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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bafilomycin A1, a selective inhibitor of vacuolar H+-ATPase, time- and dose-dependently induced the differentiation of M1 cells, a murine myeloid leukemic cell line, into macrophage-like cells as revealed by the phagocytosis of polystyrene latex particles. This differentiation was inhibited not only by actinomycin D and cycloheximide but also by ST-638 (an inhibitor of tyrosine kinase). However, it was affected neither by K-252a (an inhibitor of C-kinase) nor by H-89 (an inhibitor of A-kinase), in contrast to the M1 cell differentiation induced by leukemia inhibitory factor (LIF). Okadaic acid inhibited both the bafilomycin A1-induced and LIF-induced differentiation of M1 cells.
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PMID:Induction of phagocytic activity of M1 cells by an inhibitor of vacuolar H+-ATPase, bafilomycin A1. 750 42

We show here that a protein tyrosine phosphatase inhibitor, sodium orthovanadate, induces rat pheochromocytoma cells to express neurites, a prominent morphological marker of neuronal phenotype. Vanadate-induced differentiation and neurite outgrowth in pheochromocytoma cells was not as extensive as that induced by the positive control employed, nerve growth factor. However, neurite outgrowth responses were comparable between nerve growth factor-treated pheochromocytoma cells and cells primed and then restimulated with vanadate. In the human neuroblastoma cell line, SH-SY5Y, a single exposure to vanadate induced neurite extension in this cell line equal to that initiated by nerve growth factor. In both cell lines vanadate treatment resulted in tyrosine phosphorylation of several high-molecular-weight proteins and using anti-phosphotyrosine antibodies, intense fluorescence was observed in the cell body and neurites of pheochromocytoma cells exposed to vanadate. Vanadate mediated differentiation and neurite outgrowth in pheochromocytoma cells could be ablated by the tyrosine kinase inhibitor erbastatin, whereas nerve growth factor-induced neurite outgrowth was only partially inhibited. In SH-SY5Y cells, erbstatin mediated partial inhibition of both vanadate and nerve growth factor-induced neurite elongation with similar kinetics. In contrast, K252b, a trk tyrosine kinase inhibitor, exhibited only a 30% reduction of neurite outgrowth in vanadate treated pheochromocytoma cells but an 80% reduction in nerve growth factor-treated cells. In SH-SY5Y cells, K252a did not have a statistically significant effect on neurite elongation induced by vanadate in contrast to a 60% reduction in nerve growth factor-treated cells. The membrane impermeable analogue K252b, had no effect on neurite elongation induced with either vanadate or nerve growth factor in these cells. The effects of vanadate were not mimicked by ouabain (0.1-50 microM) indicating that vanadate does not induce differentiation and/or neurite extension by inhibiting ion channel Na,K-ATPase, which is one of its other well-characterised inhibitory activities. Evidence for the selective action of vanadate on some but not all neuronal cell lines comes from the fact that it did not induce neurite extension in the human neuroblastoma cell line SK-N-MC. These data imply that vanadate-induced neurite outgrowth responses in pheochromocytoma and SH-SY5Y cells can be induced by the inhibition of tyrosine phosphatases and appears not to simply mimic nerve growth factor signals. The target(s) of vanadate action in the two cell lines are currently being sought.
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PMID:Vanadate stimulates differentiation and neurite outgrowth in rat pheochromocytoma PC12 cells and neurite extension in human neuroblastoma SH-SY5Y cells. 752 Oct 24

