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)

A total of 116,118 basepairs (bp) derived from three cosmids spanning the ERCC1 locus of human chromosome 19q13.3 have been sequenced with automated fluorescence-based sequencers and analysed by polymerase chain reaction amplification and computer methods. The assembled sequence forms two contigs totalling 105,831 bp, which contain a human fosB proto-oncogene, a gene encoding a protein phosphatase, two genes of unknown function and the previously-characterized ERCC1 DNA repair gene. This light band region has a high average density of 1.4 Alu repeats per kilobase. Human chromosome light bands could therefore contain up to 75,000 genes and 1.5 million Alu repeats.
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PMID:Automated DNA sequencing and analysis of 106 kilobases from human chromosome 19q13.3. 130 97

Cross-linking of membrane Ig (mIg) on B lymphocytes induces protein tyrosine phosphorylation and phosphoinositide hydrolysis, events that are thought to mediate the diverse biologic responses of B cells to Ag binding. mIg stimulation also induces the expression of the putative transcriptional regulators c-myc, c-fos, egr-1, and jun-B. In this report, normal murine B cells and two murine B lymphoma cell lines were examined for the induction of mRNA expression of seven early response genes first identified in fibroblasts. Expression of four of the seven genes (nur77, nup475, pip92, and 3CH134), encoding two putative transcriptional regulators, a protein of unknown function, and a putative protein phosphatase, was induced after cross-linking of mIg in resting B cells isolated from mouse spleen. In the 2PK-3 and WEHI-231 B lymphoma cell lines three and two, respectively, of these four genes were induced. Expression of these genes could be induced in 2PK-3 cells by activating the phosphoinositide-signaling pathway independently of the tyrosine phosphorylation pathway by signaling through an M1 muscarinic acetylcholine receptor introduced by transfection. Additionally, in all but one case, these early response genes could be induced by directly activating protein kinase C with phorbol esters. In the cell line 2PK-3, the gene 3CH134 was not induced by phorbol ester treatment, but was induced by elevation of intracellular calcium. Thus, a subset of the early response genes identified in serum-stimulated fibroblasts is also induced by Ag-receptor stimulation in B lymphocytes, and this induction appears to be mediated by the phosphoinositide signaling pathway and, for the most part, protein kinase C.
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PMID:Induction of early response genes by cross-linking membrane Ig on B lymphocytes. 838 22

Association of the catalytic subunit (C2) with a variety of regulatory subunits is believed to modulate the activity and specificity of protein phosphatase 2A (PP2A). In this study we report the cloning and expression of a new family of B-subunit, the B', associated with the PP2A0 form. Polymerase chain reactions and cDNA library screening have identified at least seven cDNA isotypes, designated alpha, beta 1, beta 2, beta 3, beta 4, gamma, and delta. The different beta subtypes appear to be generated by alternative splicing. The deduced amino acid sequences of the alpha, beta 2, beta 3, beta 4 and gamma isoforms predict molecular weights of 57,600, 56,500, 60,900, 52,500, and 68,000, respectively. The proteins are 60-80% identical and differ mostly at their termini. Two of the isoforms, B' beta 3 and B' gamma, contain a bipartite nuclear localization signal in their COOH terminus. No homology was found with other B- or B- related subunits. Northern analyses indicate a tissue-specific expression of the isoforms. Expression of B' alpha protein in Escherichia coli generated a polypeptide of approximately 53 kDa, similar to the size of the B' subunit present in the purified PP2A0. The recombinant protein was recognized by antibody raised against native B' and interacted with the dimeric PP2A (A.C2) to generate a trimeric phosphatase. The deduced amino acid sequences of the B' isoforms show significant homology to mammalian, fungal, and plant nucleotide sequences of unknown function present in the data bases. Notably, a high degree of homology (55-66%) was found with a yeast gene, RTS1, encoding a multicopy suppressor of a rox3 mutant. Our data indicate that at least seven B' subunit isoforms may participate in the generation of a large number of PP2A0 holoenzymes that may be spatially and/or functionally targeted to different cellular processes.
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PMID:High complexity in the expression of the B' subunit of protein phosphatase 2A0. Evidence for the existence of at least seven novel isoforms. 857 24

