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)

The largest subunit of RNA polymerase (RNAP) II contains at it C-terminus an unusual domain comprising tandem repeats of the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser. This C-terminal domain (CTD) can undergo phosphorylation at multiple sites giving rise to a form of the enzyme designated RNAP IIO. The unphosphorylated form is designated RNAP IIA. The largest subunits of RNAPs IIO and IIA are designated IIo and IIa, respectively. In quiescent NIH 3T3 fibroblasts, subunits IIo and IIa are present in comparable amounts. Upon serum stimulation, the amount of subunit IIo increases markedly and remains elevated for several hours. The increase of subunit IIo also occurs in transcription-inhibited cells and, therefore, is not a consequence of serum-activated transcription. This observation suggests that serum stimulation activates a CTD kinase and/or inhibits a CTD phosphatase. This hypothesis is supported by the finding that serum stimulates phosphorylation of a beta-galactosidase-CTD fusion protein expressed in these cells. Furthermore, an enhanced CTD kinase activity was discovered in lysates from serum-stimulated fibroblasts and was found to copurify with MAP kinases on a Mono Q column and to bind to anti-MAP kinase antibodies. The idea that MAP kinases phosphorylate the CTD in vivo is supported by the observation that subunit IIa, but not subunit IIb which lacks the CTD, is phosphorylated at multiple sites by purified MAP kinase. Consequently, the MAP kinases are a new class of CTD kinases which appear to be involved in the phosphorylation of RNAP II following serum stimulation. This phosphorylation may contribute to the transcriptional activation of serum-stimulated genes.
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PMID:Enhanced phosphorylation of the C-terminal domain of RNA polymerase II upon serum stimulation of quiescent cells: possible involvement of MAP kinases. 795 47

In response to various external stimuli, MAP kinases are activated by phosphorylation on tyrosine and threonine by MAP kinase kinase (MAPKK), a dual specificity kinase. This kinase is in turn activated via Raf-1 and MAPKK kinase (MAPKKK). To determine regulatory phosphorylation sites of MAPKK, we isolated a Chinese hamster cDNA, that we epitope-tagged and expressed in fibroblasts. This hamster MAPKK (MEK1 isoform) can reactivate recombinant p44mapk when immunoprecipitated from growth factor-stimulated cells or when incubated with an active form of MAPKKK. Mutations at either of two residues that are conserved among kinases, D208N or S222A, abolished MAPKK activity. However, only S222A/MAPKK showed a reduction in phosphorylation in response to active MAPKKK and exerted a dominant negative effect on the serum-stimulated endogenous MAPKK. Finally, replacing Ser222 with Asp, a negatively charged residue, restored MAPKK activity independently of the upstream kinase. These results strongly suggest that Ser222 represents one key MAPKKK-dependent phosphorylation site switching on and off the activity of MAPKK, an event crucial for growth control.
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PMID:Constitutive mutant and putative regulatory serine phosphorylation site of mammalian MAP kinase kinase (MEK1). 803 96

Intracellular signaling pathways regulating vascular smooth muscle (VSM) cell growth and hypertrophy can be initiated by activation of receptor tyrosine kinases and/or protein kinase C (PKC). Mitogen-activated protein kinases (MAP kinases) are cytosolic serine/threonine kinases, proposed to act as a point of convergence for diverse growth factors utilizing these signaling pathways. The goals of this study were (1) to determine whether MAP kinase is expressed in cultured rat aortic VSM, (2) to assess the activation of MAP kinase by known proliferative and hypertrophic stimuli, and (3) to determine if stimulation of a PKC-dependent signaling pathway in these cells results in MAP kinase activation. MAP kinase activity was measured in cytosolic extracts of aortic VSM by quantifying myelin basic protein phosphorylation. Three peaks of activity were resolved chromatographically and identified as MAP kinase isoforms (MW 42, 44, and 46 kDa) by immunoblotting with antipeptide antibodies specific for MAP kinase. MAP kinase activity in quiescent growth-arrested cells (157 +/- 19 pmole 32P/min/mg) was markedly stimulated within 15 min by known mitogens (10% serum, 731 +/- 40 pmole 32P/min/mg; 40 ng/ml PDGF, 670 +/- 105 pmole 32P/min/mg; P < 0.01) and partially sustained for at least 90 min (serum, 606 +/- 34 pmole 32P/min/mg; PDGF, 323 +/- 59 pmole 32P/min/mg P < 0.05). Angiotensin II (AII, 0.1 microM) and a pharmacological PKC activator, phorbol 12,13-dibutyrate (PDB, 0.1 microM), are reported to be nonmitogenic hypertrophic stimuli in these cells. These stimuli transiently increased MAP kinase activity with a peak at 5 min (AII, 328 +/- 15 pmole 32P/min/mg; PDB, 592 +/- 41 pmole 32P/min/mg; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of MAP kinase activity by growth stimuli in vascular smooth muscle. 804 Nov 41

