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)

During the past decade, numerous Mn2+-dependent protein serine, threonine and/or tyrosine phosphatases (O-phosphatases) from prokaryotes have been characterized. Based on their amino acid sequences, they belong to PPP, PPM or PHP superfamilies. Both the PPP and PPM families of protein phosphatases are metalloenzymes which active centers contain two metal ions that function as cofactors. Results from sequence analysis also suggest that PHP family protein phosphatase is a metalloenzyme. The identified functions for PPP family protein phosphatases from different prokaryotic organisms include regulation of stress-response, nitrogen fixation and vegetative growth. At least one phosphatase, PrpB from Escherichia coli, is also implicated in bacterial pathogenesis. Prokaryotic PPM family protein phosphatases are involved in controlling spore formation, stress-response, cell density during stationary phase, carbon and nitrogen assimilation, vegetative growth, development of fruiting bodies and cell segregation. The function of CpsB, a PHP family protein tyrosine phosphatase from Streptococcus pneumonia, is to regulate biosynthesis of capsular polysaccharide, an important virulence determinant. Thus, this group of functionally diverse protein phosphatases plays an important role in prokaryotes. Discovery of Mn2+-dependent prokaryotic protein O-phosphatases and their functions also contributes to new insight into Mn2+ homeostasis and many roles played by Mn2+ and protein O-phosphorylation in prokaryotic cells.
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PMID:Manganese-dependent protein O-phosphatases in prokaryotes and their biological functions. 1497 54

Protein phosphatase 4 (Ppp4) is a ubiquitous serine/threonine phosphatase in the PPP family that is now recognised to regulate a variety of cellular functions independently of protein phosphatase 2A (PP2A). Regulatory subunits (R1 and R2) have been identified in mammals that interact with the catalytic subunit of Ppp4 (Ppp4c) and control its activity. Ppp4c-R2 complexes play roles in organelle assembly; not only are they essential for maturation of the centrosome, but they are also involved in spliceosomal assembly via interaction with the survival of motor neurons (SMNs) complex. Several cellular signalling routes, including NF-kappaB and the target of rapamycin (TOR) pathways appear to be regulated by Ppp4. Emerging evidence indicates that Ppp4 may play a role in the DNA damage response and that Ppp4c-R1 complexes decrease the activity of a histone deacetylase, implicating Ppp4 in the regulation of chromatin activities. Antitumour agents, cantharidin and fostriecin, potently inhibit the activity of Ppp4. Orthologues of mammalian Ppp4 subunits in Saccharomyces cerevisiae confer resistance to the anticancer, DNA-binding drugs, cisplatin and oxaliplatin.
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PMID:Protein phosphatase 4--from obscurity to vital functions. 1591 12

The open reading frames (ORFs) encoding two potential protein-serine/threonine phosphatases from the cyanobacterium Synechocystis sp. strain PCC 6803 were cloned and their protein products expressed in Escherichia coli cells. The product of ORF sll1033, SynPPM3, is a homologue of the PPM family of protein-serine/threonine phosphatases found in all eukaryotes as well as many members of the Bacteria. Surprisingly, the recombinant protein phosphatase dephosphorylated phosphotyrosine- as well as phosphoserine-containing proteins in vitro. While kinetic analyses indicate that the enzyme was more efficient at dephosphorylating the latter, replacement of Asp608 by asparagine enhanced activity toward a phosphotyrosine-containing protein fourfold. The product of ORF sll1387, SynPPP1, is the sole homolog of the PPP family of protein phosphatases encoded by the genome of Synechocystis sp. strain PCC 6803. Like many other bacterial PPPs, the enzyme dephosphorylated phosphoserine- and phosphotyrosine-containing proteins with comparable efficiencies. However, while previously described PPPs from prokaryotic organisms required the addition of exogenous metal ion cofactors, such as Mg2+ or Mn2+, for activity, recombinantly produced SynPPP1 displayed near-maximal activity in the absence of added metals. Inductively coupled plasma mass spectrometry indicated that recombinant SynPPP1 contained significant quantities, 0.32 to 0.44 mol/mole total, of Mg and Mn. In this respect, the cyanobacterial enzyme resembled eukaryotic members of the PPP family, which are metalloproteins. mRNA encoding SynPPP1 or SynPPM3 could be detected in cells grown under many, but not all, environmental conditions.
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PMID:The protein phosphatases of Synechocystis sp. strain PCC 6803: open reading frames sll1033 and sll1387 encode enzymes that exhibit both protein-serine and protein-tyrosine phosphatase activity in vitro. 1610 28

