Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The differential assay conditions for protein phosphatases PP1, PP2A, and PP2C were extensively studied by using crude extracts from mouse lymphoid tissues as enzyme sources. Under these conditions, the protein phosphatase activities were measured in MRL/MpJ-lpr/lpr mice (MRL/lpr mice), autoimmune-prone mice, and MRL/MpJ(-)+/+ mice (MRL/+/+ mice) and C3H/HeJ mice as the controls. In MRL/lpr mice, significant alterations in protein phosphatase activities from those in the control mice were demonstrated. In spleen and liver from MRL/lpr mice, potential activities of PP1 and PP2A were distinctly elevated over those of the control mice. These elevations appeared to be due to accumulation of the abnormal lymphocytes that emerged in MRL/lpr mice. Although the PP1 activity in MRL/lpr lymph nodes was lower than those of normal spleen and thymus, it was greatly increased by Co(2+)-trypsin treatment so that the PP1 activity of MRL/lpr lymph nodes was the highest among those of all the tissues examined. In contrast, PP2C activity showed no remarkable alteration in the autoimmune disease model mice as compared with that in the control mice. These results demonstrated a specific elevation in potency of protein dephosphorylation in the tissues of MRL/lpr mice, suggesting a new explanation for the defect in signal transduction in this disease.
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PMID:Increase in potential activities of protein phosphatases PP1 and PP2A in lymphoid tissues of autoimmune MRL/MpJ-lpr/lpr mice. 131 90

Type 2C protein phosphatase (PP2C) is one of four major serine-threonine specific phosphoprotein phosphatases which modulate various intracellular activities. By in situ hybridization analysis of the adult rat, expression signals of mRNA for PP2C were observed most highly in the granule cells and Purkinje cells of the cerebellum, the pyramidal cells of the hippocampus and granule cells of the dentate gyrus, and plexus choroideus of the lateral ventricle, whereas moderate levels of its expression were observed in the medial habenula, piriform cortex and the pineal body. Several discrete nuclei of the brainstem including pars compacta of the substantia nigra, the pontine nuclei, and the locus ceruleus expressed the mRNA moderately. Weak expression of PP2C mRNA was observed in mitral and internal granule cells of the olfactory bulb, spinal cord gray matter, the cerebral neocortex, thalamic and hypothalamic nuclei. Only faint expression was detected in the caudate putamen. These patterns of expression are different from that of calcineurin/PP2B reported by other immunohistochemical studies and it is suggested that various neuronal proteins are differentially dephosphorylated by the different types of PP.
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PMID:Localization of mRNA for protein phosphatase 2C in the brain of adult rats. 132 Jul 18

Calcineurin, a Ca2+, calmodulin-dependent protein phosphatase, was recently found to bind with high affinity to two different immunosuppressant binding proteins (immunophilins) with absolute dependence on the presence of the immunosuppressants FK506 or cyclosporin A (CsA) [Liu et al. (1991) Cell 66, 807-815]. The binding affinities of the immunophilin-drug complexes toward calcineurin and the stoichiometry of the resultant multimeric complexes have now been determined, and structural elements of FK506, CsA, and calcineurin that are critical for mediating their interactions have been identified. Analogues of FK506 (FK520, FK523, 15-O-demethyl-FK520) and CsA (MeBm2t1-CsA and MeAla6-CsA) whose affinities for their cognate immunophilins do not correlate with their immunosuppressive activities have been prepared and evaluated in biochemical and cellular assays. We demonstrate a strong correlation between the ability of these analogues, when bound to their immunophilins, to inhibit the phosphatase activity of calcineurin and their ability to inhibit transcriptional activation by NF-AT, a T cell specific transcription factor that regulates IL-2 gene synthesis in human T cells. In addition, FKBP-FK506 and CyP-CsA do not inhibit members of the PP1, PP2A, and PP2C classes of serine/threonine phosphatases. These data suggest that calcineurin is the relevant cellular target of these immunosuppressive agents and is involved in Ca(2+)-dependent signal transduction pathways in, among others, T cells and mast cells.
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PMID:Inhibition of T cell signaling by immunophilin-ligand complexes correlates with loss of calcineurin phosphatase activity. 137 50

