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)

Unrestricted protein tyrosine phosphatase (PTPase) activity may play a role in pathogenesis. For instance, the virulence determinant gene, yopH, of Yersinia pseudotuberculosis encodes a PTPase. The phosphatase activity of the YopH protein is essential for the pathogenesis of Y. pseudotuberculosis. Yersinia pestis, the bacterium which causes the bubonic plague, also contains a gene closely related to yopH. The action of YopH on host proteins appears to break down signal transduction mechanisms in many cell types including those of the immune system. This may contribute to the ability of the bacterium to escape effective surveillance by the immune system. The vaccinia virus VH1 gene, like yopH in the Yersinia bacteria, encodes a protein phosphatase. The VH1 PTPase defines a new class of phosphatases capable of dephosphorylating both phosphoserine/threonine and tyrosine containing substrates. Proteins sharing sequence identity to this dual-specificity phosphatase have been identified from other viruses, yeast and man. Although a complete understanding of the function of these dual-specificity phosphatases is not presently available, they clearly play important roles in cell cycle regulation, growth control and mitogenic signaling mechanisms. The unique catalytic properties of the dual specificity phosphatases suggest that these catalysts constitute a distinct subfamily of phosphatases.
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PMID:Bacterial and viral protein tyrosine phosphatases. 830 77

MKP-1 (also known as CL100, 3CH134, Erp, and hVH-1) exemplifies a class of dual-specificity phosphatase able to reverse the activation of mitogen-activated protein (MAP) kinase family members by dephosphorylating critical tyrosine and threonine residues. We now report the cloning of MKP-3, a novel protein phosphatase that also suppresses MAP kinase activation state. The deduced amino acid sequence of MKP-3 is 36% identical to MKP-1 and contains the characteristic extended active-site sequence motif VXVHCXXGXSRSXTXXXAYLM (where X is any amino acid) as well as two N-terminal CH2 domains displaying homology to the cell cycle regulator Cdc25 phosphatase. When expressed in COS-7 cells, MKP-3 blocks both the phosphorylation and enzymatic activation of ERK2 by mitogens. Northern analysis reveals a single mRNA species of 2.7 kilobases with an expression pattern distinct from other dual-specificity phosphatases. MKP-3 is expressed in lung, heart, brain, and kidney, but not significantly in skeletal muscle or testis. In situ hybridization studies of MKP-3 in brain reveal enrichment within the CA1, CA3, and CA4 layers of the hippocampus. Metrazole-stimulated seizure activity triggers rapid (<1 h) but transient up-regulation of MKP-3 mRNA in the cortex, piriform cortex, and some amygdala nuclei. Metrazole stimulated similar regional up-regulation of MKP-1, although this was additionally induced within the thalamus. MKP-3 mRNA also undergoes powerful induction in PC12 cells after 3 h of nerve growth factor treatment. This response appears specific insofar as epidermal growth factor and dibutyryl cyclic AMP fail to induce significant MKP-3 expression. Subcellular localization of epitope-tagged MKP-3 in sympathetic neurons reveals expression in the cytosol with exclusion from the nucleus. Together, these observations indicate that MKP-3 is a novel dual-specificity phosphatase that displays a distinct tissue distribution, subcellular localization, and regulated expression, suggesting a unique function in controlling MAP kinase family members. Identification of a second partial cDNA clone (MKP-X) encoding the C-terminal 280 amino acids of an additional phosphatase that is 76% identical to MKP-3 suggests the existence of a distinct structurally homologous subfamily of MAP kinase phosphatases.
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PMID:MKP-3, a novel cytosolic protein-tyrosine phosphatase that exemplifies a new class of mitogen-activated protein kinase phosphatase. 862 80

The tumour suppressor gene PTEN/MMAC1/TEP1 encodes a dual-specificity phosphatase that recognizes phosphatidylinositol-3,4,5-triphosphate and protein substrates. We have shown previously that over-expression of PTEN in a tetracycline-controlled inducible system blocks cell cycle progression and induces apoptosis in MCF-7 breast cancer cells. Here, we demonstrate that over-expression of wild-type PTEN leads to the suppression of cell growth through the blockade of cell cycle progression, an increase in the abundance of p27, a decrease in the protein levels of cyclin D1 and the inhibition of Akt phosphorylation. In contrast, expression of the phosphatase-dead mutant, C124S, promotes cell growth and has the opposite effect on the abundance of p27, cyclin D1 levels and the phosphorylation of Akt. The G129E mutant, which does not have lipid phosphatase activity but retains protein phosphatase activity, behaves like C124S except that the former causes decreases in cyclin D1 levels similar to wild-type PTEN. Therefore, PTEN exerts its growth suppression through lipid phosphatase-dependent and independent activities and most likely, via the coordinate effect of both protein phosphatase and lipid phosphatase activities. Addition of either estrogen or insulin abrogates PTEN-mediated up-regulation of p27 and partially blocks PTEN-mediated growth suppression, whereas the combination of estrogen and insulin eliminates the alterations of p27 and cyclin D1 and completely blocks PTEN-mediated growth suppression. Our findings demonstrate that PTEN blocks cell cycle progression differentially through down-regulating the positive cell cycle regulator, cyclin D1, by its protein phosphatase activity, and up-regulating the negative cell cycle regulator, p27, by its lipid phosphatase activity.
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PMID:PTEN coordinates G(1) arrest by down-regulating cyclin D1 via its protein phosphatase activity and up-regulating p27 via its lipid phosphatase activity in a breast cancer model. 1123 Jan 79

