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)

The polyamines, spermine and spermidine, activate a high molecular weight form of phosphorylase a phosphatase isolated from rat liver. This broad specificity protein phosphatase (type 2A) was partially purified, using both protein and non-protein phosphoester substrates. Spermine and spermidine activated isolated protein phosphatase-2A1 (apparent Mr 210,000) approximately 2-fold, when p-nitrophenyl phosphate (PNPP) was used as substrate. Freeze-thawing, which activated the phosphatase activity against a variety of phosphoprotein substrates, also increased the extent of stimulation of PNPP phosphatase activity by spermine (8 to 9-fold with Ka of 93 microM) and spermidine (6 to 7-fold with Ka 280 microM). Kinetic analysis indicated that the activation of phosphatase by polyamines was accomplished by an increase in Vmax of the enzyme, by a mechanism independent of that achieved by other cations. The data indicate that polyamines, at physiological concentrations, can activate a form of protein phosphatase widely distributed in mammalian tissues, and thereby influence cellular protein phosphorylation.
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PMID:Polyamine stimulation of protein phosphatase-2A from rat liver using a non-protein phosphoester substrate. 304 Aug 20

Mitochondria from a variety of sources possess a regulated inner membrane channel, the permeability transition pore (MTP), which is responsible for the 'permeability transition', a sudden permeability increase to solutes with molecular masses < or = 1500 Da, most easily observed after Ca2+ accumulation. The MTP is a voltage-dependent channel blocked by cyclosporin A with Ki in the nanomolar range. The MTP open probability is regulated by both the membrane potential and matrix pH. The probability of pore opening increases as the membrane is depolarized, while it decreases as matrix pH is decreased below 7.3 through reversible protonation of histidine residues. Many physiological and pathological effectors, including Ca2+ and ADP, modulate MTP operation directly through changes of the gating potential rather than indirectly through changes of the membrane potential (Petronilli, V., Cola, C., Massari, S., Colonna, R. and Bernardi, P. (1993) J. Biol. Chem. 268, 21939-21945). Here we present recent work from our laboratory indicating that (i) the voltage sensor comprises at least two vicinal thiols whose oxidation-reduction state affects the MTP gating potential; as the couple becomes more oxidized the gating potential increases; conversely, as it becomes more reduced the gating potential decreases; (ii) that MTP opening is fully reversible, as mitochondria maintain volume homeostasis through several cycles of pore opening/closure; and (iii) that the mechanism of MTP inhibition by cyclosporin A presumably involves a mitochondrial cyclophilin but does not utilize a calcineurin-dependent pathway.
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PMID:Regulation of the permeability transition pore, a voltage-dependent mitochondrial channel inhibited by cyclosporin A. 752 Dec 12

Cyclin G2, together with cyclin G1 and cyclin I, defines a novel cyclin family expressed in terminally differentiated tissues including brain and muscle. Cyclin G2 expression is up-regulated as cells undergo cell cycle arrest or apoptosis in response to inhibitory stimuli independent of p53 (Horne, M., Donaldson, K., Goolsby, G., Tran, D., Mulheisen, M., Hell, J. and Wahl, A. (1997) J. Biol. Chem. 272, 12650-12661). We tested the hypothesis that cyclin G2 may be a negative regulator of cell cycle progression and found that ectopic expression of cyclin G2 induces the formation of aberrant nuclei and cell cycle arrest in HEK293 and Chinese hamster ovary cells. Cyclin G2 is primarily partitioned to a detergent-resistant compartment, suggesting an association with cytoskeletal elements. We determined that cyclin G2 and its homolog cyclin G1 directly interact with the catalytic subunit of protein phosphatase 2A (PP2A). An okadaic acid-sensitive (<2 nm) phosphatase activity coprecipitates with endogenous and ectopic cyclin G2. We found that cyclin G2 also associates with various PP2A B' regulatory subunits, as previously shown for cyclin G1. The PP2A/A subunit is not detectable in cyclin G2-PP2A-B'-C complexes. Notably, cyclin G2 colocalizes with both PP2A/C and B' subunits in detergent-resistant cellular compartments, suggesting that these complexes form in living cells. The ability of cyclin G2 to inhibit cell cycle progression correlates with its ability to bind PP2A/B' and C subunits. Together, our findings suggest that cyclin G2-PP2A complexes inhibit cell cycle progression.
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PMID:Cyclin G2 associates with protein phosphatase 2A catalytic and regulatory B' subunits in active complexes and induces nuclear aberrations and a G1/S phase cell cycle arrest. 1195 89