Sucrose-phosphate synthase (SPS) purified from spinach leaves harvested in the dark, was activated by mammalian protein phosphatase 2A (PP2A). Activation of SPS in a fraction from darkened spinach leaves was largely prevented by either okadaic acid or microcystin-LR (specific inhibitors of PPI and PP2A), while inhibitor-2 (a PP1 inhibitor) or Mg2+ (essential for PP2C) were ineffective. In vivo, okadaic acid and microcystin-LR prevented the light-induced activation of SPS and decreased sucrose biosynthesis and CO2 fixation. It is concluded that PP2A is the major SPS phosphatase in spinach. This study is the first to employ microcystin-LR for modulating protein phosphorylation in vivo.
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PMID:Sucrose-phosphate synthase is dephosphorylated by protein phosphatase 2A in spinach leaves. Evidence from the effects of okadaic acid and microcystin. 217 89

Thyrsiferyl 23-acetate (TF23A), a cytotoxic compound from marine red alga, has been shown to potently and specifically inhibit serine/threonine protein phosphatase 2A (PP2A) with IC50 values of 4-16 microM, depending on the enzyme concentration. TF23A did not affect activity of protein phosphatase 1 (PP1), 2B (PP2B), 2C (PP2C), or protein tyrosine phosphatases (PTP) up to 1 mM. It inhibited PP2A activity in a crude extract of a human T cell line, Jurkat cell, as well as the purified catalytic subunit. Thus, TF23A proved to be a novel useful probe for clearly distinguishing the activity of PP2A from those of the other protein phosphatases in crude cell extracts and identification of cellular processes that are regulated by PP2A.
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PMID:Thyrsiferyl 23-acetate is a novel specific inhibitor of protein phosphatase PP2A. 780 52

We isolated the first membrane-bound type 2C serine/threonine protein phosphatase from the ciliated protozoan Paramecium tetraurelia (PtPP2C). Three isozymes of 33, 32, and 31 kDa with a specific activity of 1 mumol.min-1.mg1 were purified from the ciliary membrane. All enzymatic properties including (a) insensitivity toward inhibitors of other protein phosphatase families such as okadaic acid and microcystin, (b) absolute requirement for divalent cations, and (c) substrate specificity tested with synthetic phosphopeptides were identical to mammalian PP2C enzymes and identified the PtPP2C as a canonical PP2C in spite of it being about 25% smaller. The NH2-terminal was blocked. Microsequencing of six tryptic peptides established a relationship to other PP2C enzymes. The PtPP2C gene was obtained using degenerate oligonucleotide primers and the polymerase chain reaction. The gene coded for a 33-kDa protein with 300 amino acids and had an (A+T) content of 62%, typical for this protozoan. Nine of 15 Gln residues are encoded by TAA, a universal stop codon which codes for Gln in Paramecium. A large truncation at the COOH-terminal is responsible for the smaller size of the PtPP2C. Only a single transcript of 1 kilobase was detected with a Northern blot indicating that the 32- and 31-kDa proteins were proteolytic products of the 33-kDa enzyme. Sequence comparisons with PP2C enzymes from rat, rabbit, yeast, Arabidopsis, and Leishmania defined a highly diverged enzyme family which shares three conserved domains, I, II, and III, accounting for about 25% of the primary structure. We demonstrated further that the distances between domains I/II and II/III are very similar in all PP2C enzymes (9-13 and 74-80 amino acids, respectively). However, the amino acid sequences of the spacer regions are unrelated. In addition, the COOH-terminal ends of 100-200 amino acids which comprise 30-50% of the enzyme, display no identity. A dendrogramm shows that PtPP2C surprisingly is most closely related to the mammalian PP2C, and enzymes from Leishmania, Arabidopsis, and yeast are more distant relatives.
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PMID:A membrane-bound protein phosphatase type 2C from Paramecium tetraurelia. Purification, characterization, and cloning. 780 99

The gene expression for alpha and beta isoforms of type 2A protein phosphatase (PP2A-alpha and -beta) in the adult rat brain was examined by in situ hybridization analysis. No marked difference in the gene expression was discerned between the two isoforms in large portions of brain, except for the thalami in which the expression level for the alpha isoform was similar to that in the cerebral neocortex whereas that for the beta was lower than that in the neocortex. The gene expression was observed intensely in the piriform cortex, the cerebellar Purkinje and granule cell layers, and the hippocampal pyramidal and dentate granule cell layers, and the locus ceruleus, whereas the moderate levels of its expression were observed in the olfactory mitral cells and the pontine nuclei. The cerebral neocortex expressed the mRNA moderately to weakly without any laminar patterns, whereas the expression level in the caudate-putamen was very low. This expression pattern is basically similar to that of PP2C reported previously, except for the plexus choroideus and ependyma having no significant expression for PP2A.
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PMID:Localization of mRNA for protein phosphatase 2A in the brain of adult rats. 801 74

