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)

Serine/threonine phosphatase regulation of phosphorylation-mediated intracellular signaling controls a number of important processes in mammalian cells. In this study, we show that constitutively active protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase, is essential for T leukemia cell survival. Jurkat and CCRF-CEM T leukemia cells treated with the PP2A-selective inhibitor okadaic acid (OA) showed a dose- and time-dependent induction of apoptosis, as indicated by loss of mitochondrial transmembrane potential (delta psi(m)), cleavage-induced activation of caspase-3, -8, and -9, and DNA fragmentation. In addition, caspase-8 or caspase-9 inhibition with z-IETD-fmk or z-LEHD-fmk, respectively, largely prevented OA-induced apoptosis. Although OA treatment did not affect constitutive Bcl-2 expression, overexpression of Bcl-2 prevented both OA-induced DNA fragmentation and dissipation of delta psi(m). Furthermore, inhibition of caspase-3, -8, or -9 partially protected against OA-induced loss of delta psi(m). In addition, caspase-9 and caspase-3 inhibition largely prevented procaspase-3 and procaspase-8 cleavage, respectively, while caspase-8 inhibition partially interfered with procaspase-9 cleavage in OA-treated T leukemia cells. Thus, PP2A inhibition triggered the intrinsic pathway of apoptosis, which was enhanced by a mitochondrial feedback amplification loop. PP2A has also been implicated in the regulation of p38 mitogen-activated protein kinase (MAPK). Co-immunoprecipitation analysis revealed a physical association between the catalytic subunit of PP2A and p38 MAPK in T leukemia cells. Moreover, OA treatment caused p38 MAPK to be phosphorylated in a dose- and time-dependent fashion, indicating that PP2A prevented p38 MAPK activation. Although p38 MAPK activation usually promotes apoptosis, pharmacologic inhibition of p38 MAPK exacerbated OA-induced DNA fragmentation and loss of delta psi(m) in T leukemia cells, suggesting that, in this instance, the p38 MAPK signaling pathway promoted cell survival. Collectively, these findings indicate that PP2A and p38 MAPK have coordinate effects on signaling pathways that regulate the survival of T leukemia cells.
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PMID:Apoptosis induced by protein phosphatase 2A (PP2A) inhibition in T leukemia cells is negatively regulated by PP2A-associated p38 mitogen-activated protein kinase. 1684 42

Prolonged inhibition of Na,K-ATPase enzymatic activity by exposure of a variety of mammalian cells to low external K+ yields a subsequent adaptive up-regulation of Na,K-ATPase expression. The aim of this study was to examine the intracellular signal transduction system that is responsible for mediating increased Na,K-ATPase subunit gene expression in primary cultures of neonatal rat cardiac myocytes. In this work, we show long-term inhibition of Na,K-ATPase function with 0.6 mM K+ resulted in hypertrophy of cardiac myocytes and augmentation of Na,K-ATPase alpha1 and beta1 subunit gene expression. Transient transfection experiments in neonatal rat cardiac myocytes demonstrated that low K+ induction of alpha1 and beta1 gene transcription was dependent on intracellular Ca2+ and activation of calcineurin. Based on effects of pharmacological inhibitors, protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2) and histone deacetylase were found to be unique downstream components in the low K+ signal transduction pathway leading to increased alpha1 subunit promoter activity. Similarly, low K+-induced beta1 subunit gene transcription was dependent on activation of protein kinase C (PKC), c-Jun-N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). These findings indicate that persistent inhibition of Na,K-ATPase activity with low external K+ activates overlapping and Na,K-ATPase subunit gene-specific signaling pathways in cardiac myocytes.
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PMID:Divergent signaling pathways mediate induction of Na,K-ATPase alpha1 and beta1 subunit gene transcription by low potassium. 1690 6