Steroid hormone biosynthesis in the adrenal cortex is controlled by the peptide hormone adrenocorticotropin (ACTH), which acts to increase intracellular cAMP and results in the activation of cAMP-dependent protein kinase A (PKA) and subsequent increase in steroidogenic gene transcription. Protein phosphorylation by PKA activates transcription of genes encoding steroidogenic enzymes; however the precise proteins which are phosphorylated remain to be determined. We have recently shown that phosphoprotein phosphatase (PP) activity is essential for cAMP-dependent transcription of the human CYP17 (hCYP17) gene in H295R adrenocortical cells. The aim of our current studies was to determine if inhibition of PP activity attenuates cAMP-dependent mRNA expression of other steroidogenic genes in H295R cells. Using various inhibitors of serine/threonine and tyrosine PPs, we examined the role of phosphatase activity on cAMP-dependent transcription of steroidogenic genes in the adrenal cortex. CYP11A, CYP11B1/2, CYP21, and adrenodoxin also require PP activity for cAMP-stimulated gene expression. Inhibition of both serine/threonine and tyrosine PP activities suppresses the cAMP-dependent mRNA expression of several steroidogenic genes, suggesting that a dual-specificity PP is essential for conveying ACTH/cAMP-stimulated transcription. We propose that PKA phosphorylates and activates a dual-specificity phosphatase, which mediates steroidogenic gene transcription in response to ACTH/cAMP.
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PMID:cAMP-dependent transcription of steroidogenic genes in the human adrenal cortex requires a dual-specificity phosphatase in addition to protein kinase A. 1220 Feb 37

Reversible phosphorylation is recognized to be a major mechanism for the control of intracellular events in eukaryotic cells. From a human fetal brain cDNA library, we isolated a cDNA clone encoding a novel dual specificity protein phosphatase, which showed 88% identity with previously reported mouse LMW-DSP3 at the amino acid level. The deduced protein had a single dual-specificity phosphatase catalytic domain, and lacked a cdc25 homology domain. LMW-DSP3 was expressed in the heart, lung, liver, and pancreas, and the expression level in the pancreas was highest. The LMW-DSP3 gene was located in human chromosome 2q32, and consisted of five exons spanning 21kb of human genomic DNA. LMW-DSP3 fused to GST showed phosphatase activity towards p-nitrophenyl phosphate which was optimal at pH 7.0 and 40 degrees C, and the activity was enhanced by Ca(2+) and Mn(2+). The phosphatase activity of LMW-DSP3 was inhibited by orthovanate. LMW-DSP3 showed phosphatase activity toward oligopeptides containing pSer/Thr and pTyr, indicating that LMW-DSP3 is a protein phosphatase with dual substrate specificity.
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PMID:Molecular cloning and characterization of a novel human protein phosphatase, LMW-DSP3. 1247 73

Protein tyrosine phosphatases (PTPs) are comprised of two superfamilies, the phosphatase I superfamily containing a single low-molecular-weight PTP (lmwPTP) family and the phosphatase II superfamily including both the higher-molecular-weight PTP (hmwPTP) and the dual-specificity phosphatase (DSP) families. The phosphatase I and II superfamilies are often considered to be the result of convergent evolution. The PTP sequence and structure analyses indicate that lmwPTPs, hmwPTPs, and DSPs share similar structures, functions, and a common signature motif, although they have low sequence identities and a different order of active sites in sequence or a circular permutation. The results of this work suggest that lmwPTPs and hmwPTPs/DSPs are remotely related in evolution. The earliest ancestral gene of PTPs could be from a short fragment containing about 90 approximately 120 nucleotides or 30 approximately 40 residues; however, a probable full PTP ancestral gene contained one transcript unit with two lmwPTP genes. All three PTP families may have resulted from a common ancestral gene by a series of duplications, fusions, and circular permutations. The circular permutation in PTPs is caused by a reading frame difference, which is similar to that in DNA methyltransferases. Nevertheless, the evolutionary mechanism of circular permutation in PTP genes seems to be more complicated than that in DNA methyltransferase genes. Both mechanisms in PTPs and DNA methyltransferases can be used to explain how some protein families and superfamilies came to be formed by circular permutations during molecular evolution.
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PMID:Different protein tyrosine phosphatase superfamilies resulting from different gene reading frames. 1267 37

