Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.12.2 (MEK)
 18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelet-derived growth factor (PDGF) BB is a potent mitogen for renal mesangial cells and stimulates a biphasic mitogen-activated protein kinase (MAP kinase) activation. A rapid increase in activity (maximal at 10 min) is followed by a lower persistent level of activity which is maximal at 4-6 h. The second peak of MAP kinase activity is markedly attenuated by the protein synthesis inhibitor cycloheximide and, consequently, is paralleled by a marked de-novo synthesis of p42 and p44 MAP kinases, as measured by immunoprecipitation of [35S]methionine-labeled mesangial cells and by a 700% increase in total MAP kinase protein, as detected by Western-blot analysis. A 30-min treatment with PDGF-BB is sufficient to induce pronounced de-novo synthesis of MAP kinase. However, for maximal induction of MAP kinase synthesis, PDGF is required to be present for at least 4 h. In addition, an increased de-novo synthesis of MAP kinase kinase, the upstream activator of MAP kinase, is observed in response to PDGF stimulation. We propose that PDGF-induced de-novo synthesis of MAP kinase and MAP kinase kinase is important for the potent mitogenic activity of this growth factor.
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PMID:Platelet-derived growth factor stimulates de-novo synthesis of mitogen-activated protein kinase in renal mesangial cells. 785 88

We have used the two-hybrid system of Fields and Song to identify protein-protein interactions that occur in the pheromone response pathway of the yeast Saccharomyces cerevisiae. Pathway components Ste4p, Ste5p, Ste7p, Ste11p, Ste12p, Ste20p, Fus3p and Kss1p were tested in all pairwise combinations. All of the interactions we detected involved at least one member of the MAP kinase cascade that is a central element of the response pathway. Ste5p, a protein of unknown biochemical function, interacted with protein kinases that operate at each step of the MAP kinase cascade, specifically with Ste11p (an MEKK), Ste7p (an MEK), and Fus3p (a MAP kinase). This finding suggests that one role of Ste5p is to serve as a scaffold to facilitate interactions among members of the kinase cascade. In this role as facilitator, Ste5p may make both signal propagation and signal attenuation more efficient. Ste5p may also help minimize cross-talk with other MAP kinase cascades and thus ensure the integrity of the pheromone response pathway. We also found that both Ste11p and Ste7p interact with Fus3p and Kss1p. Finally, we detected an interaction between one of the MAP kinases, Kss1p, and a presumptive target, the transcription factor Ste12p. We failed to detect interactions of Ste4p or Ste20p with any other component of the response pathway.
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PMID:Protein-protein interactions in the yeast pheromone response pathway: Ste5p interacts with all members of the MAP kinase cascade. 785 59

MAP kinases (MAPK) are serine/threonine kinases which are activated by a dual phosphorylation on threonine and tyrosine residues. Their specific upstream activators, called MAP kinase kinases (MAPKK), constitute a new family of dual-specific threonine/tyrosine kinases, which in turn are activated by upstream MAP kinase kinase kinases (MAPKKK). These three kinase families are successively stimulated in a cascade of activation described in various species such as mammals, frog, fly, worm or yeast. In mammals, the MAP kinase module lies on the signaling pathway triggered by numerous agonists such as growth factors, hormones, lymphokines, tumor promoters, stress factors, etc. Targets of MAP kinase have been characterized in all subcellular compartments. In yeast, genetic epistasis helped to characterize the presence of several MAP kinase modules in the same system. By complementation tests, the relationships existing between phylogenetically distant members of each kinase family have been described. The roles of the MAP kinase cascade have been analyzed by engineering various mutations in the kinases of the module. The MAP kinase cascade has thus been implicated in higher eukaryotes in cell growth, cell fate and differentiation, and in low eukaryotes, in conjugation, osmotic stress, cell wall construct and mitosis.
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PMID:Deciphering the MAP kinase pathway. 788 35

