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:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that the sarcolemmal Na+-K+ pump current (Ip) in cardiac myocytes is stimulated by cell swelling induced by exposure to hyposmolar solutions. However, the underlying mechanism has not been examined. Because cell swelling activates stretch-sensitive ion channels and intracellular messenger pathways, we examined their role in mediating Ip stimulation during exposure of rabbit ventricular myocytes to a hyposmolar solution. Ip was measured by the whole cell patch-clamp technique. Swelling-induced pump stimulation altered the voltage dependence of Ip. Pump stimulation persisted in the absence of extracellular Na+ and under conditions designed to minimize changes in intracellular Ca2+, excluding an indirect influence on Ip mediated via fluxes through stretch-activated channels. Pump stimulation was protein kinase C independent. The tyrosine kinase inhibitor tyrphostin A25, the phosphatidylinositol 3-kinase inhibitor LY-294002, and the protein phosphatase-1 and -2A inhibitor okadaic acid abolished Ip stimulation. Our findings suggest that swelling-induced pump stimulation involves the activation of tyrosine kinase, phosphatidylinositol 3-kinase, and a serine/threonine protein phosphatase. Activation of this messenger cascade may cause activation by the dephosphorylation of pump units.
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PMID:Mechanisms of Na+-K+ pump regulation in cardiac myocytes during hyposmolar swelling. 1032 57

The insecticide carbaryl and its metabolite 1-naphthol cause partial uncoupling of karyokinesis and cytokinesis in V79 Chinese hamster fibroblasts; karyokinesis is blocked in metaphase, the microtubules of the spindle depolymerize and the chromosomes and spindle remnants become displaced to the periphery of the cell. A high frequency of these disturbed cells elongate and a smaller fraction initiate a cleavage furrow. Here, we attempt to determine the potential targets for carbaryl and 1-naphthol in cytokinesis-specific signalling, led by the fact that the potential protein phosphatase inhibitor 1-naphthyl phosphate was previously identified in treated cells. We found that the typical cytological pattern induced by carbaryl and 1-naphthol could be obtained with tyrphostins, specific tyrosine kinase inhibitors, indicating that the carbaryl-induced effects could be due to tyrosine kinase inhibition. This was confirmed by tyrosine kinase assays showing that carbaryl, 1-naphthol and 2-naphthol were equally efficient at inhibiting tyrosine kinase activity as tyrphostin B44(-). As tyrosine kinases can act as regulatory factors in determining dephosphorylation rates, the activities of type-1 (PP1) and type-2A (PP2A) serine/threonine protein phosphatases were also determined. There was a clear up-regulation of the overall PP1/PP2A activities in cells treated with carbaryl, 1-naphthol or tyrphostin B44(-). This stimulation was shown to be indirect because these compounds had no effect on the activity of purified human PP1 in the test tube. 2-Naphthol, which has been found to be less efficient with regard to displacement of chromatin, did not cause up-regulation, but a significant decrease in PP1/PP2A activity. We suggest that a net decrease in tyrosine kinase activity in combination with a net increase in PP1/PP2A activity is a precondition for cell elongation and cytokinesis in mammalian cells and that the corresponding enzymes are targets in the network of activities serving to coordinate karyokinesis and cytokinesis.
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PMID:Mitotic aberrations induced by carbaryl reflect tyrosine kinase inhibition with coincident up-regulation of serine/threonine protein phosphatase activity: implications for coordination of karyokinesis and cytokinesis. 1037 1

Ligand binding to the angiotensin II (Ang II) AT1 receptor on vascular smooth muscle cells (VSMCs) activates the Janus-activated kinase (JAK)/signal transducers and activators of transcription (STAT) pathway. We have shown previously that the JAK2 tyrosine kinase and the Src family p59 Fyn tyrosine kinase are required for Ang II-induced STAT1 tyrosine phosphorylation in VSMCs. The mitogen-activated protein kinase phosphatase, MKP-1, is required for STAT1 tyrosine dephosphorylation. In the present study, using specific enzyme inhibitors and antisense oligonucleotides, we show that Ang II-induced tyrosine phosphorylation and nuclear translocation of STAT3 in VSMCs is mediated by p60 c-Src, whereas tyrosine dephosphorylation is mediated by calcineurin. Calcineurin is activated in response to Ang II stimulation of VSMCs and is translocated to the nucleus. In addition, we show that Ang II-induced serine phosphorylation of STAT3 in VSMCs is mediated by mitogen-activated protein kinase and that dephosphorylation is mediated by protein phosphatase 2A (PP2A). PP2A translocates to the nucleus in response to Ang II stimulation of VSMCs and forms a complex with STAT3 in an Ang II-dependent manner.
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PMID:Regulation of angiotensin II-induced phosphorylation of STAT3 in vascular smooth muscle cells. 1039 29

