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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant human TNF-alpha induces increased tyrosine phosphorylation of several proteins in human neutrophils (PMN) adhered to serum-coated plastic. When PMN are kept in suspension, TNF does not induce significant tyrosine phosphorylation. In adherent PMN, a 42-kDa protein (p42) displayed the most striking increase in tyrosine phosphorylation after TNF stimulation. Cell lysates of TNF-stimulated PMN were separated by two-dimensional gel electrophoresis and were immunoblotted with either anti-phosphotyrosine (alpha-PY) mAb or anti-mitogen-activated protein kinase (alpha-MAPK) mAb. Both Abs detected p42, and the spots were superimposable. Cell lysates were immunoprecipitated with agarose-conjugated alpha-PY mAb, electrophoresed, and then immunoblotted with alpha-MAPK Ab; alternatively, cell lysates were immunoprecipitated with agarose-conjugated alpha-MAPK Ab, electrophoresed, and then immunoblotted with alpha-PY mAb. In both cases, p42 was detected. These results demonstrate that p42 is a member of the MAPK family. TNF induces a time-and dose-dependent increase in tyrosine phosphorylation of p42 and MAPK activity. The degree of p42 tyrosine phosphorylation parallels the level of MAPK activity. MAPK activity was determined by measuring 32P phosphorylation of a synthetic peptide containing the recognition site on myelin basic protein for MAPK. PMN pretreatment with genistein, a tyrosine kinase inhibitor, inhibited the TNF-induced increase in tyrosine phosphorylation and MAPK activity. These results indicate that TNF signaling involves activation of MAPK.
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PMID:TNF-alpha induces tyrosine phosphorylation of mitogen-activated protein kinase in adherent human neutrophils. 772 27

Adherence of human neutrophils to plastic, fibronectin, or collagen-coated surfaces modifies their response to several agonists including granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF-alpha), and fMet-Leu-Phe, permitting them to trigger superoxide anion (O2-) release, which they are unable to do as cells in suspension. Adherence of neutrophils causes a slight decrease in the basal level of tyrosine phosphorylation compared with that of suspended cells. The addition of GM-CSF, however, brings all proteins to a level of phosphorylation at least equal to that seen in suspended cells. In the case of a 130-kDa (p130) and a 42-kDa (p42) protein, the increase in tyrosyl phosphorylation in response to GM-CSF challenge is clearly larger in adherent than in suspended cells (6- and 4-fold increases for p130 and p42, respectively, in adherent cells vs. 1.7- and 2.1-fold in suspended cells). This is even more patient in the case of collagen-coated plates (9.4-fold increase for p42). Therefore, once neutrophils attach to surfaces, they become primed and respond to GM-CSF with greater potency than when they are in suspension. By Western blot analysis with anti-MAP kinase antibodies, we demonstrate that p42 is one member of the mitogen-activating protein kinase, namely the p42MAPK. The tyrosyl phosphorylation of p42MAPK is elevated in GM-CSF-treated adherent neutrophils in a time-dependent fashion as measured by the formation of a doublet composed of the phospho (or activated) form and the dephospho (or inactive) form of MAP kinase. MAP kinase activation and tyrosine phosphorylation are inhibited by tyrosine kinase inhibitors genistein and tyrphostin-23. Our results indicate that adherence acts to prime neutrophils for enhanced functionality and that tyrosine phosphorylation is involved in this process.
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PMID:Priming of tyrosine phosphorylation in GM-CSF-stimulated adherent neutrophils. 772 26

An evolutionarily conserved signal transduction pathway that utilizes a receptor tyrosine kinase and a Ras protein mediates the induction of vulval cell fates in the nematode Caenorhabditis elegans. We sought new genes that function in this pathway by screening for suppressors of the Multivulva phenotype caused by a mutation that activates the let-60 ras gene. Seven such suppressor mutations defined a new gene involved in vulval induction. We named this gene mek-2, because its predicted protein product is most similar to MEK, a protein-serine/threonine and tyrosine kinase. mek-2 mutations can be arranged in an allelic series. A probable null mutation eliminated vulval induction, and the strongest mutations alter codons conserved in most or all protein kinases. Our genetic analysis showed that mek-2 functions downstream of let-60 ras and is required for ras-mediated signal transduction in vivo. The MEK-2 protein may interact with the products of the lin-45 raf and mpk-1 MAP kinase genes, which also mediate vulval induction.
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PMID:The Caenorhabditis elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK. 772 91