Leaf peroxisomes are present in greening cotyledons and contain enzymes of the glycolate pathway that functions in photorespiration. However, only a few leaf peroxisomal proteins, that is hydroxypyruvate reductase (HPR), glycolate oxidase (GO) and alanine:glyoxylate aminotransferase 1 (AGT1), have been characterized, and other functions in leaf peroxisomes have not been solved. To better understand the functions of leaf peroxisomes, we established a method to isolate leaf peroxisomes of greening cotyledons. We analyzed 53 proteins by MALDI-TOF MS and then identified 29 proteins. Among them, five proteins are related to the glycolate pathway, four proteins function in scavenging of hydrogen peroxide and additionally 20 novel leaf peroxisomal proteins were identified. In particular, protein kinases and protein phosphatase were first identified as peroxisomal proteins suggesting that protein phosphorylation is one of the regulatory mechanisms in leaf peroxisomes. Novel leaf peroxisomal proteins contained five PTS1-like proteins that have sequences where one amino acid is substituted with another one in PTS1 sequences. The PTS1 motif was suggested to have novel PTS1 sequences.
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PMID:Proteomic analysis of leaf peroxisomal proteins in greening cotyledons of Arabidopsis thaliana. 1215 31

An Arabidopsis cDNA clone that encodes Athb-12, a homeobox-leucine zipper domain protein (HD-Zip), was isolated by functional complementation of the NaCl-sensitive phenotype of a calcineurin (CaN)-deficient yeast mutant (cnbDelta, regulatory subunit null). CaN, a Ca2+/calmodulin-dependent protein phosphatase, regulates Na+ ion homeostasis in yeast. Expression of Athb-12 increased NaCl tolerance but not osmotic stress tolerance of these cnbDelta cells. Furthermore, expression of two other HD-Zip from Arabidopsis, Athb-1 and -7, did not suppress NaCl sensitivity of cnbDelta cells. These results suggest that Athb-12 specifically functions in Na+ ion homeostasis in yeast. Consistent with these observations, expression of Athb-12 in yeast turned on transcription of the NaCl stress-inducible PMR2A, which encodes a Na+/Li+ translocating P-type ATPase, and decreased Na+ levels in yeast cells. To investigate the biological function of Athb-12 in Arabidopsis, we performed Northern blot analysis. Expression of Athb-12 was dramatically induced by NaCl and ABA treatments, but not by KCl. In vivo targeting experiments using a green fluorescent protein reporter indicated that Athb-12 was localized to the nucleus. These results suggest that Athb-12 is a putative transcription factor that may be involved in NaCl stress responses in plants.
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PMID:Athb-12, a homeobox-leucine zipper domain protein from Arabidopsis thaliana, increases salt tolerance in yeast by regulating sodium exclusion. 1536 84

The cAMP-dependent protein kinase (PKA) controls a large number of cellular functions. One critical PKA substrate in the brain and heart is the L-type Ca(2+) channel Ca(v)1.2, the activity of which is upregulated by PKA. The main PKA phosphorylation site is serine 1928 in the central pore forming alpha(1)1.2 subunit of Ca(v)1.2. PKA is bound to Ca(v)1.2 within a macromolecular signaling complex consisting of the beta(2) adrenergic receptor, trimeric G(s) protein, and adenylyl cyclase for fast, localized, and hence specific signaling [Davare, M. A., Avdonin, V., Hall, D. D., Peden, E. M., Buret, A., Weinberg, R. J., Horne, M. C., Hoshi, T., and Hell, J. W. (2001) Science 293, 98-101]. Protein phosphatase 2A (PP2A) serves to effectively balance serine 1928 phosphorylation by PKA through its association with the Ca(v)1.2 complex [Davare, M. A., Horne, M. C., and Hell, J. W. (2000) J. Biol. Chem. 275, 39710-39717]. We now show that native PP2A holoenzymes, as well as the catalytic subunit itself, bind to alpha(1)1.2 immediately downstream of serine 1928. Of those holoenzymes, only heterotrimeric PP2A containing B' and B' ' subunits copurify with alpha(1)1.2. Preventing the binding of PP2A by truncating alpha(1)1.2 28 residues downstream of serine 1928 hampers its dephosphorylation in intact cells. Our results demonstrate for the first time that a stable interaction of PP2A with Ca(v)1.2 is required for effective reversal of PKA-mediated channel phosphorylation. Accordingly, PKA as well as PP2A are constitutively associated with Ca(v)1.2 for its proper regulation by phosphorylation and dephosphorylation of serine 1928.
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PMID:Binding of protein phosphatase 2A to the L-type calcium channel Cav1.2 next to Ser1928, its main PKA site, is critical for Ser1928 dephosphorylation. 1651 40