The Ras oncoprotein, a GTP-activated molecular switch, interacts directly with the Raf oncoprotein to recruit the MAP kinases and their subordinates. In this way, a mitogenic signal initiated by tyrosine kinases is converted by Ras into a wave of regulatory phosphorylation on serine and threonine residues that, depending on its intensity and duration, and the variety of substrates available, results in cell differentiation or cell division.
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PMID:Raf meets Ras: completing the framework of a signal transduction pathway. 804 67

A variety of extracellular signals lead to the phosphorylation and activation of mitogen-activated protein kinases (MAP kinases). An activator of MAP kinases, Mek1, phosphorylates MAP kinases at threonine and tyrosine residues and is itself phosphorylated at serine-218 and -222 by the protooncogene product Raf-1. By introducing negatively charged residues that may mimic the effect of phosphorylation at positions 218 and 222, we have activated the capacity of Mek1 to phosphorylate MAP kinase by > 100-fold. The most effective activation by a single substitution resulted from the introduction of aspartate at position 218, whereas the introduction of either aspartate or glutamate at position 222 was ineffective. Expression of the activated Mek1 phosphorylation-site mutants in COS-7 cells led to the activation of MAP kinase in the cells and resulted in an increase in the mass of the transfected COS-7 cell population, suggesting an important role of Mek1 in the transduction of mitogenic signals.
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PMID:Constitutive activation of Mek1 by mutation of serine phosphorylation sites. 809 Jul 53

MAP (mitogen-activated protein) kinases are serine/threonine protein kinases and mediate intracellular phosphorylation events linking various extracellular signals to different cellular targets. MAP kinase, MAP kinase kinase and MAP kinase kinase kinase are functional protein kinase units that are conserved in several signal transduction pathways in animals and yeasts. Isolation of all three components was also shown in plants and suggests conservation of a protein kinase module in all eukaryotic cells. In plants, MAP kinase modules appear to be involved in ethylene signaling and auxin-induced cell proliferation. Therefore, coupling of different extracellular signals to different physiological responses is mediated by MAP kinase cascades and appears to have evolved from a single prototypical protein kinase module which has been adapted to the specific requirements of different organisms.
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PMID:MAP kinases: universal multi-purpose signaling tools. 812 84

MAP kinases (MAPK) are a family of serine/threonine (Ser/Thr) kinases that link cell surface signals to changes in enzyme activity and gene expression. They are the products of the newly described gene family referred to as extracellular signal regulated kinases (ERKs). Moreover, MAPKs phosphorylate tau in vitro at Ser/Thr Proline sites, generating a multiply phosphorylated tau protein that is similar to the hyperphosphorylated tau found in Alzheimer neurofibrillary tangles (NFTs). We studied MAPK immunoreactivity and in situ hybridization patterns of the two major genes that comprise MAPK activity, ERK1 and ERK2, in the human hippocampal formation. Our goal was to determine whether the pattern of ERK expression is consistent with the hypothesis that MAPKs contribute to NFT formation. ERK1 mRNA is present in small amounts and confined primarily to dentate gyrus granule cells. ERK2 mRNA, by contrast, gives a much stronger hybridization signal and is present in dentate gyrus granule cells and pyramidal cells throughout all hippocampal subfields and adjacent temporal neocortex. Quantitative measures of ERK2 mRNA reveal that NFT-bearing neurons contain approximately 15% less ERK2 mRNA than nearest neighbors that do not contain NFT. NFT-bearing neurons contain approximately 25% less polyA mRNA, suggesting a relative preservation of ERK2 mRNA even in metabolically compromised cells. MAPK immunoreactivity (which represents both ERK1 and ERK2) is seen in neuronal soma, dendrites, axons, and in reactive astrocytes. In Alzheimer's disease, neurons that contain NFTs are also MAPK immunoreactive, but neurons that contain the highest amounts of MAPK immunoreactivity are not necessarily vulnerable for NFT. MAPK immunoreactivity is present in the same neurons as NFT and in the same subcellular compartments as tau, supporting a role for MAPKs in tau phosphorylation in Alzheimer's disease. However, the presence of ERK immunoreactivity is not sufficient to predispose neurons to NFT formation.
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PMID:Extracellular signal regulated kinases. Localization of protein and mRNA in the human hippocampal formation in Alzheimer's disease. 812 42

