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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This work reports the cloning and sequencing of pkpA, a gene of the filamentous fungus Phycomyces blakesleeanus, whose expression seems to be coupled to vegetative growth. This gene encodes a putative serine/threonine-specific protein kinase, whose sequence is related to that of the yeast protein STE20, involved in pheromone-response pathways, and to a number of MAPK kinase proteins. However, detailed analysis of the kinase sequence suggests that PkpA is a novel serine/threonine protein kinase that probably participates as an intermediate in an intracellular system controlling nuclear proliferation in P. blakesleeanus.
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PMID:PkpA, a novel Phycomyces blakesleeanus serine/threonine protein kinase. 859 Apr 76

To isolate genes responsible for some features of Down syndrome, we performed exon trapping experiments using a series of cosmid clones derived from "the Down syndrome critical region" of chromosome 21 and isolated six exons which are highly homologous to the sequence of Drosophila minibrain (mnb) gene. The Drosophila mnb gene encodes a serine/threonine protein kinase that is required in distinct neuroblast proliferation centers during postembryonic neurogenesis. Using one of these six exons as a probe, we isolated cDNA clones for human homolog of Drosophila mnb gene (MNB) from a fetal brain cDNA library. Human MNB cDNA encodes a protein of 754 amino acids with a nuclear targeting sequence and a catalytic domain common to the serine/threonine-specific protein kinase. The human MNB protein strikingly resembles the recently discovered rat Dyrk protein kinase with a dual specificity. The MNB mRNA is expressed in various tissues including fetal and adult brains. The remarkable similarity of human MNB protein to Drosophila mnb and rat Dyrk proteins implies that human MNB protein may play a significant role in a signaling pathway regulating nuclear functions of neuronal cell proliferation, contributing to certain features of Down syndrome.
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PMID:Cloning of a human homolog of the Drosophila minibrain/rat Dyrk gene from "the Down syndrome critical region" of chromosome 21. 876 99

The presence of an extra copy of human chromosome 21 (trisomy 21), especially region 21q22.2, causes many phenotypes in Down syndrome, including mental retardation. To study genes potentially responsible for some of these phenotypes, we cloned a human candidate gene (DYRK) from 21q22.2 and its murine counterpart (Dyrk) that are homologous to the Drosophila minibrain (mnb) gene required for neurogenesis and to the rat Dyrk gene (dual specificity tyrosine phosphorylation regulated kinase). The three mammalian genes are highly conserved, >99% identical at the protein level over their 763-amino-acid (aa) open reading frame; in addition, the mammalian genes are 83% identical over 414 aa to the smaller 542-aa mnb protein. The predicted human DYRK and murine Dyrk proteins both contain a nuclear targeting signal sequence, a protein kinase domain, a putative leucine zipper motif, and a highly conserved 13-consecutive-histidine repeat. Fluorescence in situ hybridization and regional mapping data localize DYRK between markers D21S336 and D21S337 in the 21q22.2 region. Northern blot analysis indicated that both human and murine genes encode approximately 6-kb transcripts. PCR screening of cDNA libraries derived from various human and murine tissues indicated that DYRK and Dyrk are expressed both during development and in the adult. In situ hybridization of Dyrk to mouse embryos (13, 15, and 17 days postcoitus) indicates a differential spatial and temporal pattern of expression, with the most abundant signal localized in brain gray matter, spinal cord, and retina. The observed expression pattern is coincident with many of the clinical findings in trisomy 21. Its chromosomal locus (21q22. 2), its homology to the mnb gene, and the in situ hybridization expression patterns of the murine Dyrk combined with the fact that transgenic mice for a YAC to which DYRK maps are mentally deficient suggest that DYRK may be involved in the abnormal neurogenesis found in Down syndrome.
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PMID:Isolation of human and murine homologues of the Drosophila minibrain gene: human homologue maps to 21q22.2 in the Down syndrome "critical region". 897 10