ERK8 (extracellular-signal-regulated protein kinase 8) expressed in Escherichia coli or insect cells was catalytically active and phosphorylated at both residues of the Thr-Glu-Tyr motif. Dephosphorylation of the threonine residue by PP2A (protein serine/threonine phosphatase 2A) decreased ERK8 activity by over 95% in vitro, whereas complete dephosphorylation of the tyrosine residue by PTP1B (protein tyrosine phosphatase 1B) decreased activity by only 15-20%. Wild-type ERK8 expressed in HEK-293 cells was over 100-fold less active than the enzyme expressed in bacteria or insect cells, but activity could be increased by exposure to hydrogen peroxide, by incubation with the protein serine/threonine phosphatase inhibitor okadaic acid, or more weakly by osmotic shock. In unstimulated cells, ERK8 was monophosphorylated at Tyr-177, and exposure to hydrogen peroxide induced the appearance of ERK8 that was dually phosphorylated at both Thr-175 and Tyr-177. IGF-1 (insulin-like growth factor 1), EGF (epidermal growth factor), PMA or anisomycin had little effect on activity. In HEK-293 cells, phosphorylation of the Thr-Glu-Tyr motif of ERK8 was prevented by Ro 318220, a potent inhibitor of ERK8 in vitro. The catalytically inactive mutants ERK8[D154A] and ERK8[K42A] were not phosphorylated in HEK-293 cells or E. coli, whether or not the cells had been incubated with protein phosphatase inhibitors or exposed to hydrogen peroxide. Our results suggest that the activity of ERK8 in transfected HEK-293 cells depends on the relative rates of ERK8 autophosphorylation and dephosphorylation by one or more members of the PPP family of protein serine/threonine phosphatases. The major residue in myelin basic protein phosphorylated by ERK8 (Ser-126) was distinct from that phosphorylated by ERK2 (Thr-97), demonstrating that, although ERK8 is a proline-directed protein kinase, its specificity is distinct from ERK1/ERK2.
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PMID:Characterization of the reversible phosphorylation and activation of ERK8. 1633 13

