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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The interaction of CD28 with its counter-receptor, B7, induces a cosignal in T cells required to prevent clonal anergy and to promote antigen-dependent interleukin-2 production. The molecular basis of the CD28 cosignal is not well understood but involves the activation of protein tyrosine kinase(s) (PTK). In this report we demonstrate that CD28 cross-linking on Jurkat T leukemic cells causes the activation of at least two PTK pathways. A CD28-induced, p56lck kinase-independent pathway causes tyrosine-phosphorylation of a 110-kDa substrate while recruitment of p56lck kinase activity is apparently required for CD28-induced tyrosine-phosphorylation of 97- and 68-kDa substrates as well as CD28-induced increases in intracellular calcium. The tyrosine phosphorylation of p110, but not p97 or p68, correlated with CD28 calcium-independent costimulatory activity. The pp110 molecule was tentatively identified as the catalytic subunit of phosphoinositide (PI)-3 kinase based upon its coimmunoprecipitation with the p85 regulatory subunit of PI-3 kinase. PI-3 kinase protein and catalytic activity were found complexed with the CD28 receptor if the receptor was "activated" by cross-linking on the surface of intact cells prior to detergent solubilization. The kinetics of association of PI-3 kinase with the "activated" CD28 receptor was rapid, occurring within 30 s of receptor cross-linking and was stable for at least 30 min. Analysis of the CD28 cytoplasmic peptide sequence revealed a putative PI-3 kinase src homology 2 binding motif and CD28 tyrosine phosphorylation site, DYMNM. Tyrosine phosphorylation of CD28 was detected in pervanadate-treated Jurkat B2.7 cells, but not untreated cells. Pervanadate-induced tyrosine phosphorylation of CD28 correlated with receptor association of PI-3 kinase in the absence of CD28 cross-linking, suggesting that CD28 association with PI-3 kinase uses a tyrosine phosphorylation-dependent mechanism. These data provide a model for CD28 signal transduction and support a role for PI-3 kinase in mediating the CD28 calcium-independent, cyclosporin A-insensitive costimulatory signal.
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PMID:CD28 signal transduction: tyrosine phosphorylation and receptor association of phosphoinositide-3 kinase correlate with Ca(2+)-independent costimulatory activity. 795 66

A colony-stimulating factor 1 (CSF-1)-dependent murine macrophage cell line (BAC1.2F5) and peritoneal macrophages were used to investigate the relationship between growth factor-dependent phosphorylation/activation of the 85-kDa cytosolic phospholipase A2 (cPLA2) and arachidonic acid metabolism. The addition of CSF-1 to quiescent BAC1.2F5 cells was followed by the rapid phosphorylation, electrophoretic gel retardation, and stable increase in the specific activity of cPLA2 that correlated with the activation of ERK kinases. cPLA2 phosphorylation depended on the presence of growth factor and persisted throughout the cell cycle. CSF-1 inhibited prostaglandin E2 production and did not enhance arachidonic acid release or increase the levels of lysophosphatidylcholine or glycerophosphocholine. Treatment of BAC1.2F5 cells with the calcium ionophore A23187 plus CSF-1 did not stimulate eicosanoid release. Instead, CSF-1 enhanced the rate of exogenous arachidonic acid incorporation into phosphatidylcholine and its subsequent transfer to phosphatidylethanolamine suggesting that higher rates of arachidonic acid acylation may contribute to the suppression of prostaglandin production. In peritoneal macrophages, ERK kinase activity was stimulated and cPLA2 was phosphorylated and activated in response to CSF-1. However, CSF-1 did not trigger eicosanoid release but did augment arachidonic acid mobilization and prostaglandin E2 production elicited by zymosan and A23187. Thus, cPLA2 phosphorylation/activation and calcium mobilization are not the only determinants for eicosanoid release, and additional components in differentiated tissue macrophages are also required.
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PMID:Regulation of cytosolic phospholipase A2 phosphorylation and eicosanoid production by colony-stimulating factor 1. 798 42