Adenosine is arguably the most potent and widespread presynaptic modulator in the CNS, yet adenosine receptor signal transduction pathways remain unresolved. Here, we demonstrate a novel mechanism in which adenosine A1 receptor stimulation leads to p38 mitogen-activated protein kinase (MAPK) activation and contributes to the inhibition of synaptic transmission. Western blot analysis indicated that selective A1 receptor activation [with N6-cyclopentyladenosine (CPA)] resulted in rapid increases in phosphorylated p38 (phospho-p38) MAPK immunoreactivity in membrane fractions, and decreases in phospho-p38 MAPK in cytosolic fractions. Immunoprecipitation with a phospho-p38 MAPK antibody revealed constitutive association of this phosphoprotein with adenosine A1 receptors. Phospho-p38 MAPK activation by A1 receptor stimulation induced translocation of PP2a (protein phosphatase 2a) to the membrane. We then examined the actions of p38 MAPK activation in A1 receptor-mediated synaptic inhibition. Excitatory postsynaptic field potentials evoked in area CA1 of the rat hippocampus markedly decreased in response to adenosine (10 microM), the A1 receptor agonist CPA (40 nM), or a 5 min exposure to hypoxia. These inhibitory responses were mediated by A1 receptor activation because the selective antagonist DPCPX (8-cyclopentyl-1,3-dipropylxanthine) (100 nM) prevented them. In agreement with the biochemical analysis, the selective p38 MAPK inhibitor SB203580 [4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)-1H-imidazole] (25 microM) blocked the inhibitory actions of A1 receptor activation, whereas both the inactive analog SB202474 [4-ethyl-2-(p-methoxyphenyl)-5-(4'-pyridyl)-1H-imidazole] (25 microM) and the ERK 1/2 (extracellular signal-regulated kinase 1/2) MAPK inhibitor PD98059 [2'-amino-3'-methoxyflavone] (50 microM) were ineffective. In contrast, the p38 MAPK inhibitors did not inhibit GABA(B)-mediated synaptic depression. These data suggest A1 receptor-mediated p38 MAPK activation is a crucial step underlying the presynaptic inhibitory effect of adenosine on CA3-CA1 synaptic transmission.
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PMID:p38 mitogen-activated protein kinase contributes to adenosine A1 receptor-mediated synaptic depression in area CA1 of the rat hippocampus. 1713 4

Protein phosphorylation/dephosphorylation and cytoskeletal reorganization regulate the Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) during osmotic shrinkage; however, the mechanisms involved are unclear. We show that in cytoplasts, plasma membrane vesicles detached from Ehrlich ascites tumor cells (EATC) by cytochalasin treatment, NKCC1 activity evaluated as bumetanide-sensitive (86)Rb influx was increased compared with the basal level in intact cells yet could not be further increased by osmotic shrinkage. Accordingly, cytoplasts exhibited no regulatory volume increase after shrinkage. In cytoplasts, cortical F-actin organization was disrupted, and myosin II, which in shrunken EATC translocates to the cortical region, was absent. Moreover, NKCC1 activity was essentially insensitive to the myosin light chain kinase (MLCK) inhibitor ML-7, a potent blocker of shrinkage-induced NKCC1 activity in intact EATC. Cytoplast NKCC1 activity was potentiated by the Ser/Thr protein phosphatase inhibitor calyculin A, partially inhibited by the protein kinase A inhibitor H89, and blocked by the broad protein kinase inhibitor staurosporine. Cytoplasts exhibited increased protein levels of NKCC1, Ste20-related proline- and alanine-rich kinase (SPAK), and oxidative stress response kinase 1, yet they lacked the shrinkage-induced plasma membrane translocation of SPAK observed in intact cells. The basal phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) was increased in cytoplasts compared with intact cells, yet in contrast to the substantial activation in shrunken intact cells, p38 MAPK could not be further activated by shrinkage of the cytoplasts. Together these findings indicate that shrinkage activation of NKCC1 in EATC is dependent on the cortical F-actin network, myosin II, and MLCK.
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PMID:Shrinkage insensitivity of NKCC1 in myosin II-depleted cytoplasts from Ehrlich ascites tumor cells. 1722 12

