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)

A protein kinase characterized by its ability to phosphorylate microtubule-associated protein-2 (MAP2) and myelin basic protein (MBP) is thought to play a pivotal role in the transduction of signals from many receptors in response to their ligands. A kinase with such activity, named extracellular signal-regulated kinase 1 (ERK1), is activated rapidly by numerous extracellular signals, requires phosphorylation on tyrosine to be fully active, and in vitro can activate a kinase (a ribosomal S6 protein kinase) that is downstream in phosphorylation cascades. From the protein sequence predicted by the rat ERK1 cDNA, peptides were synthesized and used to elicit antibodies. The antibodies recognize both ERK1; a closely related kinase, ERK2; and a third novel ERK-related protein. Using these antibodies we have determined that ERK1 and ERK2 are ubiquitously distributed in rat tissues. Both enzymes are expressed most highly in brain and spinal cord as are their mRNAs. The third ERK protein was found in spinal cord and in testes. The antibodies detect ERKs in cell lines from multiple species, including human, mouse, dog, chicken, and frog, in addition to rat, indicating that the kinases are conserved across species. ERK1 and ERK2 have been separated by chromatography on Mono Q. Stimulation by insulin increases the phosphorylation of both kinases on tyrosine residues, as assessed by immunoblotting with phosphotyrosine antibodies, and retards their elution from Mono Q. Each of these ERKs appears to account for a distinct peak of MBP kinase activity. The activity in each peak is diminished by incubation with either phosphatase 2a or CD45. Therefore, both enzymes have similar modes of regulation and appear to contribute to the growth factor-stimulated MAP2/MBP kinase activity measured in cell extracts.
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PMID:Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. 165 26

Cys-cdc2(8-20), a synthetic peptide derived from p34cdc2, was previously reported to be a specific and efficient substrate of a pp60c-src-related tyrosine kinase isolated from bovine spleen (the spleen tyrosine kinase) (Litwin, C.M.E., Cheng, H.-C., and Wang, J.H. (1991) J. Biol. Chem. 266, 2557-2566). The longer peptide, cdc2(1-24), was found to be phosphorylated by the kinase with similar efficiency, and Tyr15 was the only amino acid residue phosphorylated. This indicated that the amino acid sequence of cdc2(8-20) peptide, EKI-GEGTYGVVYK, contained the structural features important for protein tyrosine kinase substrate activity. A stepwise procedure using synthetic peptides was employed to investigate such structural features. First, a computer search of protein sequences homologous to cdc2(8-20) uncovered five protein kinases containing homologous sequence with tyrosine at a position corresponding to Tyr15 of p34cdc2. Second, a peptide derived from ribosomal S6 protein kinase (rsk(436-456] was synthesized. The rsk(436-456) peptide contained a segment, ETIGVGSYSVCKR, which is highly homologous to that of cdc2(8-20). It was found to be a very poor substrate of the spleen tyrosine kinase. Third, peptide analogs of cdc2(6-20) with single substitutions of amino acid residues Lys9, Glu12, Thr14, Gly16, Val18, and Tyr19 by amino acid residues at corresponding positions of rsk were synthesized and tested as spleen tyrosine kinase substrates. Only Glu12 and Thr14 substituted peptide analogs showed decreased substrate activities. (The substrate activity of a peptide is the ability of the peptide to serve as the substrate of the spleen tyrosine kinase. It was determined of the spleen tyrosine kinase. It was determined either by the kinetic parameters (Km and Vmax) of phosphorylation of the peptide or by the initial phosphorylation rate of the peptide by the spleen tyrosine kinase.) An analog with double substitution at Glu12 An analog with double substitution at Glu12 and Thr14 was found to be almost as poor a substrate as the rsk peptide. In addition, peptide analogs with Tyr15 substituted by Phe or D-Tyr had poor substrate activities as well as weak inhibitory activities. Thus, Glu12, Thr14, and Tyr15 residues of p34cdc2 contained structural components essential for the efficient phosphorylation of the peptides derived from p34cdc2 by the pp60c-src-related spleen tyrosine kinase.
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PMID:Structural basis of specific and efficient phosphorylation of peptides derived from p34cdc2 by a pp60src-related protein tyrosine kinase. 171 44

