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)

1. Microglial cells represent the first line of defence in the brain against infection and damage. However, under conditions of chronic inflammation and neurodegeneration, excessive activation of microglia can contribute to the neurodegenerative process by releasing a cornucopia of potentially cytotoxic substances including the cytotoxic free radical nitric oxide (NO). Although the cell signalling events implicated in NO formation in peripheral macrophages are well defined, events occurring in the phenotypically homologous cerebral microglial cell are not yet fully characterized. 2. In the present study, a cloned murine microglial cell line (N9), stimulated with combined lipopolysaccharide/interferon-gamma (LPS/IFN) incubation, was shown to produce a significant increase in NO formation, as measured by medium nitrite levels, during 8-72 h exposure. 3. LPS/IFN-stimulated NO production was partially inhibited with the nitric oxide synthase (NOS) competitive antagonists; N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine. The ability of the selective inducible (iNOS) inhibitor, aminoguanidine, but not the selective 'neuronal-type' constitutive (cNOS) inhibitor 7-nitroindazole, to inhibit NO production suggested a primary role of iNOS in this response and was confirmed by immunolabelling of activated cells with a specific iNOS antibody. 4. A series of tyrosine kinase inhibitors, herbimycin A, genestein, tyrphostins, AG-126, AG-556 and the tyrosine phosphatase inhibitors, sodium orthovanadate and phenylarsine oxide, significantly attenuated LPS/IFN-mediated NO production. The serine/threonine kinase inhibitors, staursporine (protein kinase C), H-9 (cyclic GMP/cyclic AMP-dependent kinase) or serine/threonine phosphatase inhibitors, cyclosporin A (phosphatase 2B) and okadaic acid (phosphatase 1/2A), reduced NO formation by an apparent cytostatic mechanism, as determined by cellular reduction of 3-(4,5-dimethylthiazol-2-yi)-2,5-diphenyl-tetrazolium bromide (MTT). 5. The present results suggest that the co-ordinated activation of protein tyrosine kinases/phosphatases, and proximal signalling events implicating the interplay between serine-threonine kinases/phosphatases, is intricately linked with inflammatory mediated mechanisms of iNOS activation in microglial cells by regulating the activation of the transcription factor NFkappaB.
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PMID:Suppression of nitric oxide formation by tyrosine kinase inhibitors in murine N9 microglia. 953 16

The highly conserved Cdc2 serine/threonine kinase plays a central role in cell cycle progression. Although Cdc2 levels remain constant throughout the cell cycle, Cdc2 kinase activity peaks at the G2/M boundary, in order to drive entry into mitosis. In the model organism Schizosaccharomysces pombe, potentially active Cdc2/Cdc13 kinase complex accumulates throughout the S and G2 phases of the cell cycle. This complex, however, is maintained in an active state by Wee1/Mik1-mediated phosphorylation at Y15 (and, possibly, T14). At the G2/M boundary, the Cdc25 protein phosphatase is activated to dephosphorylate the Cdc2/Cdc13 complex, resulting in abrupt activation of Cdc2 kinase activity and entry into mitosis.
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PMID:Regulation of Cdc2 activity by phosphorylation at T14/Y15. 955 87

The current research examined the regulation of synaptic strength by protein phosphorylation during aging. Bath application of the protein phosphatase 1 and 2A (PP1 and PP2A) inhibitor calyculin A (1 microM) enhanced CA3-CA1 synaptic strength in hippocampal slices from aged male (20-24 mo) but not from young adult male (4-6 mo) Fischer 344 rats. Similarly, injection of the PP1 and PP2A inhibitor microcystin-L,R (5 microM) into CA1 cells caused an increase in the intracellular synaptic response only in slices from aged rats. In contrast, bath application of the serine/threonine kinase inhibitor H-7 (10 microM) induced a decrease in synaptic strength only in slices from the young adult group. These results demonstrate that phosphorylation dependent regulation of intrinsic synaptic efficacy changes during aging.
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PMID:Alterations in the balance of protein kinase/phosphatase activities parallel reduced synaptic strength during aging. 974 62

