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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Growth factor-receptor interactions at the cell surface eventually leading to the transcriptional activation of immediate early genes is mediated by the mitogen-activated protein kinase (MAP kinase/MAPK) cascade. Here we show that overexpression of extracellular signal-regulated kinase 1 (ERK1) cDNA, encoding p44mapk, results in the activation of Elk-1, the serum response factor accessory protein. We also show that overexpression of ERK2, encoding p42mapk, activates Myc, but not Elk-1. Therefore, the MAP kinase cascade diverges with at least one specific target for each MAP kinase isoform and provides a novel mechanism for differential regulation of this signaling pathway.
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PMID:Functional divergence of the MAP kinase pathway. ERK1 and ERK2 activate specific transcription factors. 801 39

Chemoattractants bind to seven transmembrane-spanning, G-protein-linked receptors on polymorphonuclear leukocytes (neutrophils) and induce a variety of functional responses, including activation of microtubule-associated protein (MAP) kinase. Although the pathways by which MAP kinases are activated in neutrophils are unknown, we hypothesized that activation of the Ras/Raf pathway leading to activation of MAP/ERK kinase (MEK) would be induced by the chemoattractant f-met-leu-phe. Human neutrophils exposed to 10 nM FMLP for 30 s exhibited an MAP kinase kinase activity coeluting with MEK-1. Immunoprecipitation of Raf-1 kinase after stimulation with FMLP revealed an activity that phosphorylated MEK, was detectable at 30 s, and peaked at 2-3 min. Immunoprecipitation of Ras from both intact neutrophils labeled with [32P]orthophosphate and electropermeabilized neutrophils incubated with [32P]GTP was used to determine that FMLP treatment was associated with activation of Ras. Activation of both Ras and Raf was inhibited by treatment of neutrophils with pertussis toxin, indicating predominant linkage to the Gi2 protein. Although phorbol esters activated Raf, activation induced by FMLP appeared independent of protein kinase C, further suggesting that Gi2 was linked to Ras and Raf independent of phospholipase C and protein kinase C. Dibutyryl cAMP, which inhibits many neutrophil functional responses, blocked the activation of Raf by FMLP, suggesting that interruption of the Raf/MAP kinase pathway influences neutrophil responses to chemoattractants. These data suggest that Gi2-mediated receptor regulation of the Ras/Raf/MAP kinase pathway is a primary response to chemoattractants.
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PMID:FMLP activates Ras and Raf in human neutrophils. Potential role in activation of MAP kinase. 804 Feb 99

EGF is involved in the regulation of cell proliferation in normal as well as in neoplastic tissues. The A431 cells that over-express EGFR, display in vitro ambivalent growth properties in response to EGF, since stimulation induced by low concentrations (10(-12) M-10(-10) M) is reversed with increasing concentrations (10(-9) M-10(-8) M). To assess differential mechanisms of signal transduction that determine growth stimulatory and inhibitory activity, we have studied the MAP kinase activation induced by mitotic and antimitotic concentrations of EGF. We demonstrate that the presence of a growth stimulatory concentration of EGF (10(-12) M) leads to a moderate but persistent activation of p42 MAP kinase during all the time of the EGF treatment. Conversely, an early peak of kinase activation that rapidly falls down below the basal level, is observed when a growth inhibitory concentration of EGF (10(-8) M) is used. Moreover, the addition of Na-orthovanadate in 10(-8) M EGF-treated cells leads to the rescue of the MAP kinase activity, suggesting that the loss of kinase activity induced by growth inhibitory EGF concentrations involves the dephosphorylation of the MAP kinase. In conclusion, our data demonstrate that the dual effect (stimulator/inhibitor) of EGF on the proliferation of A431 cells is associated to differential mechanisms of p42 MAP kinase regulation.
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PMID:Relationship between the MAP kinase activity and the dual effect of EGF on A431 cell proliferation. 809 84