p70 S6 kinase, a major insulin-mitogen-activated ribosomal S6 protein kinase in mammalian cells, is activated by phosphorylation of multiple Ser/Thr residues on the enzyme polypeptide. A synthetic peptide, corresponding to a 37-residue segment from the carboxyl-terminal tail of the kinase which resembles the sequence phosphorylated in S6, acts as a competitive inhibitor of p70 S6 kinase without itself being phosphorylated by the enzyme. This synthetic peptide is phosphorylated by an array of protein kinases which are rapidly activated by insulin. Thus, these sequences of p70 S6 kinase constitute a potential autoinhibitory pseudosubstrate site, whose phosphorylation is catalyzed by candidate upstream-activating protein kinases.
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PMID:Insulin-activated protein kinases phosphorylate a pseudosubstrate synthetic peptide inhibitor of the p70 S6 kinase. 190 27

Past work established a cell-free assay for a nerve growth factor (NGF)-activated protein kinase activity (designated N-kinase) that utilizes tyrosine hydroxylase and histone H1 as substrates and that is distinct from a variety of well-characterized kinases. This study explores the specificity and mechanistic pathway(s) by which N-kinase activity is regulated in PC12 rat pheochromocytoma cells. N-kinase is rapidly activated in these cells by treatment with NGF, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), phorbol ester, or dibutyryl cyclic AMP. Our data indicate that the stimulated activity is the same for each agent by several criteria: It exhibits the same characteristic biphasic elution pattern by Mono S fast protein liquid chromatography (FPLC), except for the case of dibutyryl cyclic AMP in which one of the activity peaks is somewhat shifted; it shows the same elution pattern by FPLC on a Superose 12 column; it possesses identical substrate specificity; and, except in the case of dibutyryl cyclic AMP, it does not show additivity when each agent is added simultaneously with NGF. The multiple forms of N-kinase are interconvertible in that rechromatography on a Mono S column yields a single peak of activity. Also, when NGF and dibutyryl cyclic AMP are simultaneously presented to cells, the chromatographic profile resembles that with NGF alone. Activation occurs through several independent initial pathways. Down-regulation of protein kinase C by phorbol ester pretreatment prevents N-kinase activation by phorbol ester, but not by the other agents. A PC12 cell-derived line deficient in cyclic AMP-dependent protein kinase II activity exhibits N-kinase activation by all treatments except dibutyryl cyclic AMP. The properties of N-kinase suggests that it is similar or identical to the ribosomal S6 protein kinase described by Blenis and Erikson. Additional experiments revealed that N-kinase activity can be stimulated in several cell lines in addition to PC12 cells. These findings indicate that the N-kinase can be activated via multiple second-messenger pathways and that it could therefore potentially play a significant role in mediating shared intracellular responses to various extracellular signals.
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PMID:Multiple pathways of N-kinase activation in PC12 cells. 215 51

Insulin and tumor-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) share some biological activities in normal hepatocytes and in some lines of cultured hepatoma cells. To investigate the possibility that some of these common effects might involve a common pathway, we examined the effects of insulin and PMA on several biological processes in normal and protein kinase C-deficient H4IIE rat hepatoma cells. Protein kinase C deficiency was achieved by preincubating the cells in high concentrations of PMA, and was documented by direct enzyme measurement in soluble and particulate cellular fractions, and by analysis of immunoreactive protein kinase C concentrations in whole cellular homogenates. In the protein kinase C-deficient cells, the following actions of insulin remained at near normal levels: stimulated phosphorylation of the ribosomal protein S6; activation of a ribosomal S6 protein kinase; and increases in ornithine decarboxylase activity and mRNA accumulation. PMA stimulated all of these responses in the normal cells, but none of them in the PMA-pretreated cells. We conclude that insulin can exert some of its actions in a normal manner in protein kinase C-deficient H4IIE hepatoma cells (ATCC CRL 1548) and that some of the actions insulin holds in common with PMA may be due to common activation of one or more distal pathways. A candidate for such a distal step is activation of the ribosomal protein S6 protein kinase.
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PMID:Insulin action in normal and protein kinase C-deficient rat hepatoma cells. Effects on protein phosphorylation, protein kinase activities, and ornithine decarboxylase activities and messenger ribonucleic acid levels. 333 10