We have shown okadaic acid (OA) and calyculin-A (CLA) inhibition of mouse oocyte phosphoprotein phosphatase 1 (PPP1C) and/or phosphoprotein phosphatase 2A (PPP2CA) results in aberrant chromatin condensation, as evidenced by the inability to resolve bivalents. Phosphorylation of histone H3 at specific residues is thought to regulate chromatin condensation. Therefore, we examined changes in histone H3 phosphorylation during oocyte meiosis and the potential regulation by protein PPPs. Western blot and immunocytochemical analysis revealed histone H3 phosphorylation changed during mouse oocyte meiosis, with changes in chromatin condensation. Germinal vesicle-intact (GV-intact; 0 h) oocytes had no phospho-Ser10 but did have phospho-Ser28 histone H3. Oocytes that had undergone germinal vesicle breakdown (GVBD; 2 h) and progressed to metaphase I (MI; 7 h) and MII (16 h) had phosphorylated Ser10 and Ser28 histone H3 associated with condensed chromatin. To determine whether OA-induced aberrations in chromatin condensation were due to alterations in levels of histone H3 phosphorylation, we assessed phosphorylation of Ser10 and Ser28 residues following PPP inhibition. Oocytes treated with OA (1 microM) displayed increased phosphorylation of histone H3 at both Ser10 and Ser28 compared with controls. To begin to elucidate which OA-sensitive PPP is responsible for regulating chromatin condensation and histone H3 phosphorylation, we examined spatial and temporal localization of OA-sensitive PPPs, PPP1C, and PPP2CA. PPPC2A did not localize to condensed chromatin, whereas PPP1beta (PPP1CB) associated with condensing chromatin in GVBD, MI, and MII oocytes. Additionally, Western blot and immunocytochemistry confirmed presence of the PPP1C regulatory inhibitor subunit 2 (PPP1R2) in oocytes at condensed chromatin during meiosis and indicated a change in PPP1R2 phosphorylation. Inhibition of oocyte glycogen synthase kinase 3 (GSK3) appeared to regulate phosphorylation of PPP1R2. Furthermore, inhibition of GSK3 resulted in aberrant oocyte bivalent formation similar to that observed following PPP inhibition. These data suggest that PPP1CB is the OA/CLA-sensitive PPP that regulates oocyte chromatin condensation through regulation of histone H3 phosphorylation. Furthermore, GSK3 inhibition results in aberrant chromatin condensation and appears to regulate phosphorylation of PPP1R2.
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PMID:Proper chromatin condensation and maintenance of histone H3 phosphorylation during mouse oocyte meiosis requires protein phosphatase activity. 1718 92

Natural product extracts have proven to be a rich source of small molecules that potently inhibit the catalytic activity of certain PPP-family ser/thr protein phosphatases. To date, the list of inhibitors includes okadaic acid (produced by marine dinoflagelates, Prorocentrum sp. and Dinophysis sp.), calyculin A, dragmacidins (isolated from marine sponges), microcystins, nodularins (cyanobacteria, Microcystis sp. and Nodularia sp.), tautomycin, tautomycetin, cytostatins, phospholine, leustroducsins, phoslactomycins, fostriecin (soil bacteria, Streptomyces sp.), and cantharidin (blister beetles, approx 1500 species). Many of these compounds share structural similarities, and several have become readily available for research purposes. Here we will review the specificity of available inhibitors and present methods for their use in studying sensitive phosphatases. Common mistakes in the employment of these compounds will also be addressed briefly, notably the widespread misconception that they only inhibit the activity of PP1 and PP2A. Inhibitors of PP2B (calcineurin) will only be mentioned in passing, except to state that, in our hands, cypermethrin, deltamethrin, and fenvalerate, which are sold as potent inhibitors of PP2B, do not inhibit the catalytic activity of PP2B.
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PMID:Small-molecule inhibitors of ser/thr protein phosphatases: specificity, use and common forms of abuse. 1720 May 51

A novel protein from the parasite Trypanosoma cruzi homologous to calcineurin (serine-threonine phosphatase 2B) was identified and characterized. The Calcineurin A gene is present as a single copy gene per haploid genome and encodes a protein of 43 kDa that is expressed in all major developmental stages of T. cruzi. Surprisingly, it is mainly localized in the cell nucleus, in sharp contrast with its mammalian counterpart. The T. cruzi calcineurin A protein presents the three invariants motifs characteristic of the PPP serine-threonine phosphatase superfamily. However, out of the four domains typically present in all calcineurin described to date, the T. cruzi calcineurin A possess only two domains: the catalytic and the calcineurin B binding domain. Sequence similarity searches in the T. cruzi, Trypanosoma brucei and Leishmania major genomes revealed that only L. major presents a gene encoding a putative protein containing the four domains. On the other hand, the T. cruzi Calcineurin B subunit showed a conserved structure, and a reasonable level of similarity over the entire length with calcineurin B proteins from other organisms. Interaction between Calcineurin A and Calcineurin B was analyzed by yeast Two-Hybrid and GST pull-down assays.
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PMID:The Calcineurin A homologue from Trypanosoma cruzi lacks two important regulatory domains. 1720 61