The objective of this study was to investigate the effects of insulin and insulin-like growth factor I on transepithelial Na(+) transport across porcine glandular endometrial epithelial cells grown in primary culture. Insulin and insulin-like growth factor I acutely stimulated Na(+) transport two- to threefold by increasing Na(+)-K(+) ATPase transport activity and basolateral membrane K(+) conductance without increasing the apical membrane amiloride-sensitive Na(+) conductance. Long-term exposure to insulin for 4 d resulted in enhanced Na(+) absorption with a further increase in Na(+)-K(+) ATPase transport activity and an increase in apical membrane amiloride-sensitive Na(+) conductance. The effect of insulin on the Na(+)-K(+) ATPase was the result of an increase in V(max) for extracellular K(+) and intracellular Na(+), and an increase in affinity of the pump for Na(+). Immunohistochemical localization along with Western blot analysis of cultured porcine endometrial epithelial cells revealed the presence of alpha-1 and alpha-2 isoforms, but not the alpha-3 isoform of Na(+)-K(+) ATPase, which did not change in the presence of insulin. Insulin-stimulated Na(+) transport was inhibited by hydroxy-2-naphthalenylmethylphosphonic acid tris-acetoxymethyl ester [HNMPA-(AM)(3)], a specific inhibitor of insulin receptor tyrosine kinase activity, suggesting that the regulation of Na(+) transport by insulin involves receptor autophosphorylation. Pretreatment with wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase as well as okadaic acid and calyculin A, inhibitors of protein phosphatase activity, also blocked the insulin-stimulated increase in short circuit and pump currents, suggesting that activation of phosphatidylinositol 3-kinase and subsequent stimulation of a protein phosphatase mediates the action of insulin on Na(+)-K(+) ATPase activation.
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PMID:Insulin stimulates transepithelial sodium transport by activation of a protein phosphatase that increases Na-K ATPase activity in endometrial epithelial cells. 1049 74

The effect of genistein on anion secretion via cystic fibrosis transmembrane conductance regulator (CFTR) in cultured rat cauda epididymal epithelia was studied by short-circuit current (Isc) technique. Genistein added apically stimulated a concentration-dependent rise in Isc due to Cl(-) and HCO(3)(-) secretion. The genistein-induced Isc was observed in basolaterally permeabilized monolayers, suggesting that the Isc response was mediated by the apical anion channel. The response could be blocked by the nonspecific Cl(-) channel blocker, diphenylamine-2-carboxylate (DPC), but not by the Ca(2+)-activated Cl(-) channel blocker, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS). Genistein did not increase intracellular cAMP, but H-89, a protein kinase A inhibitor, completely abolished the Isc response to genistein. Moreover, pretreatment of the tissues with MDL-12330A, an adenylate cyclase inhibitor, markedly attenuated the Isc response to genistein, but the response was restored upon the addition of exogenous cAMP. Ca(2+), protein kinase C, tyrosine kinase, and protein phosphatase signalling pathways were not involved in the action of genistein. It is speculated that genistein stimulates anion secretion by direct interaction with CFTR. This requires a low level of phosphorylation of CFTR by basal protein kinase A activity. It is suggested that genistein may provide therapeutic benefit to male infertility associated with cystic fibrosis.
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PMID:Activation of cystic fibrosis transmembrane conductance regulator in rat epididymal epithelium by genistein. 1061 Oct 78

Insulin enhances Na(+)-K(+) pump activity in various noncardiac tissues. We examined whether insulin exposure in vitro regulates Na(+)-K(+) pump function in rabbit ventricular myocytes. Pump current (I(p)) was measured using the whole-cell patch-clamp technique at test potentials (V(m)s) from -100 to +60 mV. When the Na(+) concentration in the patch pipette ([Na](pip)) was 10 mM, insulin caused a V(m)-dependent increase in I(p). The increase was approximately 70% when V(m) was at near physiological diastolic potentials. This effect persisted after elimination of extracellular voltage-dependent steps and when K(+) and K(+)-congeners were excluded from the patch pipettes. When [Na](pip) was 80 mM, causing near-maximal pump stimulation, insulin had no effect, suggesting that it did not cause an increase in membrane pump density. Effects of tyrphostin A25, wortmannin, okadaic acid, or bisindolylmaleimide I in pipette solutions suggested that the insulin-induced increase in I(p) involved activation of tyrosine kinase, phosphatidylinositol 3-kinase, and protein phosphatase 1, whereas protein phosphatase 2A and protein kinase C were not involved.
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PMID:Voltage-dependent stimulation of the Na(+)-K(+) pump by insulin in rabbit cardiac myocytes. 1071 43

Calcineurin was shown previously to be inhibited by members of the tyrphostin family of tyrosine kinase inhibitors, with the most effective inhibition suggested to be caused by the presence of a conjugated side chain (Martin BL, Biochem Pharmacol 56: 483-488, 1998). Retinoids are a family of naturally occurring biomolecules having non-aromatic ring structures and conjugated side chains as substituents on the ring. Three oxidation states of the all-trans configuration of retinoids (retinol, retinal, and retinoic acid) were tested as effectors of calcineurin. Only retinoic acid was found to inhibit calcineurin effectively, with an IC(50) value of approximately 50 microM. Retinol and retinal caused less than 30% inhibition at concentrations up to 100 microM. All three retinoids caused some precipitation of reaction components: retinoic acid and retinal above 50 microM, and retinol above 250 microM. Bacterial alkaline phosphatase was not inhibited by the retinoids, indicating that metal centers alone are insufficient for significant inhibition by retinoic acid. An aromatic ring was not required for inhibition and may not provide additional inhibition, inasmuch as an aromatic analog of retinoic acid (acitretin) showed less effective inhibition. These data are consistent with the presence of conjugated, unsaturated groups enhancing the inhibition of calcineurin.
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PMID:In vitro effect of retinoids on calcineurin activity. 1093 May 34

