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:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bovine myelin basic protein (MBP) was found to be an excellent in vitro substrate (apparent Km = 50 microM) for MAP (mitogen-activated protein) kinase and can be used in lieu of microtubule-associated protein 2 for purification and functional studies of the enzyme. MBP phosphotransferase activity co-purified with MAP kinase during sequential DE52, phenyl-Superose, and gel filtration chromatography, and kinase activities for the two substrates were co-regulated by mitogen stimulation. MAP kinase phosphorylated MBP exclusively on threonine, and only one major phosphopeptide was generated by digestion with trypsin or endoproteinase Lys-C. Using mass spectrometry, we determined that the phosphorylation site is threonine 97, present in the conserved triproline loop of MBP, with (partial) sequence -Thr-Pro-Arg-Thr97-Pro-Pro-Pro-. Thr97 is a known in vivo phosphorylation site in MBP although enzymes capable of phosphorylating this site have not been identified previously. MAP kinase phosphorylated peptide 88-109 from rabbit MBP and a synthetic peptide 91-109 from human MBP but did not phosphorylate either the histone H1 peptide, utilized by p34cdc2, or the peptide substrate for the recently described proline-directed kinase. Thus, the sequence surrounding threonine 97 in bovine MBP may contain essential features of a recognition sequence for MAP kinase.
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PMID:Identification by mass spectrometry of threonine 97 in bovine myelin basic protein as a specific phosphorylation site for mitogen-activated protein kinase. 170 Sep 79

The epidermal growth factor (EGF) receptor is both an activator and a target of growth factor-stimulated kinases involved in cellular signaling. Threonine-669 (T669) of the EGF receptor is phosphorylated in response to a wide variety of growth-modulating agents. MAP kinase is similarly phosphorylated as well as stimulated by growth activators, including EGF. To determine whether a MAP-type kinase is responsible for T669 kinase activity in EGF-stimulated 3T3-L1 cells, we partially purified and characterized the T669 peptide kinase. The results indicate that a MAP kinase phosphorylates the T669 peptide and raise the possibility that this enzyme may participate in a feedback loop, being activated by the EGF receptor and in turn phosphorylating the receptor.
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PMID:Epidermal growth factor (EGF) receptor T669 peptide kinase from 3T3-L1 cells is an EGF-stimulated "MAP" kinase. 184 6

Vasoactive intestinal peptide (VIP) is a neuropeptide that induces neuronal differentiation through a cAMP-dependent mechanism. We have previously shown that VIP induces tyrosine phosphorylation and activation of MAP kinases in PC12h cells [J. Biochem. 115, 304-308 (1994)]. In the present study, we showed by Western blotting with anti-phosphotyrosine antibodies that in PC12h cells VIP induced tyrosine phosphorylation of proteins of 140, 120, 110, and 70 kDa in addition to MAP kinases. The immunoprecipitates with anti-phosphotyrosine antibody from VIP-treated cells contained high activity of protein kinase phosphorylating poly(glu-tyr) and enolase; the activity from VIP-stimulated cells was 1.5-2 times higher than that from unstimulated cells. In vitro kinase reaction without extrinsic substrates resulted in tyrosine phosphorylation of doublet proteins which migrated slower than pp125FAK on SDS-PAGE. An increase in kinase activity of the immunecomplex was detected when the cells were stimulated with forskolin. These results suggest that protein tyrosine phosphorylation is involved in differentiation of neuronal cells stimulated by VIP and that it is regulated by a cAMP-dependent mechanism.
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PMID:Vasoactive intestinal peptide induces tyrosine phosphorylation in PC12h cells. 782 52

Prostaglandin H2 (PGH2) and thromboxane A2 (TXA2) are potent activators of platelets and vascular smooth muscle whose responses are mediated through a common G-protein coupled receptor (TXA2/PGH2 receptor). Despite the many studies describing their ability to aggregate platelets and contract vascular smooth muscle, little is known concerning the potential mitogenic capabilities of these autocoids. Mitogen-activated protein kinases (MAP kinases) and ribosomal S6 kinases are well characterized intracellular mediators involved in proliferation of cells. The present study was designed to examine the activation of MAP kinase and S6 kinase in guinea pig coronary artery smooth muscle cells (CASMC) in response to stimulation by a TXA2/PGH2 mimetic, I-BOP ([1S-(1 alpha,2 beta(5Z),3 alpha(1E,3R*),4 alpha)]-7-[3-(3-hydroxy-4-(4'- iodophenoxy)-1-butenyl)-7-oxabicyclo-[2.2.1]heptan-2-yl]-5-h eptenoic acid). Equilibrium radioligand binding assays using [125I]BOP defined a single class of high affinity TXA2/PGH2 receptors on monolayers of guinea pig CASMC (Kd = 0.18 +/- 0.03 nM; 26,476 +/- 3,600 sites/cell; 0.08 +/- 0.01 pmol/mg of protein; n = 12). I-BOP produced a concentration-dependent increase in [3H]thymidine incorporation in these cells (EC50 = 0.3 nM) which was inhibited by a series of TXA2/PGH2 receptor antagonists as well as by verapamil and staurosporine. I-BOP also produced a time-dependent increase in the activation of kinases phosphorylating myelin basic protein (MBP; a substrate for MAP kinase) and RRLSSLRA (S6 peptide; a substrate for pp85rsk kinase), reaching a peak activation between 5 and 10 min. Stimulated MBP kinases were identified as ERK1 and ERK2. The activation of these kinases by I-BOP was inhibited by the TXA2/PGH2 receptor antagonist SQ29548 and also by staurosporine. These results indicate that I-BOP, a TXA2/PGH2 mimetic, produces growth of coronary artery vascular smooth muscle cells, which is preceded by activation of MAP kinase and S6 kinase.
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PMID:Thromboxane A2/prostaglandin H2-stimulated mitogenesis of coronary artery smooth muscle cells involves activation of mitogen-activated protein kinase and S6 kinase. 811 6