The serine/threonine-specific protein kinase Raf-1 plays a key role in mitogenic signal transduction by coupling Ras to the mitogen-activated protein (MAP) kinase cascade. Ras-mediated translocation to the plasma membrane represents a crucial step in the process of serum-stimulated Raf-1 kinase activation. The exact role of the multisite phosphorylation in Raf regulation, however, is not clear. We have previously reported that the mobility shift-associated hyperphosphorylation of Raf correlates with a reduction of serum-stimulated Raf kinase activity (Wartmann, M., and Davis, R. J. (1994) J. Biol. Chem. 269, 6695-6701). Here we show that incubation of serum-starved CHO cells with D609, a purported inhibitor of phosphatidylcholine-specific phospholipase C, also results in a mobility shift of Raf-1 that is due to hyperphosphorylation on sites identical to those observed following mitogen stimulation. Subcellular fractionation analyses revealed that D609-induced mobility shift-associated hyperphosphorylation was paralleled by a decreased membrane association of Raf-1. Similar results were obtained in an in vitro reconstitution system. Furthermore, PD98059, a specific inhibitor of activation of the MAP kinase kinase MEK, prevented D609-induced Raf hyperphosphorylation and restored the amount of membrane-bound Raf to control levels. Taken together, these data suggest that mobility shift-associated hyperphosphorylation of Raf-1, by virtue of reducing the amount of plasma membrane-bound Raf-1, represents a negative feedback mechanism contributing to the desensitization of the MAP kinase signaling cascade.
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PMID:Negative modulation of membrane localization of the Raf-1 protein kinase by hyperphosphorylation. 902 94

Exon trapping was used to identify portions of human chromosome 21-encoded genes. More than 600 potential exons on the chromosome have been cloned and characterised to date. A BLAST search of databases revealed that three of these trapped "exons", hmc18a08, hmc18f10 and hmc27g09, showed strong homology to different regions of the Drosophila mnb (Genbank X70794) and rat Dyrk (Genbank X79769) genes, indicating that these three exons may be portions of a human homologue of these genes (we termed this gene MNB for minibrain). With amplification by the polymerase chain reaction and hybridisation analysis we have mapped the human MNB gene on overlapping yeast artificial chromosomes 336G11 and 806A11 of chromosome 21q22.2 between markers D21S65 and ERG. The Drosophila mnb (minibrain) gene, which encodes a member of the protein kinase family, is involved in postembryonic neurogenesis. The Dyrk gene, which encodes a dual specificity protein kinase, is a rat homologue of the Drosophila mnb gene. The kinase activity is dependent on tyrosine residues in the catalytic domain, and it has been speculated that the protein is involved in control of the cell cycle. Altered expression of the human MNB gene may be involved in the pathogenesis of certain phenotypes of Down syndrome, including mental retardation.
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PMID:Localisation of a human homologue of the Drosophila mnb and rat Dyrk genes to chromosome 21q22.2. 904 32

The RNA-regulated protein kinase, (PKR) is an interferon-inducible enzyme of widespread occurrence in eukaryotic organisms. This serine/threonine-specific protein kinase is activated by double-stranded RNA by a mechanism involving autophosphorylation. Once activated, the enzyme phosphorylates the alpha subunit of protein synthesis initiation factor eIF2, thereby inhibiting translation. Recent evidence suggests that there may be additional substrates, and that signal transduction and gene transcription pathways also may be regulated by the protein kinase. As well as being important in mediating the antiviral effects of interferons, PKR is implicated in regulating cell proliferation in uninfected cells and may have a tumour suppressor function under normal conditions. Studies using cell lines expressing inactive mutants of PKR and mice with homozygous disruptions of the PKR gene are leading to greater insights into the biological significance of this enzyme.
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PMID:PKR--a protein kinase regulated by double-stranded RNA. 937 75

