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)

We report that recombinant glia maturation factor (GMF), a 17-kDa brain protein, inhibits the activity of mitogen-activated protein (MAP) kinase in the test tube assay, in particular the ERK1/ERK2 isoforms. A preliminary phosphorylation of GMF by protein kinase A (PKA) dramatically increases its inhibitory effect by over 600-fold (Ki approximately 3 nM), making it the most potent MAP kinase inhibitor ever reported. Immunoprecipitation of GMF from cell extracts using its specific antibody coprecipitates ERK (and vice versa), suggesting the association of the two proteins in the cell. The inhibitory effect of PKA-phosphorylated GMF is specific, as it does not suppress the activity of cdc2 kinase, another proline-directed kinase. Nor does it inhibit MAP kinase kinase (MEK) and MAP kinase-activated protein (MAPKAP) kinase-2, the two enzymes immediately upstream and downstream, respectively, of ERK. Of the other three enzymes that can phosphorylate GMF, only p90 ribosomal S6 kinase (RSK) enhances the inhibitory function of GMF on ERK; protein kinase C (PKC) and casein kinase II (CKII) are without effect. The inhibition of ERK by PKA-phosphorylated GMF suggests that GMF could be one of the mediators of the suppressive effect of the PKA pathway on the MAP kinase pathway. On the other hand, that RSK-phosphorylated GMF also inhibits ERK implies a negative feedback loop in the regulation of MAP kinase activity.
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PMID:In vitro inhibition of MAP kinase (ERK1/ERK2) activity by phosphorylated glia maturation factor (GMF). 863 70

The JNK protein kinase is a member of the MAP kinase group that is activated in response to dual phosphorylation on threonine and tyrosine. Ten JNK isoforms were identified in human brain by molecular cloning. These protein kinases correspond to alternatively spliced isoforms derived from the JNK1, JNK2 and JNK3 genes. The protein kinase activity of these JNK isoforms was measured using the transcription factors ATF2, Elk-1 and members of the Jun family as substrates. Treatment of cells with interleukin-1 (IL-1) caused activation of the JNK isoforms. This activation was blocked by expression of the MAP kinase phosphatase MKP-1. Comparison of the binding activity of the JNK isoforms demonstrated that the JNK proteins differ in their interaction with ATF2, Elk-1 and Jun transcription factors. Individual members of the JNK group may therefore selectively target specific transcription factors in vivo.
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PMID:Selective interaction of JNK protein kinase isoforms with transcription factors. 865 73

The chemotactic peptide f-Met-Leu-Phe (fMLP) stimulates leukocyte functions through binding and activation of a specific G-protein-coupled formyl peptide receptor (FPR). Recent studies have shown that stimulation of neutrophils with fMLP induces the activation of two members of the mitogen-activated protein kinase (MAP kinase) family, ERK1 and ERK2, through mechanisms that are not completely understood but may involve the phosphorylation of the adapter protein SHC by the Src-related kinase Lyn. In this study, transfected fibroblasts expressing the rabbit FPR were used to investigate further the role of Lyn and SHC phosphorylation in fMLP-stimulated MAP kinase activation. Stimulation of transfected cells with fMLP resulted in the time- and dose-dependent increase in tyrosine phosphorylation and activation of ERK1 and ERK2 and the activation of MEK, the MAP kinase/ERK kinase. The activation of both ERKs and MEK was inhibited by preincubation of the cells with pertussis toxin, indicating that activation was dependent upon a Gi/Go-like protein that couples to the receptor. Our data also show that, unlike neutrophils, FPR-transfected fibroblasts do not express the Src-related kinase Lyn. In the absence of Lyn, fMLP stimulation did not result in an increased tyrosine phosphorylation of the adapter protein SHC, whereas it was still able to induce MAP kinase activation. These data suggest that Lyn and SHC are not the only upstream signals for activation of the MAP kinase/ERK pathway by fMLP and demonstrate the potential application of the FPR-transfected cells for the delineation of additional signaling mechanisms stimulated by fMLP.
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PMID:Activation of the mitogen-activated protein kinase pathway by fMet-leu-Phe in the absence of Lyn and tyrosine phosphorylation of SHC in transfected cells. 866 60