alpha-4 is an essential gene and is a dominant antiapoptotic factor in various tissues that is a regulatory subunit for type 2A protein phosphatases. A multiplexed phosphorylation site screen revealed that knockdown of alpha-4 by small interfering RNA (siRNA) increased p38 mitogen-activated protein kinase (MAPK) and c-Jun phosphorylation without changes in JNK or ERK. FLAG-alpha-4 coprecipitated hemagglutinin-MEK3 plus endogenous protein phosphatase 2A (PP2A) and selectively enhanced dephosphorylation of Thr193, but not Ser189, in the activation loop of MEK3. Overexpression of alpha-4 suppressed p38 MAPK activation in response to tumor necrosis factor alpha (TNF-alpha). The alpha-4 dominant-negative domain (DND) (residues 220 to 340) associated with MEK3, but not PP2A, and its overexpression sensitized cells to activation of p38 MAPK by TNF-alpha and interleukin-1beta, but not by ansiomycin or sorbitol. The response was diminished by nocodazole or by siRNA knockdown of the Opitz syndrome protein Mid1 that binds alpha-4 to microtubules. Interference by alpha-4 DND or alpha-4 siRNA increased caspase 3/7 activation in response to TNF-alpha. Growth of transformed cells in soft agar was enhanced by alpha-4 and suppressed by alpha-4 DND. The results show that alpha-4 targets PP2A activity to MEK3 to suppress p38 MAPK activation by cytokines, thereby inhibiting apoptosis and anoikis.
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PMID:Cytokine activation of p38 mitogen-activated protein kinase and apoptosis is opposed by alpha-4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. 1743 31

A pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta peptide (Abeta) in senile plaques. Abeta has also been implicated in vascular degeneration in cerebral amyloid angiopathy because of its cytotoxic effects on non-neuronal cells, including cerebral endothelial cells (CECs). We explore the role of apoptosis signal-regulating kinase 1 (ASK1) in Abeta-induced death in primary cultures of murine CECs. Abeta induced ASK1 dephosphorylation, which could be prevented by selective inhibition of protein phosphatase 2A (PP2A) but not PP2B. ASK1 dephosphorylation resulted in its dissociation from 14-3-3. ASK1, released from 14-3-3 inhibition, activated p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. p53, a proapoptotic transcription factor, in turn transactivated the expression of Bax, a proapoptotic protein. Transfection with various dominant-negative mutants (DNs), including ASK1 DN and p38MAPK DN, suppressed Abeta-induced p38MAPK activation, p53 phosphorylation, and Bax upregulation and partially prevented CEC death. Bax knockdown using a bax small interfering RNA strategy also reduced Bax expression and subsequent CEC death. These results suggest that Abeta activates the ASK1-p38MAPK-p53-Bax cascade to cause CEC death in a PP2A-dependent manner.
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PMID:Apoptosis signal-regulating kinase 1 in amyloid beta peptide-induced cerebral endothelial cell apoptosis. 1752 16

Calcium is a second messenger for many signaling pathways in B cells, but its role as a receptor ligand has not been well characterized. However, pulses of free calcium were found to cause the rapid release of internal calcium stores in normal human B cells. This response appeared to be mediated by a cell surface protein with receptor properties as it could be blocked by pretreatment with trypsin and with kinase and phospholipase Cgamma inhibitors. The calcium receptor on B cells was not the conventional calcium-sensing receptor (CaSR) since B cells did not express CaSR and calcium-induced responses could not be blocked by specific CaSR inhibitors. B-cell responses to extracellular calcium activated phosphoinositide-3 kinase/AKT, calcineurin, extracellular signal regulated kinase, p38 mitogen-activated protein kinase, protein kinase C, Ca(2+)/calmodulin kinase II, and nuclear factor-kappaB signaling pathways, and resulted in transcription of the early response gene, CD83. This extracellular calcium sensor enhanced B-cell responses to Toll-like receptor, B-cell receptor, and cytokine receptor agonists. These findings suggest a means by which B cells prepare to engage in immune responses by responding to calcium fluctuations in their environment.
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PMID:Extracellular calcium sensing promotes human B-cell activation and function. 1772 42

Low-level activation of N-methyl-d-aspartate receptors (NMDARs) results in a decrease in the ability of tetanic stimulation to induce long-term potentiation (LTP). This NMDAR-mediated LTP inhibition is observed with low micromolar concentrations of NMDA or chelation of ambient extracellular zinc. In rat hippocampal slices, we examined whether LTP inhibition by 1 muM NMDA and zinc chelation share common mechanisms. We found that both forms of LTP inhibition involve nitric oxide (NO) synthase (NOS) and calcineurin. Furthermore, both forms of LTP inhibition are overcome by block of p38 mitogen-activated protein kinase (MAPK), but not by inhibition of extracellular signal-regulated kinase 1/2 or c-Jun-N-terminal kinase. A p38 antagonist also overcame the block of LTP by sodium nitroprusside, an agent that releases NO, suggesting that NO release occurs upstream of MAPK activation. Despite the involvement of p38 MAPK in NMDAR-mediated LTP inhibition, p38 antagonism did not enhance LTP induction in response to weak tetanic stimulation under baseline conditions. These results indicate that p38 MAPK is part of a complex NMDAR-driven signaling pathway involving calcineurin and NO that helps to regulate synaptic plasticity in the CA1 region.
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PMID:Long-term potentiation inhibition by low-level N-methyl-D-aspartate receptor activation involves calcineurin, nitric oxide, and p38 mitogen-activated protein kinase. 1800 Aug 19