Protein phosphatase activity in crude leaf extracts and in purified intact chloroplasts of wheat (Triticum aestivum) and pea (Pisum sativum) was analyzed using exogenously supplied phosphoproteins or endogenous thylakoid proteins. Leaf extracts contain readily detectable amounts of protein phosphatase activity measured with either phosphohistone or phosphorylase a, substrates of mammalian protein phosphatases. No significant chloroplast protein phosphatase activity was detected using these exogenous phosphoproteins. The dephosphorylation of endogenous thylakoid light-harvesting chlorophyll a/b binding proteins in situ was inhibited by fluoride, but not by microcystin-LR or okadaic acid, diagnostic inhibitors of mammalian types 1 and 2A protein phosphatases. Additionally, no evidence for a pea chloroplast alkaline phosphatase activity was found using beta-glycerolphosphate or 4-methylum-belliferyl phosphate as substrates. From these results, we conclude that phosphohistone and phosphorylase a are not useful substrates for chloroplast thylakoid protein phosphatase activity and that the chloroplast enzymes may not fit into one of the canonical classifications currently used for protein phosphatases.
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PMID:Lack of Types 1 and 2A Protein Serine(P)/Threonine(P) Phosphatase Activities in Chloroplasts. 1665 37

Establishment and maintenance of apical basal cell polarity are essential for epithelial morphogenesis and have been studied extensively using the Drosophila eye as a model system. Bazooka (Baz), a component of the Par-6 complex, plays important roles in cell polarity in diverse cell types including the photoreceptor cells. In ovarian follicle cells, localization of Baz at the apical region is regulated by Par-1 protein kinase. In contrast, Baz in photoreceptor cells is targeted to adherens junctions (AJs). To examine the regulatory pathways responsible for Baz localization in photoreceptor cells, we studied the effects of Par-1 on Baz localization in the pupal retina. Loss of Par-1 impairs the maintenance of AJ markers including Baz and apical polarity proteins of photoreceptor cells but not the establishment of cell polarity. In contrast, overexpression of Par-1 or Baz causes severe mislocalization of junctional and apical markers, resulting in abnormal cell polarity. However, flies with similar overexpression of kinase-inactive mutant Par-1 or unphosphorylatable mutant Baz protein show relatively normal photoreceptor development. These results suggest that dephosphorylation of Baz at the Par-1 phosphorylation sites is essential for proper Baz localization. We also show that the inhibition of protein phosphatase 2A (PP2A) mimics the polarity defects caused by Par-1 overexpression. Furthermore, Par-1 gain-of-function phenotypes are strongly enhanced by reduced PP2A function. Thus, we propose that antagonism between PP2A and Par-1 plays a key role in Baz localization at AJ in photoreceptor morphogenesis.
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PMID:Antagonistic functions of Par-1 kinase and protein phosphatase 2A are required for localization of Bazooka and photoreceptor morphogenesis in Drosophila. 1747 33

To investigate docosahexaenoic acid (DHA, C22:6n-3) biosynthesis pathway in marine fungus Schizochytrium sp. FJU-512, a cDNA library of the fungus was constructed and analyzed. The titers of primary library were up to 5.0 x 10(6). A total of 4005 ESTs were assembled into 1947 unigenes. Sequences annotation and function analysis were carried out by using Blast, GO and KEGG programs. Compared with other eukaryote genomes, Schizochytrium sp. FJU-512 ESTs shared at least 26.6% genes with Arabidopsis thaliana (E < or = 10(-10)). The cDNA (Contig46, assembled by EH401977 and EH404532) and EH40321 were found to encode serine/threonine protein phosphatase type 1 and cell division control protein 2 which were involved in successive binary cell division. Notably, the key enzymes involved in biosynthesis of fatty acid via polyketide synthases (PKS) such as beta-ketoacyl synthase, beta-ketoacyl reductase, hydroxyacyl dehydrogenase, enoyl-CoA hydratase/isomerase, and enoyl reductase were found in the cDNA library. The results indicated that DHA synthesis in Schizochytrium sp. FJU-512 had undergone PKS pathway.
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PMID:Expressed sequence tag analysis of marine fungus Schizochytrium producing docosahexaenoic acid. 1875 27

Apical basal cell polarity is a fundamental feature of all epithelial cells. Identification of the genes involved in the polarization of epithelial cells has begun to reveal the mechanisms underlying the establishment and maintenance of cell polarity. An important issue is to understand the molecular basis for localization of cell polarity proteins in the context of the developing organism. Bazooka (Baz, Drosophila homolog of Par-3) plays a crucial role in organizing cell polarity in several different tissues. In the ovarian follicle epithelium, Par-1 protein kinase regulates Baz localization to the apical cell cortex by excluding phosphorylated Baz from the lateral region. In photoreceptor cells of retinal epithelium, Baz is targeted to the adherens junction (AJ) instead of the apical domain. Our study suggests that in photoreceptors, Par-1 blocks the localization of Baz to AJ whereas protein phosphatase 2A (PP2A) promotes Baz localization by antagonizing the Par-1 effects. In this extra view, we provide a brief overview and perspective of our findings on the antagonistic function of Par-1 and PP2A in Baz localization during photoreceptor morphogenesis.
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PMID:Par-1 and PP2A: Yin-Yang of Bazooka localization. 1882 Apr 42


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