Mitogen-activated protein (MAP) kinases have been proposed to play a critical role in receptor tyrosine kinase (RTK)-mediated signal transduction pathways. Although genetic and biochemical studies of RTK pathways in Caenorhabditis elegans, Drosophila melanogaster and mammals have revealed remarkable similarities, a genetic requirement for MAP kinases in RTK signaling has not been established. During retinal development in Drosophila, the sevenless (Sev) RTK is required for development of the R7 photoreceptor cell. Components of the signal transduction pathway activated by Sev in the R7 precursor include proteins encoded by the gap1, drk, Sos, ras1 and raf loci. In this report we present evidence that a Drosophila MAP kinase, ERK-A, is encoded by the rolled locus and is required downstream of raf in the Sev signal transduction pathway.
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PMID:The Drosophila rolled locus encodes a MAP kinase required in the sevenless signal transduction pathway. 815 2

The mitogen-activated protein (MAP) kinases are serine-threonine protein kinases that are activated by tyrosine and threonine phosphorylation by the dual specificity protein kinase MEK (MAP kinase/ERK kinase). The present report describes the purification to near homogeneity and characterization of a protein tyrosine phosphatase from Xenopus laevis eggs that dephosphorylates MAP kinase phosphorylated by MEK. Bacterially expressed Xenopus MAP kinase phosphorylated by purified Xenopus MEK was used as substrate throughout the purification. The purification procedure included anion-exchange, cation-exchange, gel filtration, heparin-Sepharose, and chromatography on a column of thiophosphorylated MAP kinase-Sepharose, resulting in a > 3000-fold purification. Upon analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a protein of 47 kDa correlated with activity. The phosphatase showed absolute specificity toward phosphotyrosine and no activity toward phosphothreonyl-phosphoseryl residues of MAP kinase. The pH optimum of the enzyme was 7.0 with a Km of 9.0 microM for phosphorylated MAP kinase. The phosphatase was inhibited by ammonium molybdate (IC50, 2 microM), vanadate (IC50, 250 microM), millimolar concentrations of MnCl2, ZnCl2 and p-nitrophenylphosphate but not by okadaic acid or microcystin. This tyrosine phosphatase may be involved in deactivating MAP kinase in vivo.
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PMID:Purification and characterization of a mitogen-activated protein kinase tyrosine phosphatase from Xenopus eggs. 822 71

The Elk-1 and SRF transcription factors form a ternary complex at the c-fos serum response element (SRE). Growth factor stimulation rapidly induces a reversible change in the electrophoretic mobility of the ternary complex, accompanied by increased phosphorylation of the Elk-1 C-terminal region and by the activation of a 42 kd cellular Elk-1 kinase. Phosphorylation of Elk-1 in vitro by partially purified p42/p44 MAP kinase induces a similar reduction in ternary complex mobility but has little effect on the efficiency of its formation. In vitro, MAP kinase phosphorylates the Elk-1 C-terminal region at multiple sites, which are also phosphorylated following growth factor stimulation in vivo. The Elk-1 C-terminal region functions as a regulated transcriptional activation domain whose activity in vivo is dependent on the integrity of the MAP kinase sites. These findings directly link transcriptional activation by the SRE to the growth factor-regulated phosphorylation of an SRE-binding protein.
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PMID:The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. 838 92

The induction of proliferation and differentiation in cultured mammalian cells is mediated by a cascade of protein phosphorylations. A key enzyme in this signaling pathway is mitogen-activated protein (MAP) kinase (or ERK, extracellular signal-regulated kinase). We report the recovery of a full-length cDNA clone encoding a MAP kinase from alfalfa. We have named the 44-kD protein encoded by this clone MsERK1. Recombinant MsERK1 (rMsERK1), when overexpressed in Escherichia coli, is recognized by antibodies raised against MAP kinases from rat, Xenopus, and sea star and by anti-phosphotyrosine antibodies. Site-directed mutagenesis of MsERK1 demonstrated that Tyr-215 is either directly or indirectly responsible for recognition of the protein by anti-phosphotyrosine antibodies. Semipurified rMsERK1 phosphorylated itself and a model substrate, myelin basic protein, in vitro, but the Tyr-215 mutant did neither. Genomic DNA gel blot analysis suggested that the gene that encodes MsERK1 is either a member of a small multigene family or a member of a polymorphic allelic series in alfalfa. Because MAP kinase activation has been associated with mitotic stimulation in animal systems, such an enzyme may play a role in the mitogenic induction of symbiotic root nodules on alfalfa by Rhizobium signal molecules.
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PMID:MsERK1: a mitogen-activated protein kinase from a flowering plant. 843 46