This study was undertaken in order to obtain information on the mode of reaction of the contractile apparatus after different forms of cardiac arrest, global ischemia and reperfusion, as well as on possible correlations between the contraction state of myofibrils and biochemical parameters. During the survival time, before the level of 3 mumol/gww creatine phosphate (CP) is reached, the contraction state shows only minor changes. During the revival time in which ATP tissue concentrations decay to 4 mumol/gww, the contribution of ATP, lactate, anorganic phosphate (Pa) and acidosis to the degree of relaxation depends on the method of cardiac arrest. At defined biochemical values, the degree of relaxation is comparable after aortic cross clamping (ACC) and St. Thomas perfusion, but significantly different compared to HTK perfusion. Thus, during the revival time, the relaxation of sarcomeres depends predominantly on the composition of the solutions used for cardiac arrest. The re-entry of contraction below 3 mumol/gww ATP is correlated with the ATP concentration, independent of the form of cardiac arrest. Reperfusion after HTK or St. Thomas cardioplegia and reversible ischemia leads to the focal formation of contraction bands, which do not occur during ischemia. This contraction state is significantly more pronounced after reperfusion of St. Thomas arrested hearts. Thus, the contraction state of myofibrils is influenced not only by alterations in metabolite concentrations, but also by the composition of cardioplegic solutions and by the characteristic conditions (sufficient energy, oxygen and Calcium) during reperfusion.
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PMID:The contraction state of myofibrils during global ischemia and after reperfusion following different forms of cardiac arrest. Correlation with metabolic parameters in the canine heart. 799 68

Stable clones of NIH 3T3 fibroblasts transfected with the cDNA of either the wild-type or deletion forms of the rat type I (or cerebellar) inositol 1,4,5-trisphosphate (IP3) receptor (IP3R) were investigated. The delta form, missing the NH2-terminal sequence that includes the IP3-binding site, is expected to be still assembled with wild-type subunits to yield a tetrameric Ca2+ channel across the endoplasmic reticulum membrane; the s form, missing the membrane-spanning sequences, is expected to remain as a soluble monomer in the cytosol. With respect to control clones transfected with the vector only, the synthesis fo IP3Rs was markedly stimulated in the receptor-transfected clones. The mass accumulation, however, was increased only moderately (deletion forms = 15-30% of the endogenous IP3R), apparently because of a compensatory increase in receptor turnover. Coordinate changes in IP3 generation and Ca2+ release were revealed in the delta clones by experiments in both intact and permeabilized cells. In these clones, the IP3R was more sensitive to IP3, and IP3 generation at the ATP P2u surface receptor was decreased. This latter effect was due neither to a defect in G protein coupling nor to changes in phospholipase C expression, but to down-regulation of the P2u receptor. In the cells expressing the s- and delta-IP3R subunits, no differences with respect to the controls were observed in epidermal growth factor-induced DNA synthesis, whereas long-term growth stimulated by serum was reduced. Even more marked, especially in the delta clones (-90%), was the inhibition of cell transformation induced by autocrine stimulation with transforming growth factor alpha of the overexpressed epidermal growth factor receptors or by other growth factor receptors and oncogenes (platelet-derived growth factor/platelet-derived growth factor receptor beta, HER2/neu, and v-erbB). These effects appear not to be connected to the signaling processes mediated by tyrosine phosphorylation since the latter was unchanged in the delta clones. These results demonstrate for the first time (a) that the changes in cellular homeostasis directly induced by deleted IP3R subunits (increased receptor synthesis and increased IP3R sensitivity) are largely compensated by indirect coordinate changes apparently aimed to keep near normal the signaling properties of the cells; (b) that modulation of intracellular Ca2+ channels induces profound consequences that differentially affect growth and oncogenesis; and (c) that IP3Rs and the Ca2+ stores are important cross-roads of intracellular signaling pathways.
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PMID:Stable expression of truncated inositol 1,4,5-trisphosphate receptor subunits in 3T3 fibroblasts. Coordinate signaling changes and differential suppression of cell growth and transformation. 803 82

