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)

Recombinant p90rsk expressed from baculovirus was found to be phosphorylated and activated by glycogen synthase kinase-3 (GSK-3) in vitro. Phosphorylation of p90rsk by both GSK-3 alpha and GSK-3 beta isoforms was predominantly on threonine residues. Activated p90rsk, resulting from co-expression in insect cells with the oncogenic protein tyrosine kinase p60v-src, was able to phosphorylate GSK-3 but was a poor GSK-3 substrate. These results suggest a potentially novel regulatory connection in the signal transduction cascades in which p90rsk participates.
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PMID:Phosphorylation and activation of p90rsk by glycogen synthase kinase-3. 769 38

The cAMP-dependent protein kinase (PKA) phosphorylates CREB327/341 at a single serine residue, Ser119/133, respectively. Phosphorylation at this site creates the sequence motif SXXXS(P), a consensus site of the glycogen synthase kinase-3 (GSK-3) enzyme (Fiol, C.J., Mahrenholz, A.M., Wang, Y., Roeske, R.W., and Roach, P.J. (1987) J. Biol. Chem. 262, 14042-14048). We examined the phosphorylation of CREB at the SXXXS(P) consensus site and its role in CREB transactivation to cAMP induction. Neither isoform of the GSK-3 enzyme (GSK-3 alpha or beta) utilizes CREB as its substrate unless CREB is already phosphorylated at Ser119/133. A 13-amino acid peptide containing the sequence surrounding Ser119/133 was phosphorylated by GSK-3, at Ser115/129, only after the primary phosphorylation of the peptide by PKA (at Ser119/133), suggesting that Ser115/129 is a GSK-3 phosphoacceptor site. Mutant CREB327/341 proteins containing Ser-->Ala substitutions confirmed Ser115/129 as the only GSK-3 phosphorylation site. Transfection assays of wild type and mutant Gal4-CREB fusion proteins in PC12 cells demonstrated that Ser-->Ala substitution of residue 129 of CREB341 impairs the transcriptional response to cAMP induction. Analogous mutation in CREB327 results in 70% decrease in its transactivation response to cAMP. In undifferentiated F9 cells, which are refractory to cAMP induction, transfected GSK-3 beta kinase induces a 60-fold increase in cyclic AMP response element-dependent transcription, mediated via the endogenous CREB protein. We propose that the hierarchical phosphorylation at the PKA and GSK-3 sites of CREB are essential for cAMP control of CREB.
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PMID:A secondary phosphorylation of CREB341 at Ser129 is required for the cAMP-mediated control of gene expression. A role for glycogen synthase kinase-3 in the control of gene expression. 779 17

Modulation of protein kinase FA/GSK-3 alpha by tyrosine phosphorylation in A431 cells was investigated. Kinase FA/GSK-3 alpha was found to exist in a highly tyrosine-phosphorylated/activated state in resting cells but could become tyrosine-dephosphorylated and inactivated down to less than 30% of control values in a concentration-dependent manner by 50-400 microM genistein (a specific tyrosine kinase inhibitor), as demonstrated by metabolic 32P-labeling of the cells followed by immunoprecipitation and two-dimensional phosphoamino acid analysis and by immunodetection in an antikinase FA/GSK-3 alpha immunoprecipitate kinase assay. Taken together, the results provide evidence that kinase FA/GSK-3 alpha may exist in a highly tyrosine-phosphorylated/activated state in resting cells which can be tyrosine-dephosphorylated and inactivated by extracellular stimulus and that tyrosine kinase(s) and/or tyrosine phosphatase(s) may play a role in the modulation of kinase FA/GSK-3 alpha activity in cells.
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PMID:Tyrosine dephosphorylation and concurrent inactivation of protein kinase FA/GSK-3 alpha by genistein in A431 cells. 780 86

The signal transduction mechanism of protein kinase FA/GSK-3 alpha by tyrosine phosphorylation in A431 cells was investigated. Kinase FA/GSK-3 alpha was found to exist in a highly tyrosine-phosphorylated/activated state in resting cells but could be tyrosine-dephosphorylated and inactivated to approximately 60% of the control level when cells were acutely treated with 1 microM tumor promoter phorbol ester (TPA) at 37 degrees C for 30 min, as demonstrated by metabolic 32P-labeling the cells, followed by immunoprecipitation and two-dimensional phosphoamino acid analysis and by immunodetection in an antikinase FA/GSK-3 alpha immunoprecipitate kinase assay. Conversely, when cells were chronically treated with 1 microM TPA at 37 degrees C for 24 h and processed under identical conditions, kinase FA/GSK-3 alpha was found to be rephosphorylated on tyrosine residue and reactivated to approximately 130% of the original control level. Taken together, the results provide initial evidence that the phosphotyrosine content and cellular activity of kinase FA/GSK-3 alpha can be modulated in a reversible manner by short-term and long-term exposure of A431 cells to TPA. Since acute exposure of cells to TPA causes up-regulation of cellular protein kinase C (PKC) activity and prolonged exposure to TPA causes down-regulation of PKC, the results further suggest that the TPA-mediated modulation of PKC may play a role in the regulation of tyrosine phosphorylation and concurrent activation of kinase FA/GSK-3 alpha in cells, representing a new mode of signal transduction pathway for the regulation of this multisubstrate/multifunctional protein kinase in cells.
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PMID:Tumor promoter phorbol ester reversibly modulates tyrosine dephosphorylation/inactivation of protein kinase FA/GSK-3 alpha in A431 cells. 789 Aug 13