Serum response factor (SRF) forms a ternary complex at the c-fos serum response element (SRE) with an accessory factor, Elk-1. We constructed altered-binding specificity derivatives of SRF and Elk-1 that form a ternary complex at a mutated, inactive SRE; like Elk-1, the Elk-1 variant only binds its target as part of a ternary complex with SRF. Simultaneous expression of these SRF and Elk-1 derivatives restores serum-regulated activity to the mutated SRE in transfected cells. Efficient transcriptional activation is dependent on the regulated phosphorylation of Elk-1 C-terminal MAP kinase sites and requires the C-terminal sequences of SRF as well as SRF sequences that mediate ternary complex formation. These experiments provide direct evidence that SRF and Elk-1 functionally cooperate in the ternary complex at the SRE to regulate transcription.
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PMID:Functional analysis of a growth factor-responsive transcription factor complex. 847 50

T lymphocytes require two signals for activation. Recognition of antigen/MHC complexes by the T cell receptor delivers the first signal, while a second signal, delivered by the cell surface receptors CD80 and/or CD86 binding to the T cell surface molecule CD28, has been shown to be effective for the initiation of effective T cell responses. While some of the cytoplasmic effector molecules involved in T cell receptor signaling is known, little is known regarding those involved in the co-stimulation of T cells by CD28. Using the T cell leukemic cell line Jurkat as a model for T cell activation, we demonstrate that cross-linking CD28 using monoclonal antibodies causes tyrosine phosphorylation and activation of MAP kinase/ERK. This activation was rapid, peaking at approximately 5 minutes post CD28 cross-linking, and transient. Activation of MAP kinase/ERK occurred 3 fold less efficiently in a Jurkat line lacking functional p56lck (JCAM.1), and was almost undetectable in a line lacking CD45 (J45.01). These results suggest that CD28 cross-linking can activate intracellular signaling pathways via several different tyrosine kinases. Thus CD28 signaling can activate src family kinases lck and fyn, as well as the Tec family kinase emt/itk. Activation of any one or a combination of these tyrosine kinases may be sufficient for the activation of MAPK following CD28 cross-linking. Activation of MAPK has been shown to cause activation of AP-1 and other transcription factors via serine and/or threonine phosphorylation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of extracellular signal-regulated protein kinase (ERK/MAP kinase) following CD28 cross-linking: activation in cells lacking p56lck. 852 74

A paradigm has been established whereby mutant tyrosine kinase receptors such as the v-erbB and v-fms gene products function as oncoproteins in the absence of ligand. A spontaneously occurring deletional mutant of the human epidermal growth factor receptor (EGFR-vIII) has been isolated from astrocytic neoplasms and transforms NIH3T3 cells in the absence of ligand. The EGFRvIII is constitutively complexed with the majority of cellular GRB2, suggesting a link to the Ras-Mitogen-activated protein (MAP) kinase pathway (D. Moscatello, R. B. Montgomery, P. Sundareshan, H. McDanel, M. Y. Wong, and A. J. Wong, submitted for publication). In this report, we document that expression of EGFRvIII in fibroblasts is associated with downstream activation of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (MEK) and modest activation of p42 and p44 MAP kinases. The presence of EGFRvIII suppresses activation of p42 and p44 MAP kinases by phorbol 12-myristate 13-acetate (PMA) and serum; however, MEK activation by PMA is not suppressed by EGFRvIII. Basal and PMA-stimulated MAP kinase activity in EGFRvIII-transfected cells is augmented by the tyrosine phosphatase inhibitor sodium vanadate. EGFR-vIII is capable of transducing downstream signals through MAP kinase as evidenced by activation of cytoplasmic phospholipase A2 at levels similar to that induced by intact EGFR. Our results suggest that EGFR-vIII constitutively activates downstream signal transduction through MAP kinase, and this chronic stimulation of the MAP kinase pathway may represent one means by which mutant EGFR transduces an oncogenic signal.
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PMID:Differential modulation of mitogen-activated protein (MAP) kinase/extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. 853 Apr 89


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