In a cultured osteoblastic cell line, MC3T3-E1 derived from newborn mouse calvaria, the mRNA encoding TRKC, which is the receptor molecule of neurotrophin-3 (NT-3), was detected by the polymerase chain reaction (PCR) method. The mRNAs of the normal type and one alternative form (C14) were highly expressed in the exponential growth phase of MC3T3-E1 cells and decreased as the cells reached the differentiation stage. NT-3, but not nerve growth factor (NGF), stimulated the proliferation of MC3T3-E1 cells in a dose-dependent manner. NT-3 also stimulated calcium incorporation through the surface of MC3T3-E1 cells, indicating the association of NT-3 and its receptor on the cell surface.
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PMID:Expression of trkC in a mouse osteoblastic cell line and its response to neurotrophin-3. 809 43

Extracellular K+ activities (aKe) and neuronal and glial membrane potentials were recorded in the nucleus tractus solitarius (NTS) and in the dorsal vagal motor nucleus (DVMN) of rat brainstem slices after orthodromic stimulation of the tractus solitarius (TS). In glial cells, repetitive stimulation of the TS induced depolarizations of up to 30 mV followed by repolarizations which were fitted by exponential curves with a time constant of 1.6-5 s. Similar stimulations induced elevations of aKe of up to 8 mM, the recovery of which was fitted by single exponential curves with a time constant ranging between 1.6 and 4 s. These elevations in aKe were reduced by 75% during blockage of synaptic transmission in low Ca2+, high Mg2+ solution, and by 24% with application of 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX, 50 microM). Perfusion with a low Mg2+ solution increased the aKe response to stimulation of the TS, an effect that was reduced by the addition of 2-amino-5-phosphono-valeric acid (AP7, 50 microM) to the bath. No significant change in aKe and glial potential was seen when superfusing high concentrations of the C-terminal octapeptide of cholecystokinin (CCK8, 1-5 microM) and C-terminal tetrapeptide (CCK4, 50-100 microM). The effect of TS stimulations on solitary complex neurons suggests that extracellular K+ concentration is increased during synaptic activation of non-NMDA or NMDA ionotropic receptors. Conversely, slow depolarizations elicited by repetitive afferent activity or excitation by CCK agonists develop in neurons in the absence of measurable extracellular K+ fluctuations or glial depolarization.
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PMID:Extracellular potassium, glial and neuronal potentials in the solitary complex of rat brainstem slices. 809 69

In pregnancy calcium antagonism is of great importance. The uterus-relaxing properties of verapamil are well known, diltiazem shows an excellent tokolytic efficacy and is also effective as hypotensive in pregnancy-induced hypotension. In contrast to verapamil and diltiazem the dihydropyridines were not clinically successful as tokolytic or hypotensive in pregnancy. Magnesium is a therapy of first choice in the EPH-gestosis.
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PMID:[Calcium antagonists in pregnancy as an antihypertensive and tocolytic agent]. 813 35

We studied the abundance, subcellular distribution of a non-receptor protein-tyrosine kinase p72syk (Taniguchi, T., Kobayashi, T., Kondo, J., Takahashi, K., Nakamura, H., Suzuki, J., Nagai, K., Yamada, T., Nakamura, S., and Yamamura, H. (1991) J. Biol. Chem. 266, 15790-15796) in porcine polymorphonuclear neutrophils and the activation upon the stimulation with concanavalin A. The abundance was about 0.1% of total proteins and mainly distributed in the particulate fraction. Upon concanavalin A stimulation, the activity of p72syk increased within 30 s, attained to the maximum level at 1 min, and then returned to the basal level within 6 min. This activation was observed in a dose-dependent manner and abrogated by simultaneous addition of methyl alpha-mannopyranoside. When both extra- and intracellular Ca2+ were depleted, the activation of p72syk was still persistent; in contrast, the deactivation process was completely abrogated even at 6 min after stimulation. The replenishment of Ca2+ in the presence of A23187 resulted in a similar deactivation pattern as seen in the Ca(2+)-rich condition. In addition, genistein and herbimycin A, potent protein-tyrosine-kinase inhibitors, were capable of reducing concanavalin A-evoked p72syk activation and Ca2+ mobilization as well as the aggregation and lysozyme release. Furthermore, A23187-induced Ca2+ accumulation in inhibitor-treated cells resulted in the restoration of those cellular responses. These lines of evidence suggest that p72syk is activated with concanavalin A in a Ca(2+)-independent manner, participating in a mechanism of Ca2+ recruitment, and negatively regulated by a feedback mechanism through Ca2+ in neutrophils.
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PMID:Activation of protein-tyrosine kinase p72syk with concanavalin A in polymorphonuclear neutrophils. 822 57