1. The contractile actions of vanadate (VO4) and pervanadate (PV, peroxide(s) of vanadate) were studied in rat gastric longitudinal muscle strips and in aortic rings. The roles of extracellular sodium and calcium were evaluated and the potential effects of nerve-released agonists were considered. The possibility that these responses were due to the potentiation of tyrosine kinase activity, as a result of PV-mediated tyrosine phosphatase inhibition was explored with the use of tyrosine kinase inhibitors (genistein, tyrphostin) and by Western blot analysis of phosphotyrosyl proteins in PV-treated tissues. The ability of PV to mimic the action of the tyrosine kinase receptor-associated agonist, epidermal growth factor-urogastrone (EGF-Uro), in the gastric preparation was also studied. 2. PV caused concentration-dependent contractions in both gastric and aorta-derived tissues, with a potency that was 1 to 2 orders of magnitude greater than that of VO4. 3. Although repeated exposure of gastric and aortic tissues to a fixed concentration of VO4 caused reproducible contractions in both tissues, repeated exposure of gastric tissue to PV caused an increased contractile response plateauing after 3 exposures. In contrast, a single exposure of aortic tissue to PV (20 microM) caused a prolonged desensitization of the tissue to the subsequent contractile actions of PV or other agonists. 4. The contractile responses to PV were unaffected in both preparations by tetrodotoxin, atropine, yohimbine and phenoxybenzamine; and in the aortic preparation, the responses to VO4 and PV were the same in the presence or absence of a functional endothelium. 5. PV-induced contractions in both tissues were observed in the absence of extracellular sodium but required extracellular calcium and were attenuated by 1 micro M nifedipine.6. In the gastric preparation, the characteristics of the contractile actions of PV paralleled those of EGF-Uro in terms of (1) inhibition by genistein, (2) inhibition by indomethacin and (3) a requirement for extracellular calcium. These response characteristics differed from those of other contractile agonists such as carbachol.7. In both the gastric and aortic preparations genistein was able to inhibit PV-induced contractions selectively without causing comparable inhibition of KCI-induced contractions. Tyrphostin (AG18) also selectively blocked PV-induced contractions in the gastric, but not in the aortic preparation.8. In both the gastric and aortic tissue, in step with an increased contractile response, PV caused increases in tissue phosphotyrosyl protein content, as detected by Western blot analysis using a monoclonal antiphosphotyrosine antibody; the increases in phosphotyrosyl protein content were reduced when tissues were treated with PV at the same time as a tyrosine kinase inhibitor.9 PV, at sub-contractile concentrations, potentiated the contractile action of angiotensin II in both the gastric and aorta tissue.10 We conclude that the growth factor-mimetic agent, PV, is a much more potent contractile agonist than V04 in both vascular and gastric smooth muscle tissue. PV can cause enhanced tissue phosphotyrosyl protein content most likely via the inhibition of tissue protein tyrosine phosphatases. The contractile actions of PV, which require extracelullar calcium and are independent of extracellular sodium, would appear not to be due either to Na+/Ca2" exchange, promoted by Na+/K+-ATPase inhibition or to the inhibition of Ca2+-ATPase and might be best explained by the ability of PV, via tyrosine phosphatase inhibition, to potentiate a tyrosine kinase pathway linked to calcium entry and to the contractile process.
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PMID:Regulation of vascular and gastric smooth muscle contractility by pervanadate. 753 May 69

We have suggested that cyclopiazonic acid (CPA), a Ca(2+)-ATPase inhibitor, produces nitric oxide (NO) by triggering a Ca(2+)-influx resulting from Ca(2+)-depletion in the endoplasmic reticulum of endothelial cells. The tyrosine kinase inhibitor methyl 2,5-dihydroxycinnamate, while having no effect on relaxations induced by A23187 or Na nitroprusside, did inhibit the CPA-induced relaxation and cyclic GMP formation in rat aorta. Tyrosine kinase may participate in endothelial NO synthesis through activation of a Ca2+ entry mechanism.
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PMID:Tyrosine kinase may participate in Ca2+ entry for endothelial nitric oxide production. 761 95

The E5 polypeptide of bovine papillomavirus type 1 is a small membrane-bound protein which induces the transformation of immortalized fibroblasts, apparently via the formation of a ternary complex with the platelet-derived growth factor receptor (PDGFR) and the 16-kDa V-ATPase protein. This interaction seems to be mediated, at least in part, by their respective transmembrane domains. E5 also cooperates with transfected beta PDGFR to induce interleukin-3 (IL-3)-independent growth of a mouse myeloid precursor cell line (32D) which normally lacks expression of most known tyrosine kinase growth factor receptors. Cell proliferation induced by beta PDGFR and E5 is also highly specific, since the highly conserved alpha PDGFR and other related receptors did not physically or functionally interact with E5 in these cells. In the current study, analysis of chimeric alpha and beta PDGFRs confirmed that a short region encompassing the beta PDGFR transmembrane domain was sufficient for complex formation with E5, receptor autophosphorylation, and sustained proliferation of 32D cells in the absence of IL-3. Furthermore, a deletion mutant lacking the entire extracellular domain efficiently bound E5 and induced IL-3-independent growth. These data provide direct evidence that the interaction between E5 and the beta PDGFR involves amino acids 531 to 556 of the receptor transmembrane region and that this specific interaction is critical for activation of the PDGFR signaling complex.
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PMID:Mutational analysis of the beta-type platelet-derived growth factor receptor defines the site of interaction with the bovine papillomavirus type 1 E5 transforming protein. 766 52