DYRK1 is a dual specificity protein kinase presumably involved in brain development. Here we show that the kinase belongs to a new family of protein kinases comprising at least seven mammalian isoforms (DYRK1A, DYRK1B, DYRK1C, DYRK2, DYRK3, DYRK4A, and DYRK4B), the yeast homolog Yak1p, and the Drosophila kinase minibrain (MNB). In rat tissues, DYRK1A is expressed ubiquitously, whereas transcripts for DYRK1B, DYRK2, DYRK3, and DYRK4 were detected predominantly in testes of adult but not prepuberal rats. By fluorescence microscopy and subcellular fractionation, a green fluorescent protein (GFP) fusion protein of DYRK1A was found to accumulate in the nucleus of transfected COS-7 and HEK293 cells, whereas GFP-DYRK2 was predominantly detected in the cytoplasm. DYRK1A exhibited a punctate pattern of GFP fluorescence inside the nucleus and was co-purified with the nuclear matrix. Analysis of GFP-DYRK1A deletion constructs showed that the nuclear localization of DYRK1A was mediated by its nuclear targeting signal (amino acids 105-139) but that its characteristic subnuclear distribution depended on additional N-terminal elements (amino acids 1-104). When expressed in Escherichia coli, DYRK1A, DYRK2, DYRK3, MNB, and Yak1p catalyzed their autophosphorylation on tyrosine residues. The kinases differed in their substrate specificity in that DYRK2 and DYRK3, but not DYRK1A and MNB, catalyzed phosphorylation of histone H2B. The heterogeneity of their subcellular localization and substrate specificity suggests that the kinases are involved in different cellular functions.
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PMID:Sequence characteristics, subcellular localization, and substrate specificity of DYRK-related kinases, a novel family of dual specificity protein kinases. 974 65

The DYRK1A gene on human chromosome 21 encodes a protein kinase presumed to be involved in the pathogenesis of mental retardation in Down's syndrome. Here we describe a highly similar homolog, DYRK1B, which is, in contrast to DYRK1A, predominately expressed in muscle and testis. The human DYRK1B gene was mapped to chromosome 19 (19q12-13.11) by radiation hybrid analysis. The amino acid sequences of DYRK1A and DYRK1B are 84% identical in the N-terminus and the catalytic domain but show no extended sequence similarity in the C-terminal region. DYRK1B contains all motifs characteristic for the DYRK family of protein kinases. In addition, the sequence comprises a bipartite nuclear localization motif. A green fluorescent protein (GFP) fusion protein of DYRK1B was found mainly in the nucleus of transfected COS-7 cells. These data suggest that DYRK1B is a muscle- and testis-specific isoform of DYRK1A and is involved in the regulation of nuclear functions.
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PMID:Cloning and characterization of DYRK1B, a novel member of the DYRK family of protein kinases. 991 63

We describe the characterization of several transcripts of the Drosophila serine/threonine protein kinase 61 (Dstpk61) gene. Dstpk61 produces at least four transcripts, including a 3.0-kb testis-specific transcript, a 4.5-kb female-specific carcass transcript, a 3.5-kb ovary-specific transcript, and a 4.7-kb non-sex-specific transcript. Two cDNAs, a 4.5-kb cDNA (cDNAB) and a 3.0-kb cDNA (cDNAA), likely to correspond to either the non-specific or the female-specific carcass and the testis-specific transcript, respectively, were fully sequenced and found to encode a novel OPA-repeat-containing serine/threonine-specific protein kinase. cDNAA and cDNAB both contain the entire ORF that encodes this predicted protein, but differ in the untranslated regions. The cDNAs contain translational control elements which are found in transcripts under male germline-specific translational control, and doublesex-like 13-nucleotide repeat elements, which are required for transformer/transformer-2-mediated splicing of the female doublesex transcript. The complex tissue and sex-specific transcripts, differing in the untranslated regions which are likely to be crucial in translational control, suggest that this kinase may have both general and sex-specific functions. The protein is homologous to human 3-phosphoinositide dependent protein kinase, which is involved in transduction of insulin signalling.
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PMID:Sex-specific transcripts of the Dstpk61 serine/threonine kinase gene in Drosophila melanogaster. 1033 30

MAP kinases have been established to be key regulators of cellular signal transduction systems and are conserved from baker's yeast to human beings. Until now, three major types of mammalian MAP kinases (ERK, p38, and JNK/SAPK) have been reported and extensively studied. Advancement of genomic research as well as homology cloning techniques has revealed that there are several other protein kinase families that are structurally modestly related to those conventional MAP kinases. Indeed, most of them possess the TXY motif characteristic to MAP kinases in their activation loop, and can be regarded as members of the MAP kinase superfamily, yet some of them show closest overall similarity to Cdks. These kinases, all of mammalian origin, include MAK, MRK, MOK, p42KKIALRE, p56KKIAMRE, NLK, DYRK/Mnb, and Prp4. Although most of their physiological roles remain unknown, recent progress starts shedding some light on their functions.
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PMID:Distantly related cousins of MAP kinase: biochemical properties and possible physiological functions. 1060 Apr 95


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