Gene expression of protein phosphatases 1 alpha, 1 gamma 1, 2A alpha, and 2C alpha in 14 rat ascites hepatoma cell lines was studied by Northern blot hybridization. The expression of PP1 alpha and PP2C alpha was increased and decreased, respectively, in all of the ascites hepatoma (AH) cells compared to rat liver, whereas the expression of PP1 gamma 1 and PP2A alpha was increased in about 50% of them. Relative gene expression was affected by several factors, such as harvest time, transplantation rate, percentage of free cells, and sex; the first factor was more important than the others. Relative gene expression of PP1 alpha had a negative correlation with harvest time, whereas gene expression of PP1 gamma 1 and PP2A alpha had a nonlinear (hyperbolic) correlation with harvest time. We suggest that there is a relationship between growth rate and expression of protein phosphatase genes. Our data also suggest that PP1 gamma 1 mRNA is positively controlled by PP2A alpha mRNA.
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PMID:Gene expression of protein phosphatases in rat ascites hepatoma cell lines. 802 93

The target site for cantharidin (CA) and its analogues was isolated recently from mouse liver and identified as protein phosphatase (PP2A) in the heterodimeric form known as PP2A2. The most toxic CA analogue, endothall thioanhydride (ETA) (mouse i.p. LD50 0.3 mg/kg), appears to have the same binding site in mouse liver and brain based on studies comparing [3H]ETA and [3H]CA. ATP and its nonhydrolyzable analogues and pyrophosphate and related compounds including phosphonoformic acid inhibited both [3H]CA and [3H]ETA binding with IC50 values ranging from 2 to 81 microM. As with CA itself, the most potent inhibitors have two negatively charged groups in close proximity to each other. Inhibition of [3H]CA binding by 5,5'-dithiobis(2-nitrobenzoic acid) and stimulation by N-ethylmaleimide indicated the involvement of a thiol site in the CA-binding domain. CA and three analogues (cantharidic acid, palasonin and endothall) inhibited PP2A and protein phosphatase 1 (PP1) but not PP2B or PP2C. The catalytic subunit of PP2A was 5- to 12-fold more sensitive to these CA analogues than the catalytic subunit of PP1. CA and the herbicide endothall also inhibited spinach leaf PP1 and PP2A and, at 50 microM, decreased the PP2A-mediated light-induced activation of nitrate reductase in intact spinach leaves by 62 and 56%, respectively. This is consistent with PP2A as their site of action in plants, and indicates the potential use of CA analogues as pharmacological probes to investigate cellular processes that are regulated by reversible protein phosphorylation in vivo.
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PMID:Protein phosphatase 2A and its [3H]cantharidin/[3H]endothall thioanhydride binding site. Inhibitor specificity of cantharidin and ATP analogues. 824 Mar 93

Using rabbit serum raised against a potent T cell-stimulating antigen fraction of Leishmania chagasi promastigotes, we have cloned and expressed the Leishmania type 2C serine/threonine protein phosphatase, LcPP2C. LcPP2C was shown to be present as a 42-kDa protein in both the infective promastigote and tissue amastigote stages of L. chagasi and Leishmania amazonensis. DNA hybridization studies established the close conservation of LcPP2C among eight of eight geographically diverse species of Leishmania which cause a spectrum of human diseases. To support the relationship between LcPP2C and mammalian type 2C protein phosphatases observed through predicted amino acid sequence comparisons, we expressed enzymatically active rLcPP2C in Escherichia coli. We demonstrated that purified rLcPP2C readily dephosphorylated [32P]casein, an activity dependent on Mg2+ and insensitive to okadaic acid. In agreement with studies of rat liver PP2C, activity was maintained when Mg+2 was replaced with Mn+2 but not with Ca2+. As these parameters are characteristic of the eukaryotic type 2C serine/threonine protein phosphatases, LcPP2C can be classified as a member of this protein family. We further showed that of the four major classes of eukaryotic serine/threonine protein phosphatases, PP2C-and PP1-like activities, are readily detectable in Leishmania.
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PMID:Molecular cloning and characterization of a 42-kDa protein phosphatase of Leishmania chagasi. 839 31


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