We have investigated the mechanism of Ca2+ entry in fura-2-loaded human platelets using the inhibitors of tyrosine kinases, genistein, and methyl-2,5-dihydroxycinnamate. Genistein (100 microM; 30 min) or methyl-2,5-dihydroxycinnamate (1 microgram/ml; 30 min) reduced ADP-evoked protein-tyrosine phosphorylation at specific bands as assessed by gel electrophoresis and Western blotting with a specific antiphosphotyrosine antibody. Both compounds also reduced ADP-evoked [Ca2+]i rises in the presence, but not the absence, of external Ca2+, suggesting a relatively selective inhibition of Ca2+ entry over internal release. The inactive analogue of genistein, daidzein, was without effect on protein-tyrosine phosphorylation or ADP-evoked Ca2+ elevation in the presence or absence of external Ca2+. Methyl-2,5-dihydroxycinnamate (1 microgram/ml; 5 min) significantly reduced the Ca2+ influx evoked by depletion of the intracellular Ca2+ stores using the inhibitor of the endomembranous Ca(2+)-ATPase, thapsigargin. These results with tyrosine kinase inhibitors are unlikely to be the result of the inhibition of other protein kinases since kinases A, C, and G all inhibit agonist-evoked rises in [Ca2+]i in platelets. These data support a role for tyrosine kinases in the control of Ca2+ entry in human platelets.
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PMID:ADP- and thapsigargin-evoked Ca2+ entry and protein-tyrosine phosphorylation are inhibited by the tyrosine kinase inhibitors genistein and methyl-2,5-dihydroxycinnamate in fura-2-loaded human platelets. 768 40

Biologically active amidated gastrin is synthesized by carboxyl-terminal alpha-amidation of a glycine-extended progastrin post-translational processing intermediate (G-Gly). Although plasma levels of G-Gly are equivalent to those of gastrin, G-Gly has essentially no acute effect on gastric acid secretion. However, we have observed that inhibition of gastrin amidation leads to increased plasma concentrations of G-Gly and enhanced gastric acid secretion. We hypothesized, therefore, that G-Gly might have a chronic effect to increase H+,K(+)-ATPase expression in gastric parietal cells. In the present studies, we observed that a 2-day preincubation with G-Gly significantly enhanced histamine-stimulated [14C]aminopyrine uptake by isolated canine gastric parietal cells but acutely administered G-Gly had no effect. On Northern blot analysis, both G-Gly and gastrin dose-dependently increased H+,K(+)-ATPase alpha-subunit gene expression with maximal induction (225 +/- 35 and 170 +/- 29% of basal, mean +/- S.E.) achieved at concentrations of 10(-9) M G-Gly and 10(-8) M gastrin, respectively. Using an H+,K(+)-ATPase alpha-subunit gene-luciferase chimeric reporter construct transfected into primary cultured parietal cells, we observed that both G-Gly and gastrin increased luciferase activity in a manner similar to that obtained by Northern blot analysis. L365,260, a specific gastrin/CCKB receptor antagonist, completely reversed the stimulation of luciferase activity induced by gastrin but had no effect on G-Gly-stimulated activity. Gastrin increased [Ca2+]i, although G-Gly did not, however, genistein (a tyrosine kinase inhibitor) significantly reduced induction of luciferase activity by both G-Gly and gastrin. Specific binding of 125I-Leu15-G2-17-Gly to gastric parietal cells was dose-dependently displaced by G2-17-Gly but not by gastrin nor L365,260. Gastrin peptides truncated at the carboxyl- (G1-13) and amino terminus (G5-17-Gly) both induced H+,K(+)-ATPase alpha-subunit gene expression and inhibited 125I-Leu15-G2-17-Gly binding, but were less potent than G2-17-Gly. These data indicate that G-Gly may have a functional role in potentiating gastric acid secretagogue action via enhanced expression of the gene responsible for H+ generation through action at a novel receptor that can be distinguished from the gastrin/CCKB receptor. Thus, both the substrate and product of the terminal progastrin processing reaction appear to have complementary functions in regulation of gastric acid secretion.
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PMID:Glycine-extended progastrin processing intermediates induce H+,K(+)-ATPase alpha-subunit gene expression through a novel receptor. 774 46