Progressive myoclonus epilepsy of Lafora type (LD, MIM 254780) is a fatal autosomal recessive disorder characterized by the presence of progressive neurological deterioration, myoclonus, epilepsy and polyglucosan intracellular inclusion bodies, called Lafora bodies. Lafora bodies resemble glycogen with reduced branching, suggesting an alteration in glycogen metabolism. Linkage analysis and homozygosity mapping localized EPM2A, a major gene for LD, to chromosome 6q24. EPM2A encodes a protein of 331 amino acids (named laforin) with two domains, a dual-specificity phosphatase domain and a carbohydrate binding domain. Here we show that, in addition, laforin interacts with itself and with the glycogen targeting regulatory subunit R5 of protein phosphatase 1 (PP1). R5 is the human homolog of the murine Protein Targeting to Glycogen, a protein that also acts as a molecular scaffold assembling PP1 with its substrate, glycogen synthase, at the intracellular glycogen particles. The laforin-R5 interaction was confirmed by pull-down and co-localization experiments. Full-length laforin is required for the interaction. However, a minimal central region of R5 (amino acids 116-238), including the binding sites for glycogen and for glycogen synthase, is sufficient to interact with laforin. Point-mutagenesis of the glycogen synthase-binding site completely blocked the interaction with laforin. The majority of the EPM2A missense mutations found in LD patients result in lack of phosphatase activity, absence of binding to glycogen and lack of interaction with R5. Interestingly, we have found that the LD-associated EPM2A missense mutation G240S has no effect on the phosphatase or glycogen binding activities of laforin but disrupts the interaction with R5, suggesting that binding to R5 is critical for the laforin function. These results place laforin in the context of a multiprotein complex associated with intracellular glycogen particles, reinforcing the concept that laforin is involved in the regulation of glycogen metabolism.
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PMID:Laforin, the dual-phosphatase responsible for Lafora disease, interacts with R5 (PTG), a regulatory subunit of protein phosphatase-1 that enhances glycogen accumulation. 1453 30

Most of dual-specificity protein phosphatases (DSPs) play an important role in the regulation of mitogenic signal transduction and controlling the cell cycle in response to extracellular stimuli. In this study, a novel human dual-specificity protein phosphatases gene named dual-specificity phosphatase 23 (DUSP23) was isolated by large-scale sequencing analysis of a human fetal brain cDNA library. Its cDNA was 726 bp in length, encoding a 150-amino acid polypeptide which contained a dual-specificity phosphatase catalytic (DSPc) domain but not a CDC25 homology (CH2) domain. Reverse transcription-PCR (RT-PCR) revealed that the DUSP23 was expressed in most fetal tissues and two adult tissues: testis and colon. Transient transfection experiment suggested that DUSP23 was localized in the cytoplasm of HEK293 cells. DUSP23 showed distinctive phosphatase activity toward p-nitrophenyl phosphate (pNPP), as well as oligopeptides containing phospho-tyrosine and phospho-threonine residues. Furthermore, DUSP23 could dephosphorylate p44ERK1 but not p38 and p54SAPKbeta in vitro. All the results indicated that DUSP23 was a novel protein phosphatase with dual substrate specificity.
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PMID:Molecular cloning and characterization of a novel dual-specificity phosphatase 23 gene from human fetal brain. 1514 33

PTEN is a dual-specificity phosphatase with both protein phosphatase and lipid phosphatase activity. PTEN is the first phosphatase identified as a tumor suppressor. Not since the discovery of p53 has a tumor suppressor generated such interest. Initial studies performed on cancer cell lines suggested that PTEN may be responsible for almost all types of cancer, both solid tumors and hematological malignancies. Biallelic deletion of PTEN has been associated with advanced stage tumors or metastatic disease. PTEN has been shown to play a pivotal role in apoptosis, cell cycle arrest, and possibly cell migration. Emerging data suggest that this may be an oversimplification of PTEN's role, and that PTEN may be haploinsufficient for tumor progression and may play important roles in other cellular functions such as angiogenesis and MAP kinase signaling.
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PMID:PTEN regulatory functions in tumor suppression and cell biology. 1544 14

Intracellular signaling pathways and their relationship to malignant progression have become a major focus of cancer biology. The dual-specificity phosphatase (DSP) family is a more recently identified family of intracellular signaling modulators. We have identified a novel protein phosphatase with a well-conserved DSP catalytic domain containing the DSP catalytic motif, xHCxxGxSRS, and mitogen-activated protein kinase phosphatase (MKP) motif, AYLM. Because of these unique characteristics, the protein was named mitogen-activated protein kinase phosphatase-8 (MKP-8). This protein is approximately 20kDa in size and mainly localizes to the nuclear compartment of the cell. MKP-8 is expressed in embryonal cancers (retinoblastoma, neuroepithelioma, and neuroblastoma) and has limited expression in normal tissues. MKP-8 displays significant phosphatase activity that is inhibited by a cysteine to serine substitution in the catalytic domain. When co-expressed with activated MAPKs, MKP-8 is able to inhibit p38 kinase phosphorylation and downstream activity.
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PMID:MKP-8, a novel MAPK phosphatase that inhibits p38 kinase. 1579 12


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