The carboxy terminus of protein phosphatase 2A (PP2A) catalytic subunit is highly conserved. Seven out of the last nine residues, including two potential in vivo phosphorylation sites, threonine 304 and tyrosine 307, are completely invariant in all known PP2As. Mutational analysis of the carboxy terminus in vivo was facilitated by efficient immunoprecipitation of trimeric PP2A holoenzyme via an epitope-tagged catalytic subunit. The results indicate that the catalytic subunit carboxy terminus is important for complex formation with the PP2A 55 kDa regulatory B subunit, but not with polyomavirus oncogene, middle tumor antigen (MT), a viral B-type regulatory subunit. Replacing catalytic subunit threonine 304 or tyrosine 307 with a negatively charged amino acid abolished binding of the B subunit to the dimeric enzyme core and altered substrate specificity. Certain other amino acid substitutions of different size and/or charge also abolished or greatly reduced B subunit binding. Substitution of alanine at position 304 or phenylalanine at position 307 did not dramatically reduce B subunit binding or phosphatase activity in vitro, yet the latter substitutions are not found in naturally occurring PP2As. Thus, the wild-type residues are important for a yet unknown function in vivo. Additionally, deleting the carboxy terminal nine amino acids inhibited binding of the B subunit to the dimeric enzyme core, indicating a requirement for one or more of these amino acids for complex formation. MT interaction with the dimeric PP2A enzyme core was not inhibited by any of these mutations. Finally, unlike B subunit, MT does not activate the phosphatase activity of the PP2A heterodimer towards cdc2-phosphorylated histone H1.
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PMID:Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen. 928 86

The Saccharomyces cerevisiae crv mutants (crv1, 2, 3 and 4) exhibit phenotypes, such as calcium resistance and vanadate sensitivity, which are apparently similar to those of calcineurin-deficient mutants. We have cloned and characterized the CRV4 gene that complements all the phenotypes of the crv4 mutant. DNA sequencing revealed that CRV4 is identical to the previously cloned gene TTP1, which encodes a type II membrane protein of unknown function. Deletion of CRV4/TTP1 causes no obvious phenotype except for Ca2+ resistance and vanadate sensitivity, but is synthetically lethal in combination with a deletion of MPK1, in a manner which is suppressible by the addition of an osmotic stabilizer. In medium containing sorbitol as an osmotic stabilizer, the enb1 mpk1 ttp1 triple mutant exhibits a more severe growth defect than does any of the double mutants enb1 ttp1, enb1 mpk1 or mpk1 ttp1. A high Ca2+ concentration (50 mM) or a constitutively active form of calcineurin partially suppresses the growth defect of the mpk1 ttp1 double mutant. These results indicate that Ttp1 participates in a cellular event essential for growth and morphogenesis, in parallel with the pathways involving Mpk1 MAP kinase and calcineurin.
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PMID:Yeast Crv4/Ttp1, a predicted type II membrane protein, is involved in an event important for growth, functionally overlapping with the event regulated by calcineurin- and Mpk1-mediated pathways. 941 31

Cyclosporin A (CsA) may achieve its immunosuppressive effects by inhibiting the calcium- and calmodulin-dependent phosphatase calcineurin which is required for activation of target genes by members of the NFAT (nuclear factor of activated T cells) transcription factor family. Among these target genes is the gene encoding interleukin-2 (IL2), a cytokine facilitating progression through the G1 phase of the cell cycle. However, IL2 does not reverse CsA inhibition, suggesting that at least one other NFAT-sensitive gene may be involved. The human G0/G1 switch gene, G0S2, has potential NFAT-binding sites in the 5' flank and encodes a small basic potential phosphoprotein of unknown function. Using a sensitive, reverse transcription-polymerase chain reaction (RT-PCR) assay, G0S2 mRNA levels were assayed in cultured blood mononuclear cells. Freshly isolated cells contain high levels of G0S2 mRNA which rapidly decline. This "spontaneous stimulation" is also noted with some other G0S genes and has been attributed to some aspect of the isolation procedure. In cells that have been preincubated to lower mRNA levels, there is a transient increase in G0S2 mRNA, peaking between 1-2 h, in response to Concanavalin-A (ConA), or to the combination of phorbol ester (TPA), and the calcium ionophore, ionomycin. Both these responses are inhibited by CsA. Our results suggest that G0S2 expression is required to commit cells to enter the G1 phase of the cell cycle, and that, while not excluding other possible targets, early inhibition of G0S2 expression by CsA may be important in achieving immunosuppression. G0S2 may be of value as a reporter gene for analyzing the mechanism of action of CsA and its influence on the positive and negative selection of lymphocytes in response to self and not-self antigens.
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PMID:Cyclosporin A inhibits early mRNA expression of G0/G1 switch gene 2 (G0S2) in cultured human blood mononuclear cells. 942 93