Ca(2+)/calmodulin-dependent protein kinase phosphatase (CaMKP) and its nuclear isoform CaMKP-N are unique Ser/Thr protein phosphatases that negatively regulate the Ca(2+)/calmodulin-dependent protein kinase (CaMK) cascade by dephosphorylating multifunctional CaMKI, II, and IV. However, the lack of specific inhibitors of these phosphatases has hampered studies on these enzymes in vivo. In an attempt to obtain specific inhibitors, we searched inhibitory compounds and found that Evans Blue and Chicago Sky Blue 6B served as effective inhibitors for CaMKP. These compounds also inhibited CaMKP-N, but inhibited neither protein phosphatase 2C, another member of PPM family phosphatase, nor calcineurin, a typical PPP family phosphatase. The minimum structure required for the inhibition was 1-amino-8-naphthol-4-sulfonic acid. When Neuro2a cells cotransfected with CaMKIV and CaMKP-N were treated with these compounds, the dephosphorylation of CaMKIV was strongly suppressed, suggesting that these compounds could be used as potent inhibitors of CaMKP and CaMKP-N in vivo as well as in vitro.
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PMID:Inhibitors of the Ca(2+)/calmodulin-dependent protein kinase phosphatase family (CaMKP and CaMKP-N). 1789 24

Protein phosphorylation appears to be a universal mechanism of protein regulation. Genomics has provided the means to compile inventories of protein phosphatases across a wide selection of organisms and this has supplied insights into the evolution of this group of enzymes. Protein phosphatases evolved independently several times yielding the groups we observe today. Starting from a core catalytic domain, phosphatases evolved by a series of gene duplication events and by adopting the use of regulatory subunits and/or fusion with novel functional modules or domains. Recent analyses also suggest that the serine/threonine specific enzymes are more ancient than the PTPs (protein tyrosine phosphatases). It is likely that the latter played a key role at the onset of metazoan evolution in conjunction with the tremendous expansion of tyrosine kinases and PTPs at this point. In the present review, we discuss the evolution of the PTPs, the serine/threonine specific PPP (phosphoprotein phosphatase) and PPM (metallo-dependent protein phosphatase) families and the more recently discovered phosphatases that utilize an aspartate-based catalytic mechanism. We will also highlight examples of convergent evolution and several phosphatases which are unique to plants.
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PMID:Evolution of protein phosphatases in plants and animals. 1909 38

The protein phosphatase 1 has conserved cores in PPP gene family flanked by non-conserved N-terminal domains. PP1 with residues 1-8 deleted or substituted by residues 1-42 of calcineurin catalytic subunit were designated PP1-(9-330) and CNA(1-42)-PP1(9-330), respectively. When compared with PP1, PP1-(9-330) had higher and CNA(1-42)-PP1(9-330) had lower activity with three kinds of substrates; PP1-(9-330) has higher and CNA(1-42)-PP1(9-330) has lower sensitivity to okadaic acid. These results imply that the N-terminal residues influence the activity and sensitivity to inhibitors of PP1. PP1-(9-330), PP1, and CNA(1-42)-PP1(9-330) displayed increasing K (m) and decreasing V (max) with three kinds of substrates, which suggest that the N-terminal residues are connected with the substrates affinity and catalytic efficiency of PP1. PP1-(9-330) has higher and CNA(1-42)-PP1(9-330) has lower fluorescence intensity than PP1, and the emission wavelength maximum was blue-shifted from PP1 to PP1-(9-330) and red-shifted from PP1 to CNA(1-42)-PP1(9-330). Our findings provide evidence that the N-terminal domain is an important region influencing the structure and properties of PP1.
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PMID:The N-terminal domain influences the structure and property of protein phosphatase 1. 1924 55


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