We have investigated the signalling pathways involved in the stimulation of glycogen and fatty acid synthesis by insulin in rat fat cells using wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, which blocks activation of p70 ribosomal S6 protein kinase (p70S6K). Insulin produced a decrease in the activity of glycogen synthase kinase-3 which is likely to be important in the observed stimulation of glycogen synthase. Both of these actions were found to be sensitive to inhibition by wortmannin. Activation of three processes is involved in the stimulation of fatty acid synthesis from glucose by insulin, namely glucose uptake, acetyl-CoA carboxylase and pyruvate dehydrogenase. Whereas wortmannin largely abolished the effects of insulin on glucose utilization and acetyl-CoA carboxylase activity, it was without effect on the stimulation of pyruvate dehydrogenase. Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase. Rapamycin also failed to have any appreciable effect on stimulation of these parameters by insulin, although it did block the effect of insulin on p70S6K. We conclude that the activity of phosphatidylinositol 3-kinase is required for the effects of insulin on glycogen synthesis, glucose uptake and acetyl-Co-AN carboxylase, but is not involved in signalling to pyruvate dehydrogenase. Activation of mitogen-activated protein kinase or p70S6K, however, does not appear to be sufficient to bring about the stimulation of fatty acid or glycogen synthesis. Altogether is seems likely that at least four distinct signalling pathways are involved in the effects of insulin on rat fat cells.
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PMID:Multiple signalling pathways involved in the stimulation of fatty acid and glycogen synthesis by insulin in rat epididymal fat cells. 748 1

The mechanisms of signaling pathways shared by interleukin (IL)-11, IL-6, leukemia inhibitory factor (LIF), and oncostatin M (ONC) remain elusive. We report here that treatment of 3T3-L1 cells with IL-11, IL-6, LIF, and ONC induces overlapping but distinct patterns of tyrosine phosphorylation and activates indistinguishable primary response genes. We further demonstrate for the first time that IL-11, IL-6, LIF, and ONC can trigger the activation of mitogen-activated protein kinases and the 85-92-kDa ribosomal S6 protein kinase (pp90rsk). In addition, our data also show that preincubation of cells with a tyrosine kinase inhibitor herbimycin A, but not with a serine/threonine kinase inhibitor H7, blocks activation of mitogen-activated protein kinases and pp90rsk. Interestingly, H7, but not herbimycin A, inhibits pp90rsk activity in the in vitro kinase assays. These results suggest that pp90rsk is one of the potential candidates for the H7-sensitive protein kinase(s), which is critical for the activation of primary response genes by these cytokines.
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PMID:Mitogen-activated protein kinases and ribosomal S6 protein kinases are involved in signaling pathways shared by interleukin-11, interleukin-6, leukemia inhibitory factor, and oncostatin M in mouse 3T3-L1 cells. 750 17