In this report, the phosphorylation sites of neurofilament protein of medium molecular mass (NF-M) by protein kinase FA/glycogen synthase kinase 3 alpha (kinase FA/GSK-3 alpha) were determined by two-dimensional electrophoresis/TLC, phosphoamino acid analysis, HPLC, Edman degradation, and peptide sequencing. Kinase FA/GSK-3 alpha phosphorylates NF-M predominantly on serine residue. Three major tryptic phosphopeptide peaks were resolved by C18 reverse-phase HPLC. Edman degradation and peptide sequence analysis revealed that AKS(p)PVSK is the phosphorylation site sequence for the first major peak. When mapping with the amino acid sequence of neurofilament, we finally demonstrate Ser603-Pro, one of the in vivo sites in NF-M, as the major site phosphorylated by kinase FA/GSK-3 alpha. By using the same approach, we also identified the in vivo sites of Ser502-Pro, Ser506-Pro, and Ser666-Pro as the other three major sites in NF-M phosphorylated by kinase FA/GSK-3 alpha. Taken together, the results provide initial evidence that kinase FA/GSK-3 alpha may represent a physiologically relevant protein kinase involved in the vivo phosphorylation of NF-M. Because Ser502, Ser506, Ser603, and Ser666 are all flanked by a carboxyl-terminal proline residue, the results provide further evidence that FA/GSK-3 alpha may represent a proline-directed protein kinase involved in the structure-function regulation of the neuronal cytoskeletal system.
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PMID:Protein kinase FA/glycogen synthase kinase 3 alpha predominantly phosphorylates the in vivo sites of Ser502, Ser506, Ser603, and Ser666 in neurofilament. 789 Nov 13

Previously, we identified protein kinase FA/glycogen synthase kinase-3 alpha (GSK-3 alpha) as a brain microtubule-associated tau kinase that phosphorylates Ser235 and Ser404 of tau and causes its electrophoretic mobility shift in gels, a unique property characteristic of paired helical filament-associated pathological tau (PHF-tau) in Alzheimer's disease brains. In this study, we found that the activity of kinase FA/GSK-3 alpha towards phosphorylation of brain tau could be stimulated approximately fourfold by heparin. The phosphorylation molar ratio was increased simultaneously up to 9 mol of phosphates/mol of tau, resulting in a reduced mobility of tau with an apparent molecular mass shift to approximately 68 kDa in sodium dodecyl sulfate gels, which is very similar to that observed in Alzheimer-tau. Tryptic digestion of 32P-labelled tau, followed by HPLC and two-dimensional separation on TLC cellulose plates, revealed eight major phosphopeptides. Phosphoamino acid analysis together with sequential manual Edman degradation and protein sequence analysis further revealed that, in addition to Ser235 and Ser404, heparin generated Thr212, Thr231, Ser262, Ser324, and Ser356, the five extra phosphorylation sites in tau. As Ser235, Ser262, Ser324, Ser356, and Ser404 (particularly the site of Ser262) have been identified as five of the most potent sites in tau responsible for reducing microtubule binding possibly involved in neuronal degeneration, and Thr231, Ser235, Ser262, and Ser404 are four of the most well documented sites abnormally phosphorylated in Alzheimer-tau, the results provide initial evidence that protein kinase FA/GSK-3 alpha after heparin potentiation may represent one of the most potent systems possibly involved in the abnormal phosphorylation of PHF-tau in Alzheimer's disease brains.
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PMID:Protein kinase FA/glycogen synthase kinase-3 alpha after heparin potentiation phosphorylates tau on sites abnormally phosphorylated in Alzheimer's disease brain. 793 Dec 92

Many yeast genes that are essential for meiosis are expressed only in meiotic cells. Known regulators of early meiotic genes include IME1, which is required for their expression, and SIN3 and UME6, which prevent their expression in nonmeiotic cells. We report here the molecular characterization of the RIM11 gene, which we find is required for expression of several early meiotic genes. A close functional relationship between RIM11 and IME1 is supported by two observations. First, sin3 and ume6 mutations are epistatic to rim11 mutations; prior studies have demonstrated their epistasis to ime1 mutations. Second, overexpression of RIM11 can suppress an ime1 missense mutation (ime1-L321F) but not an ime1 deletion. Sequence analysis indicates that RIM11 specifies a protein kinase related to rat glycogen synthase kinase 3 and the Drosophila shaggy/zw3 gene product. Three partially defective rim11 mutations alter residues involved in ATP binding or catalysis, and a completely defective rim11 mutation alters a tyrosine residue that corresponds to the site of an essential phosphorylation for glycogen synthase kinase 3. Immune complexes containing a hemagglutinin (HA) epitope-tagged RIM11 derivative, HA-RIM11, phosphorylate two proteins, p58 and p60, whose biological function is undetermined. In addition, HA-RIM11 immune complexes phosphorylate a functional IME1 derivative but not the corresponding ime1-L321F derivative. We propose that RIM11 stimulates meiotic gene expression through phosphorylation of IME1.
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PMID:Analysis of RIM11, a yeast protein kinase that phosphorylates the meiotic activator IME1. 796 31