Two cDNA clones, cATMPK1 and cATMPK2, encoding MAP kinases (mitogen-activated protein kinases) have been cloned from Arabidopsis thaliana and their nucleotide sequences have been determined. Putative proteins encoded by ATMPK1 and ATMPK2 genes, designated ATMPK1 and ATMPK2, contain 370 and 376 amino acid residues, respectively, and are 88.7% identical at the amino acid sequence level. ATMPK1 and ATMPK2 exhibit significant similarity to rat ERK2 (49%) and Xenopus MAP kinase (50%). The amino acid residues corresponding to the sites of phosphorylation (Thr-Glu-Tyr) that are involved in the activation of MAP kinases are conserved in ATMPK1 and ATMPK2. Northern blot analysis indicates that the ATMPK1 and ATMPK2 mRNAs are significantly present in all the organs except seeds. Genomic Southern blot analysis suggests that there are a few additional genes that are related to ATMPK1 and ATMPK2 in the Arabidopsis genome. Purified Xenopus MAP kinase kinase (MAPK kinase) phosphorylates ATMPK1 and ATMPK2 proteins that have been expressed in Escherichia coli, activating these enzymes. A rapid and transient activation of 46-kDa protein kinase activity that phosphorylated myelin basic protein (MBP) was detected when auxin-starved tobacco BY-2 cells were treated with synthetic auxin, 2,4-dichlorophenoxyacetic acid (2,4-D). Protein kinase activities which phosphorylated the recombinant ATMPK2 protein also increased rapidly after auxin treatment in the auxin-starved BY-2 cells. These results suggest that auxin may function as an activator of plant MAP kinase homologues, as do various mitogens in animal systems.
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PMID:Characterization of two cDNAs that encode MAP kinase homologues in Arabidopsis thaliana and analysis of the possible role of auxin in activating such kinase activities in cultured cells. 813 Jul 95

Ligation of Ag receptors in T and B lymphocytes initiates signal transduction cascades which alter the expression of genes that regulate cellular proliferation and differentiation. The transmission of signals from the membrane to the nucleus is mediated principally through the action of protein tyrosine and serine/threonine kinases. We have identified and characterized a novel serine/threonine kinase that phosphorylated the proto-oncogene product, c-Fos, and is termed Fos kinase. Fos kinase was rapidly activated after ligation of the CD3 and CD2 receptors in Jurkat and normal human T lymphocytes and in response to IL-6 and anti-IgM in the human B cell lines AF10 and Ramos, respectively. The phorbol ester, PMA, was also a potent inducer of Fos kinase activity in all of the above populations, suggesting that PKC plays a role in the regulation of this enzyme. Fos kinase phosphorylates c-Fos at a site near the C-terminus, as well as a peptide derived from this region (residues 359-370, RKGSSSNEPSSD), and Fos peptide competitively inhibited c-Fos phosphorylation. Fos kinase was shown to be distinct from other identified serine/threonine kinases, including protein kinase A, protein kinase C, casein kinase II, MAP kinases, p70S6K and p90RSK. Fos kinase was purified by anion exchange chromatography and exhibited an apparent M(r) = 65,000 and isoelectric point = 6.1. Fos kinase may play a role in transcriptional regulation through its capacity to phosphorylate c-Fos at a site required for expression of the transcriptional transrepressive activity of this molecule. Moreover, its rapid activation suggests it may have a wider role within signal transduction cascades in lymphocytes.
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PMID:Activation of a novel serine/threonine kinase that phosphorylates c-Fos upon stimulation of T and B lymphocytes via antigen and cytokine receptors. 815 58

Signal transduction pathways that respond to external signals through the MAP kinase family of protein kinases are involved in diverse responses in eukaryotic cells. MAP kinases are one element in a series of kinases that serve to connect the plasma membrane with cytoplasmic and nuclear events. MAP kinases have the unusual feature that their activation requires threonine and tyrosine phosphorylation carried out by a dual specificity protein kinase. Recent advances have shown that in two MAP kinase pathways (the mating response pathway in the fission yeast Schizosaccharomyces pombe, and receptor tyrosine kinase signalling), the small GTP binding protein ras p21 links membrane events to kinase pathway activation.
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PMID:MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. 819 45


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