Mitogen-activated protein (MAP) kinase cascades represent one of the major signal systems used by eukaryotic cells to transduce extracellular signals into cellular responses. Four MAP kinase subgroups have been identified in humans: ERK, JNK (SAPK), ERK5 (BMK), and p38. Here we characterize a new MAP kinase, p38beta. p38beta is a 372-amino acid protein most closely related to p38. It contains a TGY dual phosphorylation site, which is required for its kinase activity. Like p38, p38beta is activated by proinflammatory cytokines and environmental stress. A comparison of events associated with the activation of p38beta and p38 revealed differences, most notably in the preferred activation of p38beta by MAP kinase kinase 6 (MKK6), whereas p38 was activated nearly equally by MKK3, MKK4, and MKK6. Moreover, in vitro and in vivo experiments showed a strong substrate preference by p38beta for activating transcription factor 2 (ATF2). Enhancement of ATF2-dependent gene expression by p38beta was approximately20-fold greater than that of p38 and other MAP kinases tested. The data reported here suggest that while closely related, p38beta and p38 may be regulated by differing mechanisms and may exert their actions on separate downstream targets.
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PMID:Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). 866 24

The transcription factor, Nuclear Factor of Activated T cells (NFAT) is a major target for p21ras and calcium signalling pathways in the IL-2 gene and is induced by p21ras signals acting in synergy with calcium/calcineurin signals. One p21ras effector pathway involves the MAP kinase ERK-2, and we have examined its role in NFAT regulation. Expression of dominant negative MAPKK-1 prevents NFAT induction. Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1, but does not substitute for activated p21ras and synergize with calcium/calcineurin signals to induce NFAT. Expression of dominant negative N17Rac also prevents TCR and p21ras activation of NFAT, but without interfering with the ERK-2 pathway. The transcriptional activity of the NFAT binding site is mediated by a complex comprising a member of the NFAT group and AP-1 family proteins. The induction of AP-1 by p21ras also requires Rac-1 function. Activated Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT. Moreover, the combination of activated MAPKK-1 and Rac-1 could not substitute for activated p21ras and synergize with calcium signals to induce NFAT. Thus, p21ras regulation of NFAT in T cells requires the activity of multiple effector pathways including those regulated by MAPKK-1/ERK-2 and Rac-1.
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PMID:Multiple p21ras effector pathways regulate nuclear factor of activated T cells. 867 Aug 97

Drosophila Jun (D-Jun) is a nuclear component of the receptor tyrosine kinase/Ras signal transduction pathway which triggers photoreceptor differentiation during eye development. Here we show that D-Jun is a substrate for the ERK-related Drosophila MAP kinase Rolled, which has previously been shown to be a part of this pathway. A D-Jun mutant that carries alanines in place of the Rolled phosphorylation sites acts as a dominant suppressor of photoreceptor cell fate if expressed in the eye imaginal disc. In contrast, a mutant in which the phosphorylation sites are replaced by phosphate-mimetic Asp residues, as well as a VP16-D-Jun fusion protein, can promote photoreceptor differentiation. These data implicate Jun phosphorylation in the choice between neuronal and non-neuronal fate during Drosophila eye development.
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PMID:Phosphorylation of Drosophila Jun by the MAP kinase rolled regulates photoreceptor differentiation. 867 Aug 99