In eukaryotic cells, accumulation of unfolded proteins in the lumen of the endoplasmic reticulum (ER) leads to a stress response. Cells respond to ER stress by upregulating the synthesis of ER resident protein chaperones, thus increasing the folding capacity in this organelle. In addition, this response also activates pathways to induce programmed cell death. The stress-induced chaperone synthesis is regulated at the level of transcription. In Saccharomyces cerevisiae, the transmembrane protein, Ire1p, with both serine/threonine kinase and site-specific endoribonuclease activities is implicated as the sensor of unfolded proteins in the ER that transmits the signal from the ER to activate transcription in the nucleus. Activation of the unfolded protein response (UPR) pathway also requires the bZIP transcription factor, Haclp. Although HACl is transcribed constitutively, the mRNA is poorly translated. Upon accumulation of unfolded proteins, Ire1p generates a new processed form of HACl mRNA that is efficiently translated by removal of a 252 base sequence. Using the yeast-interaction trap system we identified additional components of the UPR. A yeast transcriptional coactivator complex, Gcn5p/Ada, which is composed of Gcn5p, Ada2p, Ada3p, and Ada5p, was identified that interacts with Ire1p and Hac1p. Deletion of GCN5, ADA2, and/or ADA3 reduces, and deletion of ADA5 completely abrogates, the transcriptional induction in response to misfolded protein in the ER. A protein phosphatase, Ptc2p, was also identified as a negative regulator of the UPR that directly interacts with and dephosphorylates activated Ire1p. Recently, two mammalian homologues of Ire1p, IRE1 and IRE2, were identified. hIre1p, is preferentially localized to the nuclear envelope and requires a functional nuclease activity to transmit the UPR. These results indicate that some features of the UPR are conserved from yeast to humans and may be composed of a multicomponent complex that is regulated by phosphorylation status and is associated with the nuclear envelope to regulate processes including transcriptional induction and mRNA processing. We propose that activation of Ire1p induces splicing of HACl mRNA as well as engages and targets the Gcn5/Ada/Hac1 protein complex to genes that are transcriptionally activated in response to unfolded protein in the ER. The transcriptional activation is facilitated by targeting the histone acetylase, Gcn5p in yeast, to promote histone acetylation at chromatin encoding ER stress-responsive genes. In addition, activation of Ire1p leads to increased lipid biosynthesis, thereby allowing ER expansion to accommodate increasing lumenal constituents. Under conditions of more severe stress, cells activate an Ire1p-dependent death pathway that is mediated through induction of GADD153/CHOP.
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PMID:The cellular response to protein misfolding in the endoplasmic reticulum. 1044 Feb 30

The physiological state of the cell is controlled by signal transduction mechanisms which regulate the balance between protein kinase and protein phosphatase activities. Here we report that a single protein can, depending on which particular amino-acid residue is phosphorylated, function either as a kinase or phosphatase inhibitor. DARPP-32 (dopamine and cyclic AMP-regulated phospho-protein, relative molecular mass 32,000) is converted into an inhibitor of protein phosphatase 1 when it is phosphorylated by protein kinase A (PKA) at threonine 34. We find that DARPP-32 is converted into an inhibitor of PKA when phosphorylated at threonine 75 by cyclin-dependent kinase 5 (Cdk5). Cdk5 phosphorylates DARPP-32 in vitro and in intact brain cells. Phospho-Thr 75 DARPP-32 inhibits PKA in vitro by a competitive mechanism. Decreasing phospho-Thr 75 DARPP-32 in striatal slices, either by a Cdk5-specific inhibitor or by using genetically altered mice, results in increased dopamine-induced phosphorylation of PKA substrates and augmented peak voltage-gated calcium currents. Thus DARPP-32 is a bifunctional signal transduction molecule which, by distinct mechanisms, controls a serine/threonine kinase and a serine/threonine phosphatase.
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PMID:Phosphorylation of DARPP-32 by Cdk5 modulates dopamine signalling in neurons. 1060 60

PKR is a cellular serine/threonine kinase that phosphorylates eukaryotic translation initiation factor 2alpha (eIF2alpha) to regulate protein synthesis. PKR also plays a role in the regulation of transcription, programmed cell death and the cell cycle, processes which likely involve other substrates. In a yeast two-hybrid screen, we isolated human protein phosphatase 2A (PP2A) regulatory subunit B56alpha as a PKR-interacting protein. The interaction between B56alpha and PKR was confirmed by in vitro binding assays as well as by in vivo coimmunoprecipitation, and this interaction is dependent on the catalytic activity of PKR. Moreover, recombinant B56alpha was efficiently phosphorylated by PKR in vitro and an isoelectric point shift in B56alpha was detected in extracts from cells induced with the PKR activator pIC. An in vitro dephosphorylation assay showed that when B56alpha was phosphorylated by PKR, the activity of PP2A trimeric holoenzyme was increased. A functional interaction between B56alpha and PKR was observed in cotransfection assays, where a B56alpha-mediated increase in luciferase expression was inhibited by cotransfection with wild-type PKR. This is likely due to a decreased level of eIF4E phosphorylation caused by an increase in PP2A activity following PKR phosphorylation of B56alpha. Taken together, our data indicate that PKR can modulate PP2A activity by phosphorylating B56alpha to regulate cellular activities.
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PMID:The B56alpha regulatory subunit of protein phosphatase 2A is a target for regulation by double-stranded RNA-dependent protein kinase PKR. 1086 85

