Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In resting human epithelial and fibroblastic cells, c-Jun is phosphorylated on serine and threonine at five sites, three of which are phosphorylated in vitro by glycogen synthase kinase 3 (GSK-3). These three sites are nested within a single tryptic peptide located just upstream of the basic region of the c-Jun DNA-binding domain (residues 227-252). Activation of protein kinase C results in rapid, site-specific dephosphorylation of c-Jun at one or more of these three sites and is coincident with increased AP-1-binding activity. Phosphorylation of recombinant human c-Jun proteins in vitro by GSK-3 decreases their DNA-binding activity. Mutation of serine 243 to phenylalanine blocks phosphorylation of all three sites in vivo and increases the inherent trans-activation ability of c-Jun at least 10-fold. We propose that c-Jun is present in resting cells in a latent, phosphorylated form that can be activated by site-specific dephosphorylation in response to protein kinase C activation.
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PMID:Activation of protein kinase C decreases phosphorylation of c-Jun at sites that negatively regulate its DNA-binding activity. 184 81

The effect of long term intraportal infusion of insulin on liver regeneration has been studied in rats 24, 36 and 48 hrs after partial hepatectomy. Our studies showed an enhancement by insulin of some parameters of rat liver regeneration, i.e. a rapid increase of the DNA and RNA levels as well as the TTK activity in the whole liver homogenate and all the subcellular fractions examined. The influence of insulin was marked during the whole time of experiment, but the most significant changes occur during the first 24 hrs after partial hepatectomy.
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PMID:Effect of long term insulin infusion into rat portal vein on regenerating liver. 210 85

The conservation in evolution of fundamental signal transduction modules offers a means of isolating genes likely to be involved in plant development. We have amplified by PCR Arabidopsis cDNA and genomic sequences related to the product of the shaggy/zeste-white 3 (sgg) segment polarity gene of Drosophila. This regulatory protein is functionally homologous to glycogen synthase kinase-3 in mammals (GSK-3), which regulates, among others, the DNA-binding activity of the c-jun/AP1 transcription factor. Analysis of PCR products led to the identification of five genes; for two of which, corresponding full-length cDNAs, ASK-alpha and gamma (for Arabidopsis shaggy-related protein kinase), were characterized. The encoded proteins were 70% identical to GSK-3 and sgg over the protein kinase catalytic domain and, after production in Escherichia coli, autophosphorylated mainly on threonine and serine residues, but phosphotyrosine was also detected. ASK-alpha and ASK-gamma also phosphorylated phosphatase inhibitor-2 and myelin basic protein, on threonine and serine, respectively. The high conservation of the protein kinases of GSK-3 family, and their action at the transcriptional level, suggest that the ASK proteins have important functions in higher plants.
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PMID:Arabidopsis homologs of the shaggy and GSK-3 protein kinases: molecular cloning and functional expression in Escherichia coli. 750 23

We report here the sequence of RPK1 (for Regulatory cell Proliferation Kinase), a new Saccharomyces cerevisiae gene coding for a protein with sequence similarities to serine/threonine protein kinases. The protein sequence of 764 amino acids includes an amino-terminal domain (residues 1-410), which may be involved in regulation of the kinase domain (residues 411-764). The catalytic domain of Rpk1 is not closely related to other known yeast protein kinases but exhibits strong homology to a newly discovered group of mammalian kinases (PYT, TTK, esk) with serine/threonine/tyrosine kinase activity. Null alleles of RPK1 are lethal and thus this gene belongs to the small group of yeast protein kinase genes that are essential for cell growth. In addition, eliminating the expression of RPK1 gives rise to the accumulation of non-viable cells with less than a 1 N DNA content suggesting that cells proceed into mitosis without completion of DNA synthesis. Therefore, the Rpk1 kinase may function in a checkpoint control which couples DNA replication to mitosis. The level of the RPK1 transcript is extremely low and constant throughout the mitotic cycle. However it is regulated during cellular differentiation, being decreased in alpha-factor-treated a cells and increased late in meiosis in a/alpha diploids. Taken together, our results suggest that Rpk1 is involved in a pathway that coordinates cell proliferation and differentiation.
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PMID:RPK1, an essential yeast protein kinase involved in the regulation of the onset of mitosis, shows homology to mammalian dual-specificity kinases. 802 80