Rapid tyrosine phosphorylation of key cellular proteins is a crucial event in signal transduction. The regulatory role of protein-tyrosine phosphatases (PTPs) in this process was explored by studying the effects of a powerful PTP inhibitor, pervanadate, on the activation of the mitogen-activated protein (MAP) kinase cascade. Treatment of HeLa cells with pervanadate resulted in a marked inhibition of PTP activity, accompanied by a drastic increase in tyrosine phosphorylation of cellular proteins. The increased tyrosine phosphorylation coincided with the activation of the MAP kinase cascade as indicated by enzymatic activity assays of MEK (MAP kinase/ERK-kinase) and MAP kinase and gel mobility shift analyses of Raf-1 and MAP kinase. The activation was sustained but reversible. Upon removal of pervanadate, both tyrosine phosphorylation and MAP kinase activation declined to basal levels. Therefore, inhibition of PTP activity is sufficient per se to initiate a complete MAP kinase activation program.
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PMID:Activation of mitogen-activated protein (MAP) kinase pathway by pervanadate, a potent inhibitor of tyrosine phosphatases. 870 41

The Ras protein is involved in tyrosine kinase signal transduction pathway steps such as EGFR signalling. Most human pancreatic carcinomas harbor a point mutation of K-ras oncogene and overexpress transforming TGF-alpha. We studied how K-ras gene mutation could influence the EGFR signal transduction mechanism and the autonomous proliferation of pancreatic carcinoma cells, using PANC-1 human pancreatic carcinoma line and W1-38 normal human fibroblast cell line as a control. PANC-1 cells responded to neither EGF nor exogenous TGF-alpha, although anti-TGF-alpha MAb suppressed their growth. Expression of TGF-alpha mRNA was detected only in PANC-1 cells, which confirmed EGFR being within an autocrine loop. Ras protein and MAP kinase were constitutively activated in PANC-1 cells so that the cells did not respond to treatment with staurosporine or herbimycin A, and exhibited slight response to EGF stimulation. PANC-1 cells harbored K-ras gene mutation in codon 12. In contrast, EGF stimulation induced an elevation of GTP-bound ratio to Ras protein and an activation of MAP kinase with accelerated growth in W1-38 cells. From these findings, we concluded that K-ras gene mutation possibly plays an important role in the autonomous proliferation of PANC-1 pancreatic carcinoma cells, and that an autocrine loop represented by TGF-alpha and EGFR may further accelerate the growth of PANC-1 cells.
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PMID:An effect of K-ras gene mutation on epidermal growth factor receptor signal transduction in PANC-1 pancreatic carcinoma cells. 876 May 97

Studies in mammalian cells have established the existence of at least three distinct mitogen-activated protein kinase (MAP kinase) signaling pathways that are activated by a variety of growth factors and/or environmental stressors. We determined whether physical exercise, a physiological stressor, and insulin, a metabolic stimulator and growth factor, activate the c-jun NH2-terminus kinase (JNK), the p38 kinase, and/or the extracellular regulatory kinases (ERK; p42MAPK and p44MAPK) signaling pathways in rat skeletal muscle. Animals were studied immediately after running on a motorized treadmill for 10-60 min (20 m/min, 10% grade) or 5-30 min after an intraperitoneal injection of insulin (20 U/rat). Exercise increased skeletal muscle JNK activity by two- to threefold throughout the time course studied, whereas insulin did not significantly increase JNK activity. The p38 activity was slightly stimulated by exercise and not by insulin. The ERK kinase pathway, as assessed by ribosomal S6 kinase-2 activity assays and phosphospecific p42MAPK/p4NAPK immunoblotting, was stimulated by both exercise and insulin. These data are the first demonstration of exercise stimulating multiple intracellular signaling pathways in skeletal muscle. Activation of these MAP kinase signaling pathways may mediate changes in skeletal muscle growth and metabolism that occur in response to exercise.
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PMID:Effects of exercise and insulin on mitogen-activated protein kinase signaling pathways in rat skeletal muscle. 877 36

Tyrosine kinases of the JAK family are required for activation of both STAT transcription factors and the ERK/MAP kinase pathway, suggesting a mechanism for the optimization of gene induction via the coordinate activation of multiple transcription factors.
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PMID:Intracellular signalling: putting JAKs on the kinase MAP. 879 90


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