Insulin-like growth factor I (IGF-I) protects cells from apoptosis primarily through the action of phosphatidylinositol-3 kinase and the downstream serine/threonine kinase Akt. The PTEN gene product, a protein which dephosphorylates phosphatidylinositol lipids, prevents activation of Akt and regulates several cellular functions, including cell cycle progression, cell migration, and survival from apoptosis. In this study, PTEN overexpression decreases IGF-I-induced Akt activity, enhances serum withdrawal-induced apoptosis, and decreases IGF-I protection and cell growth in SHEP cells. The PTEN lipid phosphatase mutant G129E fails to inhibit IGF-I-stimulated Akt activity and protection from apoptosis. The C124S mutation, which abolishes both lipid and protein phosphatase activity, fails to inhibit Akt activity and IGF-I protection against hyperosmotic-induced apoptosis but still inhibits growth and IGF-I protection against serum withdrawal-induced apoptosis. These data suggest a role for PTEN in modulating the effect of IGF-I on Akt activity, neuroblastoma cell growth, and protection against apoptotic stimuli.
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PMID:PTEN/MMAC1 overexpression decreases insulin-like growth factor-I-mediated protection from apoptosis in neuroblastoma cells. 1145 34

STK15 is an Aurora/Ipl-1 related serine/threonine kinase that is associated with centrosomes and induces aneuploidy when overexpressed in mammalian cells. It is well known that phosphorylation and dephosphorylation of kinases are important for regulation of their activity. But mechanisms by which STK15 activity is regulated have not been elucidated. We report that STK15 contains two functional binding sites for protein phosphatase type 1 (PP1), and the binding of these proteins is cell cycle-regulated peaking at mitosis. Activated STK15 at mitosis phosphorylates PP1 and inhibits PP1 activity in vitro. In vivo, PP1 activity co-immunoprecipitated with STK15 is also reduced. These data indicate that STK15 inhibits PP1 activity during mitosis. Also, PP1 is shown to dephosphorylate active STK15 and abolish its activity in vitro. Furthermore, we show that non-binding mutants of STK15 for PP1 are superphosphorylated, but their kinase activities are markedly reduced. Cells transfected with these non-binding mutants manifest aberrant chromosome alignment during mitosis. Our results suggest that a feedback regulation through phosphorylation/dephosphorylation events between STK15 kinase and PP1 phosphatase operates through the cell cycle. Deregulation of this balance may contribute to anomalous segregation of chromosomes during mitotic progression of cancer cells.
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PMID:Interaction and feedback regulation between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic cell division cycle. 1155 64

The PAS domain is a versatile protein fold found in many archaeal, bacterial, and plant proteins capable of sensing environmental changes in light intensity, oxygen concentration, and redox potentials. The oxygen sensor FixL from Rhizobium species contains a heme-bearing PAS domain and a histidine kinase domain that couples sensing to signaling. We identified a novel mammalian PAS protein (PASKIN) containing a domain architecture resembling FixL. PASKIN is encoded by an evolutionarily conserved single-copy gene which is ubiquitously expressed. The human PASKIN and mouse Paskin genes show a conserved intron-exon structure and share their promoter regions with another ubiquitously expressed gene that encodes a regulator of protein phosphatase-1. The 144-kDa PASKIN protein contains a PAS region homologous to the FixL PAS domain and a serine/threonine kinase domain which might be involved in signaling. Thus, PASKIN is likely to function as a mammalian PAS sensor protein.
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PMID:Mammalian PASKIN, a PAS-serine/threonine kinase related to bacterial oxygen sensors. 1168 72

Protein kinases and protein phosphatases exert coordinated control over many essential cellular processes. Here, we describe the cloning and characterization of a novel human transmembrane protein KPI-2 (Kinase/Phosphatase/Inhibitor-2) that was identified by yeast two-hybrid using protein phosphatase inhibitor-2 (Inh2) as bait. KPI-2 mRNA was predominantly expressed in skeletal muscle. KPI-2 is a 1503-residue protein with two predicted transmembrane helices at the N terminus, a kinase domain, followed by a C-terminal domain. The transmembrane helices were sufficient for targeting proteins to the membrane. KPI-2 kinase domain has about 60% identity with its closest relative, a tyrosine kinase. However, it only exhibited serine/threonine kinase activity in autophosphorylation reactions or with added substrates. KPI-2 kinase domain phosphorylated protein phosphatase-1 (PP1C) at Thr(320), which attenuated PP1C activity. KPI-2 C-terminal domain directly associated with PP1C, and this required a VTF motif. Inh2 associated with KPI-2 C-terminal domain with and without PP1C. Thus, KPI-2 is a kinase with sites to associate with PP1C and Inh2 to form a regulatory complex that is localized to membranes.
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PMID:A novel transmembrane Ser/Thr kinase complexes with protein phosphatase-1 and inhibitor-2. 1239 58


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