Four naturally occurring platelet-activating factor (PAF) analogs, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphocholine, 1-hexadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, 1-octadecanoyl-2-acetyl-sn-glycero-3-phosphocholine, and 1-alkyl-2-acetyl-sn-glycero-3-phosphoethanolamine, stimulated human neutrophils (PMN) to mobilize Ca2+, degranulate, and produce superoxide anion. They were, respectively, 5-, 300-, 500-, and 4000-fold weaker than PAF in each assay; inhibited PMN-binding of [3H]PAF at concentrations paralleling their biological potencies; and showed sensitivity to the inhibitory effects of PAF antagonists. PAF and the analogs, moreover, desensitized PMN responses to each other but not to leukotriene B4 and actually increased (or primed) PMN responses to N-formyl-MET-LEU-PHE. Finally, 5-hydroxyeicosatetraenoate-enhanced PMN responses to PAF and the analogs without enhancing the actions of other stimuli. It stereospecifically raised each analog's potency by as much as 100-fold and converted a fifth natural analog, 1-alk-1'-enyl-2-acetyl-sn-glycero-3-phosphoethanolamine from inactive to a weak stimulator of PMN. PAF and its analogs thus represent a structurally diverse family of cell-derived phospholipids which can activate, prime, and desensitize neutrophils by using a common, apparently PAF receptor-dependent mechanism.
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PMID:Comparison of 1-O-alkyl-, 1-O-alk-1'-enyl-, and 1-O-acyl-2-acetyl-sn-glycero-3-phosphoethanolamines and -3-phosphocholines as agonists of the platelet-activating factor family. 828 Jul 72

Src-homology region 2 (SH2) domains are stretches of about 100 amino acids which are found to be structurally conserved in a number of signaling molecules. These regions have been shown to bind with high affinity to phosphotyrosine residues within activated receptor tyrosine kinases. Here we report the bacterial expression and purification of individual N-terminal SH2 (NSH2) domains of phosphatidylinositol 3-kinase (PI-3K) binding subunit (p85) and Ras GTPase activating protein (GAP) in amounts suitable for structure-function studies. The p85NSH2 domain stains dark purple and absorbs around 620-640 nm with Stains-all, a dye known to bind to calcium binding proteins. This effect was not observed for the GAPNSH2 domain. Circular dichroism analysis of the N-terminal SH2 domain of these proteins shows that p85NSH2, but not GAPNSH2, undergoes a significant dose-dependent change in conformation in the presence of increasing calcium concentrations. Moreover, the conformational change of p85NSH2 induced by calcium could be replicated by addition of a phosphorylated hexapeptide (DYpMDMK) representing the alpha-PDGFR binding site for p85. Limited proteolysis studies showed a significant calcium-dependent increase in protection of p85NSH2 but not GAPNSH2 from degradation by subtilisin. Our results further indicate that holmium, a trivalent lanthanide ion, which has been previously shown to substitute for calcium, could also protect the p85NSH2 domain from proteolysis even at 10-fold lower concentrations. In vitro binding studies using purified preparations of activated alpha-PDGFR show that calcium did not affect the binding of GAPNSH2 domains to activated alpha-PDGFR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of calcium-dependent conformational changes in the N-terminal SH2 domains of p85 and GAP defines distinct properties for SH2 domains. 829 2


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