MEK1 is a dual specificity kinase that phosphorylates and activates the Erk/MAP kinases Erk-1 and Erk-2 by phosphorylating them on threonine and tyrosine. We report the cloning of a second MEK-like complementary DNA, Mek2, which predicts a protein of a molecular weight of 44,500. The MEK2 protein bears substantial sequence homology to MEK1, except at its amino terminus, and at a proline-rich region insert between the conserved kinase subdomains 9 and 10. MEK1 and MEK2 are shown to be encoded by different genes and are located on murine chromosomes 9 and 10, respectively. Northern analysis indicates that Mek2 is expressed at low levels in adult mouse brain and heart tissue, and at higher levels in other tissues examined. Low expression levels of Mek2 in brain tissue are in contrast to the high levels of Mek1 expressed in brain. Mek2 is expressed at high levels in neonatal brain, however. Recombinant MEK2 produced in bacteria phosphorylates a kinase-inactive Erk-1 on tyrosine and threonine, whereas a kinase-inactive mutant MEK2 does not. These findings suggest that MEK2 is a member of a multigene family.
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PMID:MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. 829 98

The family of MAP kinases consists of several subgroups of serine/threonine protein kinases. Together with their activating kinases, they function to regulate cellular responses to diverse extracellular signals, including osmotic stress, heat shock, proinflammatory cytokines, and mitogens. It is now clear that as in yeast, separate MAP kinase cascades exist in mammalian cells, responding selectively to different stimuli by phosphorylating cytoplasmic components and nuclear transcription factors. Down-regulation of MAP kinase pathways may occur through dephosphorylation by serine/threonine phosphatases, tyrosine phosphatases, or dual-specificity phosphatases and through feedback inhibitory mechanisms that involve the phosphorylation of upstream kinases. The functional integrity of each MAP kinase cascade is thought to be established and maintained by specific molecular interactions both between the kinases and with cytoplasmic anchors that nucleate complex formation. The recent demonstration that a series of pyridinyl-imidazole compounds can bind and inhibit certain MAP kinases suggests that other MAP kinase subgroups may also be susceptible to synthetic compounds. Drugs that selectively down-regulate MAP kinase cascades could prove to be valuable as therapeutic agents in the control of malignant disease.
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PMID:The growing family of MAP kinases: regulation and specificity. 879 86

To clarify the molecular mechanism for the transduction of light signals in plants, we have established an in vitro system that uses crude membrane and soluble fractions of stem sections of etiolated Pisum sativum L. cv. Alaska after irradiation by red light, or sequential application of red and far-red light to the stem section. In a previous report (T. Hamada et al., J. Photochem. Photobiol. B: Biol. 33 (1996) 143-151) the labelling of proteins in membrane fraction by [gamma-32P] ATP at 0 degree C for 15 s and subsequent separation of proteins by two-dimensional electrophoresis allowed unambiguous identification of a heavily phosphorylated protein spot at 18 kDa (p18). In the present study we have confirmed the former results in the membrane fraction, and obtained the result that an increase in the phosphorylation of p18 by red-light irradiation is observed in the soluble fraction. Further, we have provided evidence that the p18 in the soluble fraction is purified and identified as nucleoside diphosphate (NDP) kinase by Western blotting, immuno-precipitation, amino acid sequencing and cDNA analysis. Purified p18 shows autophosphorylation activity and strong phosphorylating activity against myelin basic protein (MBP), a substrate of MAP (mitogen activated protein) kinase. The results show that phytochrome-mediated light signals are transduced to NDP kinase, which may elicit signals by providing high concentrations of, for example, GTP from GDT and ATP, by the autophosphorylation and by the protein kinase activity similar to MAP kinase.
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PMID:Phytochrome-mediated light signals are transduced to nucleoside diphosphate kinase in Pisum sativum L. cv. Alaska. 986 1