In view of the potent mitogenic effect exerted by insulin in human colonic cells, we used Caco-2 cells transfected with an activated (Val12) human Ha-ras gene or the polyoma middle T (PyMT) oncogene, a constitutive activator of pp60c-src tyrosine kinase activity, to investigate the effect of oncogenic p21ras and PyMT/pp60c-src on insulin mitogenic signaling. As compared to vector control Caco-2 cells, both oncogene-transfected cells exhibited: 1) a lost of response to insulin's stimulatory effect on mitogen-activated protein (MAP) kinase activity and cell proliferation, both of which were constitutively increased; 2) a decrease in insulin receptor (IR) affinity and insulin-stimulated exogenous tyrosine kinase activity, which resulted, at least in part, from increased protein kinase C (PKC) activity (4), since both IR alterations were partially corrected by PKC down-regulation; and 3) a decrease in both insulin receptor mRNA level and insulin receptor number, which was independent of PKC since it persisted after PKC down-regulation. In conclusion, oncogenic p21ras and PyMT/pp60c-src abolished insulin mitogenic signaling in Caco-2 cells through mechanisms involving (i) constitutive activation of MAP kinase, and (ii) marked decreases in both insulin receptor function and expression which were mediated by PKC-dependent and PKC-independent pathways respectively. This is the first evidence that, when oncogenically activated, p21ras and pp60c-src not only exert a negative control on insulin receptor function but also repress insulin receptor gene expression in human colonic cells.
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PMID:[Oncogenic activation of p21(ras) and pp60(c-src) in human colonic Caco-2 cells decreases insulin receptor function and expression through protein kinase C-dependent and independent pathways]. 773 71

Rap1 proteins belong to the Ras superfamily of small molecular weight GTP-binding proteins. Although Rap1 and Ras share approximately 50% overall amino acid sequence identity, the effector domains of the two proteins are identical, suggesting either similar or antagonistic signaling roles. Several pathways leading to Ras activation have been defined, including those initiated by agonist binding to tyrosine kinase or Gi-coupled receptors. Nothing is known about such events for Rap1 proteins. The cAMP-mediated inhibition of Ras-dependent MAP kinase activation is well documented and resembles that caused by expression of GTPase-deficient Rap1. We have developed a system whereby signals leading to Rap1b activation, i.e. an increase in Rap1b-bound GTP/GDP ratio, can be measured. We report here that treatment of cells with agents that elevate intracellular cAMP levels result in Rap1b activation. These results demonstrate for the first time agonist-dependent activation of Rap1 proteins.
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PMID:Cyclic AMP-dependent activation of Rap1b. 773 67

We report the identification of 16 of the 30 cellular proteins which are rapidly phosphorylated in tumour-necrosis-factor-(TNF)-treated or interleukin-1-(IL-1)-treated primary human fibroblasts. Phosphorylation assays of proteins found in the cytosolic extract of human fibroblasts by in vitro assays indicate that at least 12 of these proteins are likely to be substrates for mitogen-activated protein kinase(s) (MAP kinase), mitogen-activated protein-kinase-activated protein kinase 2 (MAPKAP kinase 2), a pp60c-src-like tyrosine kinase as well as for a putative dual nucleotide protein kinase (DNK) in TNF-treated or IL-1-treated cells. Comparison of the phosphorylation of cytosolic proteins in vitro by exogenously added protein kinases with that observed in cells treated with TNF or IL-1 enabled the identification of cellular substrates of TNF-activated and IL-1-activated cellular protein kinases. Comparison of protein kinase activities of cytosolic extracts derived from TNF-treated or IL-1-treated and control fibroblasts also show the activation of MAP kinase, MAPKAP kinase 2, a putative DNK and a pp60src-like tyrosine kinase 3-19 fold. The data suggest TNF or IL-1 signal transduction may involve the phosphorylation of protein phosphatase type 2A by a pp60src-like tyrosine kinase, followed by the activation of MAP kinase, MAPKAP kinase 2 and the putative DNK. However, the activation of MAP kinase and MAPKAP kinase 2 may be independent of the earlier activation of pp60src-like tyrosine kinase and the inactivation of protein phosphatase type 2A.
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PMID:Activation of protein kinases and the inactivation of protein phosphatase 2A in tumour necrosis factor and interleukin-1 signal-transduction pathways. 774 73

Transgenic mice which overexpress kinase-deficient human insulin receptors in muscle were used to study the relationship between insulin receptor tyrosine kinase and the in vivo activation of several downstream signaling pathways. Intravenous insulin stimulated insulin receptor tyrosine kinase activity by 7-fold in control muscle versus < or = 1.5-fold in muscle from transgenic mice. Similarly, insulin failed to stimulate tyrosyl phosphorylation of receptor beta-subunits or insulin receptor substrate 1 (IRS-1) in transgenic muscle. Insulin substantially stimulated IRS-1-associated phosphatidylinositol (PI) 3-kinase in control versus absent stimulation in transgenic muscles. In contrast, insulin-like growth factor 1 modestly stimulated PI 3-kinase in both control and transgenic muscle. The effects of insulin to stimulate p42 mitogen-activated protein kinase and c-fos mRNA expression were also markedly impaired in transgenic muscle. Specific immunoprecipitation of human receptors followed by measurement of residual insulin receptors suggested the presence of hybrid mouse-human heterodimers. In contrast, negligible hybrid formation involving insulin-like growth factor 1 receptors was evident. We conclude that (i) transgenic expression of kinase-defective insulin receptors exerts dominant-negative effects at the level of receptor auto-phosphorylation and kinase activation; (ii) insulin receptor tyrosine kinase activity is required for in vivo insulin-stimulated IRS-1 phosphorylation, IRS-1-associated PI 3-kinase activation, phosphorylation of mitogen-activated protein kinase, and c-fos gene induction in skeletal muscle; (iii) hybrid receptor formation is likely to contribute to the in vivo dominant-negative effects of kinase-defective receptor expression.
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PMID:Impaired insulin signaling in skeletal muscles from transgenic mice expressing kinase-deficient insulin receptors. 775 7