Components of cellular stress responses can be identified by correlating changes in stress tolerance with gain or loss of function of defined genes. Previous work has shown that yeast cells deficient in Ppz1 protein phosphatase or overexpressing Hal3p, a novel regulatory protein of unknown function, exhibit increased resistance to sodium and lithium, whereas cells lacking Hal3p display increased sensitivity. These effects are largely a result of changes in expression of ENA1, encoding the major cation extrusion pump of yeast cells. Disruption or overexpression of HAL3 (also known as SIS2) has no effect on salt tolerance in the absence of PPZ1, suggesting that Hal3p might function upstream of Ppz1p in a novel signal transduction pathway. Hal3p is recovered from crude yeast homogenates by using immobilized, bacterially expressed Ppz1p fused to glutathione S-transferase, and it also copurifies with affinity-purified glutathione S-transferase-Ppz1p from yeast extracts. In both cases, the interaction is stronger when only the carboxyl-terminal catalytic phosphatase domain of Ppz1p is expressed. In vitro experiments reveal that the protein phosphatase activity of Ppz1p is inhibited by Hal3p. Overexpression of Hal3p suppresses the reduced growth rate because of the overexpression of Ppz1p and aggravates the lytic phenotype of a slt2/mpk1 mitogen-activated protein kinase mutant (thus mimicking the deletion of PPZ1). Therefore, Hal3p might modulate diverse physiological functions of the Ppz1 phosphatase, such as salt stress tolerance and cell cycle progression, by acting as a inhibitory subunit.
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PMID:The yeast halotolerance determinant Hal3p is an inhibitory subunit of the Ppz1p Ser/Thr protein phosphatase. 963 53

Syk-family tyrosine kinases are essential for lymphocyte development and activation. Using a yeast two-hybrid screen to identify Syk kinases-interacting proteins (SKIPs), we isolated 3BP2, an Abl SH3-interacting protein of unknown function. 3BP2 was selectively expressed in hematopoietic/lymphoid tissues and bound via its SH2 domain activated Syk-family kinases in mammalian cells, including in antigen receptor-stimulated T cells. In addition to Zap-70, the 3BP2 SH2 domain associated in vitro with LAT, Grb2, PLCgamma1, and Cbl from activated T cell lysates. Transient 3BP2 overexpression induced transcriptional activation of the IL-2 promoter and its NFAT or AP-1 elements. This activity was dependent on the SH2 and pleckstrin-homology domains of 3BP2, and required functional Syk kinases, Ras, and calcineurin. Thus, 3BP2 is an important adaptor that may couple activated Zap-70/Syk to a LAT-containing signaling complex involved in TCR-mediated gene transcription.
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PMID:Adaptor function for the Syk kinases-interacting protein 3BP2 in IL-2 gene activation. 984 81

Signal-regulatory proteins (SIRPs) are cell-surface glycoproteins expressed on myeloid and neural cells that have been shown to recruit SH2 domain-containing protein phosphatase 1 (SHP-1) and SHP-2 and to regulate receptor tyrosine kinase-coupled signaling. One SIRP of unknown function, designated SIRP beta 1, contains a short cytoplasmic domain that lacks sequence motifs capable of recruiting SHP-1 and SHP-2. Using a SIRP-specific mAb, we show that SIRP beta 1 is expressed in monocytes and dendritic cells and associates with the signal transduction molecule DAP12. SIRP beta 1/DAP12 complex formation was required for efficient cell-surface expression of SIRP beta 1. Stimulation of this complex induced tyrosine phosphorylation, mitogen-activated protein kinase activation, and cellular activation. Thus, SIRP beta 1 is a new DAP12-associated receptor involved in the activation of myeloid cells.
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PMID:Cutting edge: signal-regulatory protein beta 1 is a DAP12-associated activating receptor expressed in myeloid cells. 1060 85

Protein phosphatase 2A (PP2A) is a multifunctional serine/threonine phosphatase that is critical to many cellular processes including development, neuronal signaling, cell cycle regulation, and viral transformation. PP2A has been implicated in Ca(2+)-dependent signaling pathways, but how PP2A is targeted to these pathways is not understood. We have identified two calmodulin (CaM)-binding proteins that form stable complexes with the PP2A A/C heterodimer and may represent a novel family of PP2A B-type subunits. These two proteins, striatin and S/G(2) nuclear autoantigen (SG2NA), are highly related WD40 repeat proteins of previously unknown function and distinct subcellular localizations. Striatin has been reported to associate with the post-synaptic densities of neurons, whereas SG2NA has been reported to be a nuclear protein expressed primarily during the S and G(2) phases of the cell cycle. We show that SG2NA, like striatin, binds to CaM in a Ca(2+)-dependent manner. In addition to CaM and PP2A, several unidentified proteins stably associate with the striatin-PP2A and SG2NA-PP2A complexes. Thus, one mechanism of targeting and organizing PP2A with components of Ca(2+)-dependent signaling pathways may be through the molecular scaffolding proteins striatin and SG2NA.
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PMID:WD40 repeat proteins striatin and S/G(2) nuclear autoantigen are members of a novel family of calmodulin-binding proteins that associate with protein phosphatase 2A. 1068 96


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