Extracellular signals are transduced into the nucleus through a variety of signalling mechanisms to elicit changes in patterns of gene expression. This review is focused in the MAP kinase cascades and the part they play in the induction of the immediate-early (IE) genes. We discuss the MAP kinases and their downstream effectors that are known to phosphorylate substrates in the nucleus. In addition to phosphorylating specific transcription factors, MAP kinases and their downstream kinases are implicated in eliciting rapidly targeted alterations in the chromatin environment of specific genes by modulating the phosphorylation and/or acetylation of nucleosomal and chromatin proteins.
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PMID:MAP kinase-mediated signalling to nucleosomes and immediate-early gene induction. 1044 Oct 69

Troglitazone (TRO) is an oral insulin-sensitizer that has direct effects on the vasculature to inhibit cell growth and migration. In vascular smooth muscle cells (VSMCs), insulin transduces a mitogenic signal that is dependent on the ERK1/2 MAP kinases. We examined the effects of TRO on this pathway and found that it inhibits mitogenic signaling. In quiescent VSMCs, insulin (1 microM) induced a 3.2-fold increase in DNA synthesis. TRO (1-20 microM) inhibited insulin-stimulated DNA synthesis by 72.8% at the maximal concentration. TRO at I and 10 microM had no significant effect on insulin-stimulated ERK1/2 activity. At 20 microM, however, TRO modestly enhanced insulin-stimulated ERK1/2 activity by 1.5-fold. ERKs transduce a mitogenic signal by phosphorylating transcription factors such as Elk-1. which regulate critical growth-response genes. We used GAL-Elk-1 expression plasmids to detect ERK-dependent activation of Elk-1. TRO at 1-20 microM potently inhibited insulin-stimulated, ERK1/2-dependent Elk-1 transcription factor activity. Neither early steps in insulin signaling nor the phosphatidylinositol 3-kinase (PI3K) branch of this pathway were affected by TRO, because it had no effect on IRS-1 phosphorylation, PI3K/IRS-1 association, or Akt phosphorylation. Because TRO is a known ligand for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma), we tested two other ligands for this receptor, rosiglitazone (RSG) and 15-deoxy-delta12,14 prostaglandin J2 (15d-PGJ2). Both also inhibited insulin-induced DNA synthesis. In summary, these data show that TRO inhibits mitogenic signaling by insulin at a point distal of ERK1/2 activation, potentially by a PPARgamma-mediated inhibition of ERK-dependent phosphorylation and activation of nuclear transcription factors that regulate cell growth.
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PMID:Troglitazone inhibits mitogenic signaling by insulin in vascular smooth muscle cells. 1081 77

Protein kinase C (PKC) is a family of multifunctional isoenzymes, activated by diacylglycerols (DAGs), which play a central role in signal transduction and intracellular crosstalk by phosphorylating at serine/threonine residues an array of substrates, including cell-surface receptors, enzymes, contractile proteins, transcription factors and other kinases. Individual isozymes vary in their pattern of tissue and subcellular distribution, function and Ca2+/phospholipid cofactor requirements, and in diabetes there is widespread activation of the DAG-PKC pathway in metabolic, cardiovascular and renal tissues. In liver, muscle and adipose tissue, PKC isozymes have been implicated both as mediators and inhibitors of insulin action. Activation of DAG-sensitive PKC isoforms, such as PKC-theta and PKC-epsilon, down-regulates insulin receptor signalling and could be an important biochemical mechanism linking dysregulated lipid metabolism and insulin resistance in muscle. On the other hand, atypical PKC isozymes, such as PKC-zeta and PKC-lambda, have been identified as downstream targets of PI-3-kinase involved in insulin-stimulated glucose uptake, especially in adipocytes. Glucose-induced de novo synthesis of (palmitate-rich) DAG and sustained isozyme-selective PKC activation (especially but not exclusively PKC-beta) has been strongly implicated in the pathogenesis of diabetic microangiopathy and macroangiopathy through a host of undesirable effects on endothelial function, VSM contractility and growth, angiogenesis, gene transcription (in part by MAP-kinase activation) and vascular permeability. Interventions that increase DAG metabolism (e. g. vitamin E) and/or inhibit PKC isozymes (e. g. the beta-selective inhibitor LY333531) ameliorate the biochemical and functional consequences of DAG-PKC activation in experimental diabetes, for example improving retinal blood flow and albuminuria in parallel with reductions in membrane-associated PKC isozyme activities. Thus, a greater understanding of the functional diversity and pathophysiological regulation of PKC isozymes is likely to have important clinical and therapeutic benefits.
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PMID:Protein kinase C activation: isozyme-specific effects on metabolism and cardiovascular complications in diabetes. 1144 Mar 58


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