Regucalcin was discovered in 1978 as a Ca(2+)-binding protein that does not contain EF-hand motif of Ca(2+)-binding domain [Yamaguchi, M., and Yamamoto T., Chem. Pharm. Bull. 26, 1915-1918, 1978]. The name regucalcin was proposed for this Ca(2+)-binding protein, which can regulate liver cell functions related to Ca(2+). Regucalcin has been demonstrated to play a multifunctional role in liver and kidney cells, for which regucalcin mRNA expression and its protein content are pronounced. Hepatic regucalcin mRNA expression has been shown to be mediated through signaling pathway of Ca(2+)/calmodulin-dependent protein kinase, protein kinase C, and tyrosine kinase. AP-1- and NF-1-like factors can bind to the promotor region of the rat regucalcin gene to mediate the Ca(2+) response for transcriptional activation. Growing evidence supports the view, moreover, that regucalcin plays an important role in the regulation of Ca(2+) signaling from the cytoplasm to nuclei in the proliferative cells of regenerating rat liver. Also, regucalcin has been demonstrated to be transported to liver nucleus, and it can inhibit nuclear protein kinase, protein phosphatase, and DNA and RNA synthesis in regenerating liver. Regucalcin plays a physiologic role in the control for overexpression of proliferative cells. Regucalcin has been proposed to be an important regulatory protein in nuclear signaling system.
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PMID:The role of regucalcin in nuclear regulation of regenerating liver. 1100 72

Several lines of evidence suggest that phosphorylation events play an important role in transducing neurite outgrowth signals. Here we tested if such phosphorylation events altered filopodial dynamics on neuronal growth cones and thereby might affect pathfinding decisions. The general protein kinase inhibitor K252a caused an increase in the overall length of filopodia, thereby increasing the action radius of a growth cone. Application of specific kinase inhibitors demonstrated that myosin light chain kinase, Ca/calmodulin-dependent kinase II, and protein kinase A were likely not involved in this filopodial response. Inhibition of protein kinase C (PKC) with calphostin C or cerebroside, however, induced filopodial elongation similar to that seen with K252a. Activation of PKC with the phorbol ester PMA produced the opposite effect, namely filopodial shortening. Consistent with this finding, the protein phosphatase activator C(2)-ceramide resulted in a significant increase in filopodial length, whereas application of the protein phosphatase inhibitor okadaic acid caused the opposite effect, filopodial shortening. Lastly, the tyrosine kinase inhibitor genistein also caused filopodial elongation, and this effect could be negated by the tyrosine phosphatase inhibitor sodium ortho-vanadate. Using the calcium indicator fura-2, we further showed that these drugs did not cause a measurable change in the free intracellular calcium concentration ([Ca(2+)](i)) in growth cones. Taken together, these results suggest that the action radius of a growth cone and its resulting pathfinding abilities could be rapidly altered by contact with extracellular cues, leading to changes in the activity of protein kinases and phosphatases.
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PMID:Filopodial behavior is dependent on the phosphorylation state of neuronal growth cones. 1109 53

Nuclear inhibitor of protein phosphatase-1 (NIPP1; 351 residues) is a nuclear RNA-binding protein that also contains in its central domain two contiguous sites of interaction with the catalytic subunit of protein phosphatase-1 (PP1(C)). We show here that mutation of these phosphatase-interaction sites did not completely abolish the ability of NIPP1 to bind and inhibit PP1(C). This could be accounted for by an additional inhibitory phosphatase-binding site in the C-terminal region (residues 311-351), with an inhibitory core corresponding to residues 331-337. Following mutation of all three PP1(C)-binding sites in the central and C-terminal domains, NIPP1 no longer interacted with PP1(C). Remarkably, while both NIPP1 domains inhibited the phosphorylase phosphatase activity of PP1(C) independently, mutation of either domain completely abolished the ability of NIPP1 to inhibit the dephosphorylation of myelin basic protein. The inhibitory potency of the C-terminal site of NIPP1 was decreased by phosphorylation of Tyr-335 and by the addition of RNA. Tyr-335 could be phosphorylated by tyrosine kinase Lyn, but only in the presence of RNA. In conclusion, NIPP1 contains two phosphatase-binding domains that function co-operatively but which are controlled independently. Our data are in agreement with a shared-site model for the interaction of PP1(C) with its regulatory subunits.
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PMID:The C-terminus of NIPP1 (nuclear inhibitor of protein phosphatase-1) contains a novel binding site for protein phosphatase-1 that is controlled by tyrosine phosphorylation and RNA binding. 1110 70


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