The glycogen synthase kinase-3 (GSK-3) family of protein-serine kinases is implicated in the development and hormonal regulation of higher eukaryotes. GSK-3-related genes have been cloned and characterized in mammals (alpha and beta forms), Drosophila melanogaster (shaggy/zeste-white3) and Saccharomyces cerevisiae (MCK1). Using the polymerase chain reaction and primers designed to hybridize to conserved catalytic domain sequences of this family, a genomic fragment was amplified from budding yeast DNA. Genomic clones encompassing the entire reading frame were subsequently isolated and sequenced. The protein encoded by this gene, termed ScGSK-3, displays high identity with members of the GSK-3 family, sharing several structural features including a regulatory Tyr residue. A phylogenetic analysis of the catalytic domains of these protein kinases suggests that ScGSK-3 represents the bona fide homologue of GSK-3 and the shaggy product, while the related MCK1 protein kinase is encoded by a paralogous gene which originated by a gene duplication event in the yeast lineage.
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PMID:A Saccharomyces cerevisiae protein-serine kinase related to mammalian glycogen synthase kinase-3 and the Drosophila melanogaster gene shaggy product. 824 30

c-Myc is a nuclear phosphoprotein which binds DNA as a heterodimer with Max. We have identified two in vivo phosphorylation sites, Thr58 and Ser62, within a domain highly conserved among all Myc family members. Thr58 is mutated in several viral forms of the protein and constitutes a mutational hot-spot in Burkitt's lymphoma. Members of the GSK-3 and MAP kinase families, but not CKII, specifically phosphorylated these sites in vitro. The effect of these phosphorylation sites on Myc function was assessed by cotransformation of primary rat embryo fibroblasts with Ras. Mutagenesis of Thr58 to alanine potentiated focus formation, whereas substitution of Ser62 severely inhibited transformation. Mutation of both residues restored wild-type activity. These data suggest acute, post-translational modulation of Myc via phosphorylation of a conserved region previously implicated in transactivation, transformation and autorepression.
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PMID:Site-specific modulation of c-Myc cotransformation by residues phosphorylated in vivo. 830 4

The expression of the Drosophila segmentation gene fushi tarazu (ftz) is controlled at the level of transcription. The proximal enhancer, located approximately 3.4 kb upstream of the transcription start site, directs lacZ fusion gene expression in a ftz-like seven-stripe pattern in transgenic fly embryos. We have taken a biochemical approach to identify DNA-binding proteins that regulate ftz gene expression through the proximal enhancer. DNase I footprinting and methylation interference experiments with staged Drosophila embryo nuclear extracts identified nine protein binding sites in the proximal enhancer. Ten different sequence-specific DNA-binding complexes that interact with eight of these sites were identified. Some interact with multiple sites, while others bind to single sites in the enhancer. Two of the complexes that interact with multiple sites appear to contain the previously described ftz regulators, FTZ-F1 and TTK/FTZ-F2. These in vitro studies allowed us to narrow down the proximal enhancer to a 323-bp DNA fragment that contains all of the protein binding sites. Expression directed by this minimal enhancer element in seven ftz-like stripes in transgenic embryos is identical to that directed by the full-length enhancer. Internal deletions of several sites abolish reporter gene expression in vivo. Thus, the ftz proximal enhancer, like other cell-type-specific eukaryotic enhancers, interacts with an array of proteins that are expected to mediate the establishment, maintenance, and repression of transcription of the ftz gene in seven stripes in the developing embryo.
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PMID:Multiple proteins interact with the fushi tarazu proximal enhancer. 835