Isolated explants from the animal hemisphere of Xenopus embryos were incubated with Xenopus basic fibroblast growth factor (XbFGF) or human activin A. XbFGF incubation resulted in the rapid activation of mitogen-activated protein kinase (MAPK) and ribosomal S6 protein kinase (pp90rsk) in a dose-dependent manner with the highest levels of activation occurring at 50 ng/ml. Maximal activation occurred within 6-10 min after the addition of growth factor, and the activity of both kinases declined to unstimulated levels after 30 min. Activin was unable to activate either MAPK or pp90rsk in the Xenopus explants to a substantial level, although it induced dorsal mesoderm better than XbFGF under the same experimental conditions. The regulatory protein Xwnt-8 did not activate MAPK, nor did it enhance the activation of MAPK by XbFGF. XbFGF was able to activate MAPK through at least the midgastrula stage, suggesting that this family of growth factors may have a role in gastrula-stage events.
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PMID:Fibroblast growth factor, but not activin, is a potent activator of mitogen-activated protein kinase in Xenopus explants. 751 Apr 4

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step in hepatic gluconeogenesis. Glucagon (via the second messenger cAMP) and glucocorticoids stimulate the transcription of the PEPCK gene, whereas insulin and phorbol esters inhibit, in a dominant fashion, these effects. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, prevents the stimulation of glycogen synthesis, glucose transport, mitogen-activated protein kinase, and p70/p85 ribosomal S6 protein kinase by insulin. We now show that wortmannin can also block the inhibition of glucocorticoid- and cAMP-stimulated PEPCK gene expression by insulin. PEPCK-chloramphenicol acetyltransferase fusion gene experiments demonstrate that wortmannin blocks an activity that is required for insulin signaling to elements within the PEPCK promoter. Phorbol esters mimic the action of insulin on the regulation of PEPCK gene expression, but wortmannin does not block the effect of these agents. Thus, phosphatidylinositol 3-kinase is required for the regulation of PEPCK gene expression by insulin, but not by phorbol esters. The immunosuppressant rapamycin, a potent inhibitor of insulin or phorbol ester stimulation of p70/p85 ribosomal S6 protein kinase, has no significant effect on the regulation of PEPCK gene expression by insulin or phorbol esters. Thus, p70/p85 ribosomal S6 protein kinase does not have a role in signaling to the PEPCK promoter by insulin or phorbol esters.
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PMID:Phosphatidylinositol 3-kinase, but not p70/p85 ribosomal S6 protein kinase, is required for the regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression by insulin. Dissociation of signaling pathways for insulin and phorbol ester regulation of PEPCK gene expression. 779 43

Two protein kinase genes (atpk1 and atpk2) were isolated from Arabidopsis thaliana genomic DNA with a probe generated by polymerase chain reaction (PCR) using oligonucleotide primers encoding conserved eukaryotic protein kinase sequences. atpk1 and atpk2 are organized in a head-to-tail tandem array on chromosome 3 and have about 80% nucleotide sequence identity. atpk1 encodes a hydrophilic polypeptide of 465 amino acids, M(r) = 52,554. The centrally located catalytic domain contains all the conserved residues characteristic of eukaryotic protein kinases, with greatest similarity to the catalytic domains of 70-kDa ribosomal S6 protein kinase, protein kinase C, and protein kinase A. The C-terminal 75 residues also show homology to protein kinase C and S6 protein kinase. In contrast, the N-terminal 130 residues have no homology to any known protein, and thus may represent a new class of protein kinase regulatory domain. Other motifs found in the Atpk1 protein include two putative autophosphorylation sites, a pseudosubstrate site, two acidic domains, a lysine-rich domain, and two putative PEST sequences, which may contribute to the regulation of protein kinase activity. RNA-blot hybridization showed that atpk1 encoded a 1.8-kb mRNA. Analysis of atpk1 promoter/beta-glucuronidase reporter gene fusions in transgenic plants showed that atpk1 was expressed in all tissues and at all developmental stages, with the strongest expression observed in metabolically active tissues, suggesting that atpk1 is involved in the control of plant growth and development. The first intron of atpk1 functions as an enhancer in atpk1 expression.
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PMID:atpk1, a novel ribosomal protein kinase gene from Arabidopsis. I. Isolation, characterization, and expression. 791 97


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