Glycogen synthase kinase 3 (GSK-3) is involved in the regulation of several metabolic enzymes and transcription factors in response to extracellular signals. Here we report the use of a synthetic peptide derived from the sequence of the cyclic AMP responsive element binding protein (CREB) as a specific substrate for GSK-3 isoforms. The 13-amino acid peptide, KRREILSRRPSYR, was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PKA) and purified on a C18 cartridge. Phosphorylation of the COOH-terminal serine of the peptide by PKA creates a phosphorylation site for GSK-3 since GSK-3 recognizes the consensus motif -S-X-X-X-S(P)-. Although the COOH-terminal serine of the peptide can be phosphorylated by PKA and several other kinases, the phospho-CREB peptide is specific for GSK-3 with Kms of 140 and 200 microM for GSK-3 alpha and GSK-3 beta isoforms, respectively. Using the phospho-CREB peptide, we have successfully purified GSK-3 activity from rabbit skeletal muscle and Escherichia coli cells transformed with a GSK-3 expression vector. The assay described provides a convenient and specific determination of GSK-3 activity.
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PMID:Use of a synthetic peptide as a selective substrate for glycogen synthase kinase 3. 797 84

Although protein kinase FA/GSK-3 alpha (an activating factor of ATP.Mg-dependent protein phosphatase) has been established as a cytosolic enzyme in mammalian nonnervous tissues involved in the metabolic regulation, immunological and biochemical studies on tissue and subcellular distributions demonstrate that kinase FA/GSK-3 alpha is in fact a membrane-associated enzyme and most abundantly exists in brain particulate membrane fractions depending on the tissue homogenization conditions. For instance, when brain was homogenized in Polytron without 0.32 M sucrose, approximately 40% of the total FA/GSK-3 alpha was found in the cytosol. However, when brain was homogenized in buffer containing 0.32 M sucrose and in a glass homogenizer with Teflon pestle, more than 80% of the total FA/GSK-3 alpha was found associated with the particulate membrane fractions. By manipulating these findings, we have developed a simplified procedure for purification of homogeneous kinase FA/GSK-3 alpha in high recovery and in a substantial amount from brain tissue. The data explain why kinase FA/GSK-3 alpha cannot be isolated in a reasonable amount from most mammalian tissues for the past years. The specific pure antibody that can specifically recognize kinase FA/GSK-3 alpha from crude tissue extracts together with the high quantity purification of the enzyme as presented in this report provides an initial key step for studies on the role of kinase FA/GSK-3 alpha in the regulation of brain functions especially in the brain particulate membrane fractions.
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PMID:Immunological and biochemical study on tissue and subcellular distributions of protein kinase FA (an activating factor of ATP.Mg-dependent protein phosphatase): a simplified and efficient procedure for high quantity purification from brain. 813 17

CTP:phosphocholine cytidylyltransferase (CT) is an important regulatory enzyme in phosphatidylcholine biosynthesis. The enzyme exists as a soluble, inactive form that is highly phosphorylated; activation of the enzyme is accompanied by dephosphorylation and translocation to the membrane. We have used a recombinant baculovirus clone to obtain CT labeled in vivo with 32PO4. The tryptic phosphopeptide pattern of the baculovirus-expressed CT was the same as for CT expressed in mammalian cells, indicating that insect cells modify the same phosphorylation sites as do mammalian cells. 32PO4-labeled, baculovirus-expressed CT was digested with trypsin and the peptides purified by reversed-phase high performance liquid chromatography. Phosphoamino acid analysis of the complete protein as well as individual peptides revealed that only serine residues were phosphorylated. Sequence analysis of purified radioactive peptides revealed that phosphorylation of CT was confined to the carboxyl-terminal region and that all or nearly all Ser residues from Ser315 to the carboxyl terminus were labeled. Ser315, Ser319, Ser329, Ser323, Ser331, Ser343, and Ser347 all reside in potential sites for proline-directed kinases. Two other phosphorylated serine residues, Ser315 and Ser333, are found within protein kinase C consensus phosphorylation sites. Ser321, Ser322, Ser333, Ser345, Ser346, Ser350, Ser352, and Ser362 were also found to be phosphorylated. Serine362 resides within a putative casein kinase II phosphorylation site, and there are five potential sites for phosphorylation by glycogen synthase kinase 3. Identification of these sites will allow investigations that focus on the establishment of the physiological function of phosphorylation at each site.
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PMID:Identification of phosphorylation sites in rat liver CTP: phosphocholine cytidylyltransferase. 814 39


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