Progesterone (P) has previously been shown to induce a rapid increase in [Ca2+]i as well as tyrosine phosphorylation of proteins in human spermatozoa. Both these effects are essential for induction of the acrosome reaction by P. We investigated a possible relationship between the P-induced calcium increase and tyrosine kinase activation, by evaluating the effect of the tyrosine kinase inhibitor genistein on these two effects. We found that preincubation with genistein abolished P-induced tyrosine phosphorylation of two sperm proteins of 97 and 75 kDa molecular weight and significantly inhibited the plateau phase of P-induced [Ca2+]i increase without affecting the peak phase. Conversely, the plateau phase was enhanced by the tyrosine phosphatase inhibitor Na3VO4. The effect of genistein was specific for P, since no inhibition was observed on the [Ca2+]i increase induced by thapsigargin, an inhibitor of endoplasmic Ca(2+)-ATPase previously shown to mobilize Ca2+ in spermatozoa. These results indicate that tyrosine kinase activation is involved in the generation of the plateau phase of Ca2+ influx induced by P, and suggest the possibility that two different pathways are involved in the induction of Ca2+ entry by P in human sperm.
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PMID:Tyrosine kinase inhibition reduces the plateau phase of the calcium increase in response to progesterone in human sperm. 775 May 49

In fetal rat brain neurons, activation of voltage-dependent Na+ channels induced their own internalization, probably triggered by an increase in intracellular Na+ level. To investigate the role of phosphorylation in internalization, neurons were exposed to either activators or inhibitors of cyclic AMP- and cyclic GMP-dependent protein kinases, protein kinase C, and tyrosine kinase. None of the tested compounds mimicked or inhibited the effect of Na+ channel activation. An increase in intracellular Ca2+ concentration induced either by thapsigargin, a Ca(2+)-ATPase blocker, or by A23187, a Ca2+ ionophore, was unable to provoke Na+ channel internalization. However, Ca2+ seems to be necessary because both neurotoxin- and amphotericin B-induced Na+ channel internalizations were partially inhibited by BAPTA-AM. The selective inhibitor of Ca2+/calmodulin-dependent protein kinase II, KN-62, caused a dose-dependent inhibition of neurotoxin-induced internalization due to a blockade of channel activity but did not prevent amphotericin B-induced internalization. The rate of increase in Na+ channel density at the neuronal cell surface was similar before and after channel internalization, suggesting that recycling of internalized Na+ channels back to the cell surface was almost negligible. Pretreatment of the cells with an acidotropic agent such as chloroquine prevented Na+ channel internalization, indicating that an acidic endosomal/lysosomal compartment is involved in Na+ channel internalization in neurons.
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PMID:Internalization of voltage-dependent sodium channels in fetal rat brain neurons: a study of the regulation of endocytosis. 779 Aug 86

The capacitative regulation of intracellular chloride concentration ([Cl-]i) was measured in intact human lymphocytes using the Cl(-)-sensitive fluorescence dye 6-methoxy-1-(3-sulfonato-propyl)-quinolinium (SPQ). The fluorescence was measured at 433 nm with the excitation wavelength of 344 nm. The emptying of intracellular Ca2+ stores after the specific inhibition of the endoplasmic Ca2+ ATPase by thapsigargin produced a concentration-dependent transplasmamembrane Cl- influx. The thapsigargin-induced Cl- increase was also seen in the absence of extracellular Ca2+, but it was significantly reduced after the addition of the Cl- exchange blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. The thapsigargin-induced Cl- increase was significantly reduced after the specific inhibition of tyrosine kinase by genistein or tyrphostin A25. It is concluded that the depletion of intracellular Ca2+ pools triggers transplasmamembrane Cl- influx by a tyrosine kinase-dependent mechanism.
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PMID:Depletion of intracellular calcium stores triggers transplasmamembrane chloride influx in human lymphocytes: regulation by tyrosine kinase. 779 54


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