Ca2+ signalling plays an important role in excitation-contraction coupling and the resultant force output of skeletal muscle. It is also known to play a crucial role in modulating both short- and long-term muscle cellular phenotypic adaptations associated with these events. Ca2+ signalling via the Ca2+/calmodulin (CaM)-dependent phosphatase calcineurin (CnA) and via Ca2+/CaM-dependent kinases, such as CaMKI and CaMKII, is known to regulate hypertrophic growth in response to overload, to direct slow versus fast fibre gene expression, and to contribute to mitochondrial biogenesis. The CnA- and CaMK-dependent regulation of the downstream transcription factors nuclear factor of activated T cells (NFAT) and myocyte-specific enhancer factor 2 are known to activate muscle-specific genes associated with a slower, more oxidative fibre phenotype. We have also recently shown the expression of utrophin A, a cytoskeletal protein that accumulates at the neuromuscular junction and plays a role in maturation of the postsynaptic apparatus, to be regulated by CnA-NFAT and Ca2+/CaM signalling. This regulation is fibre-type specific and potentiated by interactions with the transcriptional regulators and coactivators GA binding protein (also known as nuclear respiratory factor 2) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha. Another downstream target of CnA signalling may be myostatin, a transforming growth factor-beta family member that is a negative regulator of muscle growth. While the list of the downstream targets of CnA/NFAT- and Ca2+/CaM-dependent signalling is emerging, the precise interaction of these pathways with the Ca2+-independent pathways p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, phosphoinositide-3 kinase, and protein kinase B (Akt/PKB) must also be considered when deciphering fibre responses and plasticity to altered contractile load.
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PMID:Ca2+/calmodulin-based signalling in the regulation of the muscle fibre phenotype and its therapeutic potential via modulation of utrophin A and myostatin expression. 1805 17

We used Western blot analysis to examine the effect of dietary K intake on the expression of serine/threonine protein phosphatase in the kidney. K restriction significantly decreased the expression of catalytic subunit of protein phosphatase (PP)2B but increased the expression of PP2B regulatory subunit in both rat and mouse kidney. However, K depletion did not affect the expression of PP1 and PP2A. Treatment of M-1 cells, mouse cortical collecting duct (CCD) cells, or 293T cells with glucose oxidase (GO), which generates superoxide anions through glucose metabolism, mimicked the effect of K restriction on PP2B expression and significantly decreased expression of PP2B catalytic subunits. However, GO treatment increased expression of regulatory subunit of PP2B and had no effect on expression of PP1, PP2A, and protein tyrosine phosphatase 1D. Moreover, deletion of gp91-containing NADPH oxidase abolished the effect of K depletion on PP2B. Thus superoxide anions or related products may mediate the inhibitory effect of K restriction on the expression of PP2B catalytic subunit. We also used patch-clamp technique to study the effect of inhibiting PP2B on renal outer medullary K (ROMK) channels in the CCD. Application of cyclosporin A or FK506, inhibitors of PP2B, significantly decreased ROMK channels, and the effect of PP2B inhibitors was abolished by blocking p38 mitogen-activated protein kinase (MAPK) and ERK. Furthermore, Western blot demonstrated that inhibition of PP2B with cyclosporin A or small interfering RNA increased the phosphorylation of ERK and p38 MAPK. We conclude that K restriction suppresses the expression of PP2B catalytic subunits and that inhibition of PP2B decreases ROMK channel activity through stimulation of MAPK in the CCD.
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PMID:K restriction inhibits protein phosphatase 2B (PP2B) and suppression of PP2B decreases ROMK channel activity in the CCD. 1818 75


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