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)

Embryonal carcinoma (EC) cells are the malignant stem cells of teratocarcinoma and have the capacity to proliferate in the absence of serum growth factors. As yet no receptor protein tyrosine kinases have been identified on undifferentiated EC cells and as a consequence tyrosine kinase signaling pathways could not be studied in these cells. We have used stably transfected P19 embryonal carcinoma cells expressing a well-characterized receptor protein tyrosine kinase, the human epidermal growth factor receptor (hEGF-R) to study protein tyrosine kinase signaling mechanisms in undifferentiated EC cells. Here we report that the ectopically expressed hEGF-R contains EGF-inducible autophosphorylation activity and is rapidly internalized and degraded upon ligand binding. In addition, the exogenous hEGF-R confers EGF-responsiveness to these cells in that inositol phosphate formation and cytoplasmic-free Ca2+ concentration are enhanced in response to EGF. Furthermore, the Na+/H+ exchanger is activated in response to EGF, leading to a sustained rise in intracellular pH. Our results show that undifferentiated P19 EC cells contain the necessary components of protein tyrosine kinase signal transduction machinery.
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PMID:Characterization of a tyrosine kinase signaling pathway in undifferentiated P19 embryonal carcinoma cells. 165 71

Desensitization to the effects of acetylcholine (ACh) or carbachol (CCh) on ACh-regulated potassium current (IK(ACh)) and the voltage-dependent L-type, calcium current (ICa(L)) was studied in single guinea-pig atrial cells under voltage clamp at room temperature (22-24 degrees C). At a holding potential of -40 mV, CCh (100 microM) activated IK(ACh) repeatedly and reproducibly when applied for 15-s periods with 60-s intervals between applications. Prolonged (10 min) exposure to CCh caused a time-dependent decline of IK(ACh) and a marked reduction (desensitization) of the response to subsequent application of CCh. In the absence of guanosine triphosphate (GTP) in the pipette, only partial resensitization occurred within 20 min after CCh washout. The desensitization to CCh could also be obtained when adenosine (20 microM) was used to activate this current. Therefore, this desensitization must be heterologous. In the presence of isoproterenol (ISO, 3 microM), ICa(L) increased. Acetylcholine continued to inhibit this current at a time when its activation of IK(ACh) had become desensitized. Muscarinic inhibition of ICa(L) eventually desensitized but only after IK(ACh) desensitization had occurred. Because of its heterologous nature, as well as of the ability of ACh to desensitize in the presence of intrapipette dextran, which is reported to inhibit beta-adrenergic receptor kinase (beta ARK), it seems unlikely that beta ARK-dependent phosphorylation of the muscarinic receptor (mAChR) accounted for desensitization. The differential desensitization time course is consistent with the hypothesis that different subunits of Gi, the inhibitory guanine nucleotide binding protein, not only transduce the agonist effects of ACh on IK(ACh) and ICa(L) but are also subjected to different inactivation/regulation processes.
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PMID:Muscarinic agonist-induced actions on potassium and calcium channels in atrial myocytes: differential desensitization. 166 56

The possible chemical interaction between synthetic hydroxyapatite or bovine enamel and a functional monomer of 4-methacryloxyethyl trimellitic acid (4-MET) diluted in methyl methacrylate (MMA) was examined by measuring the Raman spectra. It was concluded that the carboxyl group of 4-MET reacted with the calcium in the substrate to form a salt that was detected by the Raman band at around 1,380 cm-1. However, formation of the salt on the surface of the hydroxyapatite (HAP) with the carboxyl group, and polymerization of the 4-MET in the methacryl group near the surface were mutually exclusive reactions for the same 4-MET molecule.
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PMID:Laser-Raman Spectroscopic study of the adhesive interface between 4-MET/MMA-TBB resin and hydroxyapatite or bovine enamel. 166 97

We examined calcium and calmodulin regulation of atrial natriuretic factor stimulation of particulate-membrane guanylate cyclase (ANF-s-GC) in SK-NEP-1 cells. W7 and trifluoropiperazine, but not W5, inhibited whole cellular ANF-stimulated cyclic GMP accumulation (ANF-s-cGMP). EGTA and LaCl3 decreased ANF-s-GC and calmodulin reversed this inhibition. A23187-induced inhibition of ANF-s-cGMP was only partly reversible by IBMX. H7 or staurosporine counteracted the inhibitory effect of A23187. Calcium inhibited basal and ANF-s-GC. These data suggest that at low concentrations of calcium, ANF-s-GC was calcium-calmodulin dependent but high concentrations of calcium inhibited ANF-s-GC through phosphodiesterase, through inhibition of GC, and probably through protein kinase C.
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PMID:Calcium and calmodulin regulate atrial natriuretic factor stimulation of cyclic GMP in a human renal cell line. 168 32

