cells. These data showed that MDR1+ K/Dau600 cells exhibited a higher basal level of PKA activity than MDR- parental cells. The significance of this on tumour necrosis factor alpha (TNFalpha)-induced apoptosis and cytostasis was investigated further. In comparison with MDR1- parental cells, K/Dau600 cells had a higher expression of PKA regulatory subunit RIalpha and nuclear catalytic subunit PKAcalpha. They were also more susceptible to inhibition of proliferation and induction of apoptosis by TNFalpha and/or forskolin, but this could be attenuated by H89. An increase in cAMP was associated with the apoptosis in the K/Dau600 cell line. Forskolin inactivated NF-kappaB in K/Dau600 cells but not in K562 cl. 6 cells, whereas TNF activated NF-kappaB in K562 cl.6 cells but not in K/Dau600 cells. 8-Cl-cAMP exhibited similar inhibitory effects on the proliferation of all of the cell lines used via its metabolite 8-Cl-adenosine, which indicates that these effects were independent of residual PKA or cAMP. Therefore, the differential sensitivity to apoptosis and/or growth inhibition could be mediated via cAMP, partly through PKA via NF-kappaB and partly by PKA-independent pathways.
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PMID:Constitutive levels of cAMP-dependent protein kinase activity determine sensitivity of human multidrug-resistant leukaemic cell lines to growth inhibition and apoptosis by forskolin and tumour necrosis factor alpha. 1075 15

Substance P plays an important role in neurogenic inflammation with granulocyte infiltration. To investigate cytokines involved in the substance P-induced inflammation and the mechanism of cell activation, we studied the release of TNF (tumor necrosis factor)-alpha and histamine from human skin slices in response to substance P and antigen. Substance P induced the release of histamine and TNF-alpha in a dose-dependent manner at concentrations from 0.8 to 100 microM. PD 098059 (2'-amino-3'-methoxyflavone) selectively inhibited the release of TNF-alpha, but not the release of histamine induced by either substance P or antigen. SB 203580 ([4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-++ +imida zole]) slightly inhibited TNF-alpha release induced by antigen, but not that induced by substance P, and slightly enhanced histamine release induced by either stimulation. The release of TNF-alpha in response to either stimulation was inhibited by 1 nM-1 microM dexamethasone, but histamine release was not affected. These results suggest that substance P, in addition to antigen, induced TNF-alpha release from human skin by a mitogen-activated protein (MAP) kinase, predominantly extracellular signaling-regulated protein kinase (ERK)-dependent, and dexamethasone-sensitive pathway, which is separate from that for histamine release from mast cells.
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PMID:Substance P induces tumor necrosis factor-alpha release from human skin via mitogen-activated protein kinase. 1085 44

CD153 (CD30 ligand) is a member of the TNF ligand/cytokine family expressed on the surface of human B cells. Upon exposure to IL-4, a critical Ig class switch-inducing cytokine, Ag-activated T cells express CD30, the CD153 receptor. The observation that dysregulated IgG, IgA, and/or IgE production is often associated with up-regulation of T cell CD30 prompted us to test the hypothesis that engagement of B cell CD153 by T cell CD30 modulates Ig class switching. In this study, we show that IgD+ IgM+ B cells up-regulate CD153 in the presence of CD154 (CD40 ligand), IL-4, and B cell Ag receptor engagement. In these cells, CD153 engagement by an agonistic anti-CD153 mAb or T cell CD30 inhibits S mu-->Sgamma, Smu-->Salpha, and S mu-->Sepsilon class switch DNA recombination (CSR). This inhibition is associated with decreased TNFR-associated factor-2 binding to CD40, decreased NF-kappaB binding to the CD40-responsive element of the Cgamma3 promoter, decreased Igamma3-Cgamma3 germline gene transcription, and decreased expression of Ku70, Ku80, DNA protein kinase, switch-associated protein-70, and Msh2 CSR-associated transcripts. In addition, CD153 engagement inhibits IgG, IgA, and IgE production, and this effect is associated with reduced levels of B lymphocyte maturation protein-1 transcripts, and increased binding of B cell-specific activation protein to the Ig 3' enhancer. These findings suggest that CD30+ T cells modulate CSR as well as IgG, IgA, and IgE production by inducing reverse signaling through B cell CD153.
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PMID:Engagement of CD153 (CD30 ligand) by CD30+ T cells inhibits class switch DNA recombination and antibody production in human IgD+ IgM+ B cells. 1087 52

A recent report suggested that platelet-derived growth factor (PDGF) activates nuclear factor-kappa B (NF-kappa B) by phosphorylation of the protein kinase Akt [Romashkova and Makarov, Nature 401 (1999) 86-90]. The present study investigates the role of Akt in the activation of NF-kappa B by tumor necrosis factor-alpha (TNF alpha, 10 ng/ml) and PDGF-BB (20 ng/ml) in human vascular smooth muscle cells (SMC), skin and foreskin fibroblasts. TNF alpha stimulated serine phosphorylation and degradation of the inhibitory protein I kappa B alpha and strongly induced nuclear NF-kappa B translocation and binding activity. PDGF did not induce serine phosphorylation or degradation of I kappa B alpha and did not enhance binding activity of NF-kappa B. In contrast, stimulation with PDGF resulted in a marked phosphorylation of Akt, but no Akt phosphorylation occurred after stimulation with TNF alpha. These data suggest that Akt phosphorylation is not involved in NF-kappa B activation in human SMC and fibroblasts.
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PMID:PDGF-induced Akt phosphorylation does not activate NF-kappa B in human vascular smooth muscle cells and fibroblasts. 1098 5

TR2(L) is a 56-amino-acid polypeptide that has been shown to block TNF cytotoxicity. FE65-like (FE65L) proteins possess this conserved TR2(L) sequence at their C-termini, whereas variations in the sequences are found in the FE65 proteins. To further analyze the antiapoptotic function of TR2(L), here we utilized an isolated murine partial FE65L cDNA that encodes an N-terminal phosphotyrosine-binding domain (PTB) and the conserved C-terminal TR2(L) sequence. When L929 cells were stably transfected with the FE65L cDNA or its 3' end TR2(L) DNA sequence, these cells became resistant to TNF killing. Replacement of the N-terminal PTB domain with GFP failed to abolish the FE65L-mediated TNF resistance. Ablation of the C-terminal TR2(L) sequence through frame-shift mutation resulted in a complete loss of the FE65L function against TNF. Various protein kinase inhibitors, including lavendustin A, tyrphostin, H7, and staurosporine, which may affect the PTB domain function, could not abolish the FE65L-mediated TNF resistance. A prolonged exposure of L929 cells to these inhibitors for 24 h resulted in cell death, whereas FE65L significantly blocked the cell death. Polyclonal antibodies were generated against a synthetic peptide and shown to interact with a 38-kDa FE65L in L929 cells. Hyaluronidase downregulates the expression of FE65L gene and protein in L929 cells, and this correlates with its enhancement of TNF killing of these cells. Together, our data indicate that the TR2(L) amino acid sequence is an apoptosis-inhibitory domain commonly present in the FE65 and FE65-like family proteins.
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PMID:Characterization of an apoptosis inhibitory domain at the C-termini of FE65-like protein. 1102 57


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