As a first step in addressing the question of function for basic fibroblast growth factor (bFGF) in the adult myocardium, expression of bFGF receptors by adult rat myocytes was investigated. Cross-linking of 125I-labeled bFGF to purified sarcolemmal vesicles from adult hearts indicated specific binding to 90- to 104-kDa proteins, whereas equilibrium binding studies revealed the presence of "low"-affinity (1 nM) and "high"-affinity (115 pM) sites. Adult myocytes were found to express short and long variants of bFGF receptor 1 (FGFR-1, tyrosine kinase) mRNA. Adult heart overall levels of FGFR-1 mRNA were decreased by about one-third of corresponding fetal values. Several lines of evidence indicated that bFGF receptors in adult cardiomyocytes in situ and/or in isolation are functional. Isolated adult myocytes were found to be capable of heparin-resistant internalization of 125I-labeled bFGF, to lose their viability after interaction with bFGF-saporin (a mitotoxin known to kill cells after entry via the bFGF receptor), and to respond to bFGF by activation of mitogen-activated protein kinase. In addition, introduction of exogenous bFGF into the myocardium by Langendorff perfusion resulted in stimulation of tyrosine phosphorylation in association with cardiomyocyte intercalated disks, as assessed by immunofluorescence. It is concluded that adult cardiomyocytes express functionally coupled high-affinity bFGF receptors and that they are capable of a biologic response to bFGF in vivo.
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PMID:Adult cardiomyocytes express functional high-affinity receptors for basic fibroblast growth factor. 777 42

Brefeldin A (BFA) is a potent inhibitor of intracellular vesicle traffic. We have investigated the effects of BFA on the traffic of the insulin receptor in HIRcB cells, a cell line derived from Rat-1 fibroblasts that over-expresses a normal human insulin receptor. We report here that insulin-dependent receptor redistribution is inhibited by BFA and that this drug has no effects on the insulin-dependent redistribution of the receptor. Auto-phosphorylation of the insulin receptor and the stimulation of mitogen-activated protein kinase (MAPK) by insulin were not affected by treatment with the drug. The effects of BFA were further shown to require addition of the drug prior to the addition of insulin. BFA added 10 min after stimulation with insulin had no effects on the redistribution of the receptor. Dose-response studies demonstrated that the effects of BFA were half-maximal at a dose of 1 microgram/ml and maximal at about 10 micrograms/ml. These findings suggest that BFA blocks an early step in the chain of events that lead to insulin receptor internalization without affecting the interactions of the receptor with insulin, the stimulation of the tyrosine kinase activity of the receptor by the hormone, or other insulin-regulated signalling pathways, such as the activation of MAPK.
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PMID:Brefeldin A inhibits insulin-dependent receptor redistribution in HIRcB cells. 780 75

Interleukin (IL)-1 plays a central role in human host defense. Binding of IL-1 to its receptor is associated with phosphorylation of various cellular target proteins, most of which are unidentified. The kinases responsible for target protein phosphorylation after IL-1 stimulation are also still not completely understood. We report here that IL-1 induced activation of mitogen-activated protein (MAP) kinase in primary monocytes and in the human monocytic leukemia cell line U-937. Activation of MAP kinase was followed by activation of MAP kinase-activated protein (MAPKAP) kinase 2, a serine/threonine kinase, leading to subsequent phosphorylation of the small heat shock protein [27-kDa heat shock protein (Hsp27)]. Phosphorylation of Hsp27 triggered by IL-1 was both dose and time dependent. IL-1 failed to phosphorylate Hsp27 when cells had been previously deactivated with tyrosine kinase inhibitors such as genistein. In those cells, however, Hsp27 phosphorylation could be reconstituted when activated immunoprecipitated MAP kinase or purified MAPKAP kinase 2 was added. Phosphorylation of Hsp27 could also be inhibited when NaF, a serine/threonine phosphatase inhibitor, was omitted. Taken together, our findings indicate that IL-1-induced intracellular signaling pathways converge in the activation of MAP kinase and MAPKAP kinase 2 and the subsequent phosphorylation of Hsp27.
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PMID:Interleukin-1-induced intracellular signaling pathways converge in the activation of mitogen-activated protein kinase and mitogen-activated protein kinase-activated protein kinase 2 and the subsequent phosphorylation of the 27-kilodalton heat shock protein in monocytic cells. 780 27


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