Expression of immediate-early genes involving the 12-O-tetradecanoyl phorbol 13-acetate (TPA)-responsive element (TRE) is modulated by post-translational modification of pre-existing activator protein 1 (AP-1) constituents. One of the components of AP-1, c-Jun, has been shown to be phosphorylated by glycogen synthase kinase 3 (GSK-3) in vitro in a region proximal to the DNA-binding domain, resulting in decreased DNA binding. Here, we have used transient transfection to show that AP-1 activity is inhibitable by coexpression of GSK-3 in intact cells. Furthermore, we show that the c-Jun-related proteins JunD and JunB are subject to similar regulation by GSK-3 in intact cells. Comparison of tryptic phosphopeptide maps of the three Jun proteins incubated with GSK-3 in vitro with maps of the same proteins immunoprecipitated from 32P-labelled cells indicates similar sites of phosphorylation. Together, these data support the hypothesis that GSK-3 is an important regulator of AP-1 activity in vivo.
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PMID:Glycogen synthase kinase 3 phosphorylates Jun family members in vitro and negatively regulates their transactivating potential in intact cells. 838 54

Transcription factor AP-1 is constituted by the products of the various fos and jun genes. AP-1 activity is modulated by second messengers and appears to involve post-translational modifications of Fos and Jun. It has been shown that phosphorylation mediated by glycogen synthase kinase 3 (GSK-3) is involved in negative regulation of c-Jun DNA-binding function in vitro. Here we show that two forms of GSK-3 function to decrease the DNA-binding activity as well as the transcriptional activation elicited by c-Jun in vivo. Similarly, the other members of the jun family, JunB, JunD and v-Jun, are negatively regulated by GSK-3 in vivo, although to a slightly lesser extent than c-Jun. We have also tested the proteins encoded by the Drosophila shaggy gene (sgg) in our assays. The sgg proteins share homology with the mammalian GSK-3 and appear to be important for the normal segregation of bristle precursor cells in the imaginal epithelium in Drosophila. Here we show that the products of the sgg gene can also function as negative regulators of Jun/AP-1.
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PMID:Negative regulation of Jun/AP-1: conserved function of glycogen synthase kinase 3 and the Drosophila kinase shaggy. 838 55

The thi80 mutant of Saccharomyces cerevisiae (Nishimura, H., Kawasaki, Y., Nosaka, K., Kaneko, Y., and Iwashima, A. (1991) J. Bacteriol. 173, 2716-2719) shows markedly reduced activity of thiamin pyrophosphokinase (TPK; EC 2.7.6.2). We have isolated a DNA fragment carrying the THI80 gene from a yeast genomic library by its ability to complement constitutive synthesis of the thiamin-repressible acid phosphatase, encoded by the PHO3 gene, of thi80 mutant cells. On the other hand, the thi80 locus was found to be located 3.3 centimorgans proximal to the smp3 locus on the right arm of chromosome XV by genetic mapping analysis, and one more fragment bearing the THI80 gene trailing SMP3 gene was obtained by the plasmid eviction method. The nucleotide sequence of the overlapped region between the two isolated DNAs contained an open reading frame of 957 base pairs, encoding a 319-amino acid polypeptide with a calculated molecular weight of 36,616. When the intact THI80 open reading frame was expressed as a fusion protein carrying three vector-encoded amino acids at its N terminus in Escherichia coli lacking TPK, marked TPK activity was detected in the procaryotic cells, proving that the THI80 gene of S. cerevisiae encodes a structural gene of TPK. A gene disruption experiment demonstrated that the THI80 gene was essential for growth, and therefore, revealed that TPK is the only enzyme capable of synthesizing thiamin pyrophosphate in yeast. Studies of Northern blot analysis and the enzyme assay demonstrated that the THI80 gene expression is regulated mainly at the mRNA level by the intracellular thiamin pyrophosphate and requires the positive regulatory factors encoded by THI2 and THI3 genes. However, unlike thiamin-repressible acid phosphatase and the enzymes involved in thiamin synthesis of S. cerevisiae, TPK was found to be expressed constitutively at a low level and incompletely repressed by exogenous thiamin.
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PMID:Isolation and characterization of a thiamin pyrophosphokinase gene, THI80, from Saccharomyces cerevisiae. 839 43


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