Charybdotoxin, a blocker of K+ channels, and the imidazole drug SC38249, a blocker of both voltage- and second messenger-operated Ca2+ channels, were employed in mouse NIH-3T3 fibroblasts overexpressing the epidermal growth factor (EGF) receptor 1) to characterize the ionic events activated by EGF; and 2) to establish the role of those events in cell growth. The [Ca2+]i response by EGF was little changed by charybdotoxin while the parallel hyperpolarization was inhibited in a dose-dependent manner. At high toxin concentrations (greater than 3 x 10(-8) M), the effect of EGF on membrane potential was turned into a persistent depolarization sustained by both Na+ and Ca2+. Pretreatment with 10 microM SC38249 induced only minor changes of the intracellular Ca2+ release by EGF (the process responsible for the initial phase of the [Ca2+]i and membrane potential responses) and blocked the persistent, second phase [Ca2+]i and the hyperpolarization responses, both dependent on Ca2+ influx, as well as the depolarization in the charybdotoxin-pretreated cells. Long term (up to 2-day) treatment with either charybdotoxin or SC38249 failed to affect the viability and growth of unstimulated EGFR-T17 cells. Moreover, in these cells, the ionic responses to EGF were restored after a 30-min incubation in fresh medium. In contrast, growth stimulated by EGF was inhibited, moderately (-20%) by charybdotoxin and markedly (-60%) by SC38249. These results indicate for the first time that both hyperpolarization and, especially, the persistent increase of [Ca2+]i sustained by Ca2+ influx play a role in the activity of EGF, ultimately cooperating with other intracellular events in mitogenesis.
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PMID:Ionic events induced by epidermal growth factor. Evidence that hyperpolarization and stimulated cation influx play a role in the stimulation of cell growth. 170 15

The receptor for hepatocyte growth factor, also known as scatter factor (HGF/SF), has recently been identified as the 190-kDa heterodimeric tyrosine kinase encoded by the MET proto-oncogene (p190MET). The signaling pathway(s) triggered by HGF/SF are unknown. In A549 cells, a lung epithelial cell line, nanomolar concentrations of HGF/SF induced tyrosine phosphorylation of the p190MET receptor. The autophosphorylated receptor coprecipitated with phosphatidylinositol 3-kinase (PI 3-kinase) activity. In GTL16 cells, a cell line derived from a gastric carcinoma, the p190MET receptor, overexpressed and constitutively phosphorylated on tyrosine, coprecipitated with PI 3-kinase activity and with the 85-kDa PI 3-kinase subunit. In these cells activation of protein kinase C or the increase of intracellular [Ca2+] inhibits tyrosine phosphorylation of the p190MET receptor as well as the association with both PI 3-kinase activity and the 85-kDa subunit of the enzyme. In an in vitro assay, tyrosine phosphorylation of the immobilized p190MET receptor was required for binding of PI 3-kinase from cell lysates. These data strongly suggest that the signaling pathway activated by the HGF/SF receptor includes generation of D-3-phosphorylated inositol phospholipids.
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PMID:The tyrosine-phosphorylated hepatocyte growth factor/scatter factor receptor associates with phosphatidylinositol 3-kinase. 171 89

The sialyl-fucosyl-lactosamine-epitope present in sialyl (SA)-Lex (NeuAc alpha 2-3Gal beta 1-4 [Fuc alpha 1-3]GlcNAc beta 1-3Gal beta 1-4Glc-Cer), a carcinoembryonic antigen, has been recognized recently as a ligand for the binding of leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) to myeloid and tumour cell surfaces. We have recently detected the presence of an alpha 1-3 fucosyltransferase (FucT-3) activity in both embryonic chicken brain (ECB) and human colon carcinoma cells (Colo-205) which catalyses the biosynthesis in vitro of SA-Lex and SA-diLex. Fucosyltransferase activities from both sources are stimulated in the presence of divalent cations (Mn2+, Mg2+, Ca2+, Co2+ and Fe2+), although absolute metal requirement is not observed. Substrate specificity studies with this partially purified (ECB, 3000-fold; Colo-205, 100-fold) novel FucT-3 indicate the preference for terminally sialyl-substituted glycolipid acceptors, as observed by the lower Km values when sialyl-neolactotetraosyl ceramide, LM1, (Neu-Gc alpha 2-3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4 Glc-Cer; Km = 0.048 mM) and sialyl-norhexaosylceramide, NeuGc-nLc6, (Neu-Gc alpha 2-3Gal beta 1-4 GlcNAc beta 1-3Gal beta 1-4GlcNAc beta 1-3Gal beta 1-4Glc-Cer; Km = 0.032 mM) were used as substrates. Fucosyltransferase from Colo-205 requires the presence of the acyl group of the ceramide moiety and an acetyl group on glucosamine in the acceptor glycolipid since lyso-LM1 was found to be completely inactive.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biosynthesis in vitro of SA-Lex and SA-diLex by alpha 1-3 fucosyltransferases from colon carcinoma cells and embryonic brain tissues. 172 78

There is a critical need for new targets, in addition to DNA, for anticancer drug development. A recently discovered target is the intracellular signalling pathways that mediate the actions of growth factors and oncogenes on cell proliferation. Two important pathways, the myo-inositol and protein tyrosine kinase signalling pathways are reviewed. Three classes of compounds that modulate myo-inositol signalling are discussed. These are: 1) the D-3-substituted-3-deoxy-myo-inositol analogues that act as antimetabolites of myo-inositol and show selective growth inhibition of some transformed cells; 2) the alkaloid staurosporine that acts as a potent inhibitor of protein kinase C and of platelet-derived growth factor (PDGF) receptor protein tyrosine kinase activity; 3) the ether lipid analogues that block growth factor signalling at several points by acting as inhibitors of protein kinase C, phosphoinositide specific phospholipase C and inositol(1,4,5)trisphosphate-induced Ca2+ release. It is suggested that inhibition of signalling pathways may explain the growth inhibitory effects of these compounds. Other potential signalling target sites for anticancer drug development are discussed.
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PMID:Growth factor and oncogene signalling pathways as targets for rational anticancer drug development. 176 Aug 77

cDNA clones coding for novel protein kinase C delta (nPKC delta) were isolated from a mouse brain cDNA library. Mouse nPKC delta consists of 674 amino acid residues and has sequence identity of 95% with rat nPKC delta. Antiserum raised against a C-terminal peptide of rat nPKC delta identified a 79-kDa protein in COS cells transfected with a mouse nPKC delta cDNA expression plasmid. nPKC delta expressed in COS1 cells had phorbol-ester-binding activity and protein kinase activity in a phorbol-ester- or diacylglycerol-dependent manner, like conventional protein kinase C (cPKC) isozymes and nPKC epsilon. However, nPKC delta, like nPKC epsilon, is not activated by Ca2+, a known activator of cPKCs, and requires lower concentrations of Mg2+ for full activation than cPKCs. Moreover, apparent kinetic constants for synthetic oligopeptides (MBP4-14, EGFR peptide and epsilon-peptide) were quite different between nPKC delta and cPKC in two different conditions. Among various phospholipids tested, phosphatidylinositol is the most potent activator of nPKC delta, in clear contrast to cPKCs and nPKC epsilon. Limited proteolysis of nPKC delta generated a C-terminal active fragment with a cofactor-independent kinase activity. Northern blot analysis indicated that nPKC delta, like cPKC alpha, is widely distributed in almost all the tissues and cells examined and, in some cases such as fibroblast cells, exists as a major PKC type. These results suggest that nPKC delta is involved in fundamental cellular functions regulated by diacylglycerols and mimicked by phorbol esters.
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PMID:Structure and properties of a ubiquitously expressed protein kinase C, nPKC delta. 176 3

The effects of electrical field stimulation and of purine compounds, adenosine and adenosine-5'-triphosphate (ATP) were examined on the mouse isolated rectum. Electrical field stimulation induced frequency-dependent contractions of mouse rectal muscles which were potentiated by physostigmine and inhibited by atropine or tetrodotoxin. Contractile amplitude at 37 degrees C was significantly (P less than 0.05) greater than at 25 degrees C, but the degree of potentiation by physostigmine was significantly (P less than 0.05) greater at 25 degrees C. ATP (1.6 x 10(-4)-1.28 x 10(-3) M) and adenosine (1.8 x 10(-4)-1.48 x 10(-3) M) inhibited in concentration-related fashion contractile responses induced by KCl (1.34 x 10(-2) M-1.07 x 10(-1) M) by acetylcholine (2.2 x 10(-7) M-1.4 x 10(-5) M) and by CaCl2 in high KCl (120 mM)-CaCl2-free Tyrode solution. Theophylline and quinidine ('purinoceptor' antagonists) antagonized ACH contractile effects and so could not be satisfactorily employed in the characterization of the purine receptors in the mouse rectum. It may be concluded from this study that in the mouse rectum, acetylcholine is an excitatory neurotransmitter and that there is a non-adrenergic, non-cholinergic inhibitory neuromuscular transmission in this tissue. Further, ATP and adenosine have been demonstrated to cause relaxation in this tissue by possibly a post-synaptic mechanism involving inhibition of Ca2+ influx into the depolarized muscle.
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PMID:The effects of electrical stimulation, adenosine and adenosine-5'-triphosphate (ATP) on mouse rectal muscle. 187 77


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