An IL-1-stimulated protein kinase cascade resulting in phosphorylation of the small heat shock protein hsp27 has been identified in KB cells. It is distinct from the p42 MAP kinase cascade. An upstream activator kinase phosphorylated a 40 kDa kinase (p40) upon threonine and tyrosine residues, which in turn phosphorylated a 50 kDa kinase (p50) upon threonine (and some serine) residues. p50 phosphorylated hsp27 upon serine. p40 and p50 were purified to near homogeneity. All three components were inactivated by protein phosphatase 2A, and p40 was inactivated by protein tyrosine phosphatase 1B. The substrate specificity of p40 differed from that of p42 and p54 MAP kinases. The upstream activator was not a MAP kinase kinase. p50 resembled MAPKAPK-2 and may be identical.
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PMID:Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. 792 54

The phorbol ester PMA/TPA (phorbol 12-myristate 13-acetate) is a potent tumor promoter which mimics distinct intracellular signalling events triggered by activated growth factor receptors, e.g. the activation of MAP kinases. The largest known family of TPA-binding proteins comprise members of the protein kinase C (PKC) family although other TPA-binding proteins outside the PKC family have recently been identified. In this report we addressed the mechanism and the pathway by which TPA induces the activation of MAPkinases. Using recombinant proteins and in vitro phosphorylation reactions we identified the components in the signal transduction pathway from TPA to MAPkinase and we show that the activation of MAPkinase by TPA requires the presence of protein kinase C, c-raf and the MAPkinase activator MEK. We also find that the activation of raf autophosphorylation in vitro correlates with the ability of Raf to signal to MAPkinase. Thus the activation of Raf by PKC apparently can trigger the same signalling pathway as oncogenic Raf or Raf activation by ras in combination with tyrosine phosphorylation.
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PMID:Signalling from TPA to MAP kinase requires protein kinase C, raf and MEK: reconstitution of the signalling pathway in vitro. 793 44

Glycogen synthase kinase-3 (GSK3) is inactivated in vitro by p70 S6 kinase or MAP kinase-activated protein kinase-1 beta (MAPKAP kinase-1 beta; also known as Rsk-2). Here we show that GSK3 isoforms are inhibited by 40% within minutes after stimulation of the rat skeletal-muscle cell line L6 with insulin-like growth factor-1 (IGF-1) or insulin. GSK3 was similarly inhibited in rabbit skeletal muscle after an intravenous injection of insulin. Inhibition resulted from increased phosphorylation of GSK3, probably at a serine/threonine residue(s), because it was reversed by incubation with protein phosphatase-2A. Rapamycin blocked the activation of p70 S6 kinase by IGF-1 in L6 cells, but had no effect on the inhibition of GSK3 or the activation of MAPKAP kinase-1 beta. In contrast, wortmannin, a potent inhibitor of PtdIns 3-kinase, prevented the inactivation of GSK3 and the activation of MAPKAP kinase-1 beta and p70 S6 kinase by IGF-1 or insulin. Wortmannin also blocked the activation of p74raf-1. MAP kinase kinase and p42 MAP kinase, but not the formation of GTP-Ras by IGF-1. The results suggest that the stimulation of glycogen synthase by insulin/IGF-1 in skeletal muscle involves the MAP-KAP kinase-1-catalysed inhibition of GSK3, as well as the previously described activation of the glycogen-associated form of protein phosphatase-1.
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PMID:The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. 794 42

Exposure of rat glomerular mesangial cells to transforming growth factor beta 2 (TGF beta 2) stimulates a biphasic mitogen-activated protein kinase (MAP kinase) activation. A rapid increase in activity (maximal at 10 min) is followed by a second persistent level of activity which steadily increases over 24 h. The second peak of MAP kinase activity is markedly attenuated by the protein synthesis inhibitor cycloheximide and consequently is paralleled by a pronounced de-novo synthesis of p42 and p44 MAP kinase as measured by immunoprecipitation of [35S]methionine-labeled mesangial cells. In addition, an increased de-novo synthesis of MAP kinase kinase (MEK), the upstream activator of MAP kinase, is observed in response to TGF beta 2 stimulation. We propose that TGF beta-induced activation and de-novo synthesis of MAP kinases and MEK is important for the multifunctional actions of this cytokine in mesangial cells and its role in disease states characterized by excessive fibrosis.
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PMID:Transforming growth factor beta 2 stimulates acute and chronic activation of the mitogen-activated protein kinase cascade in rat renal mesangial cells. 795 34

Bacterial LPS is a potent macrophage activator. The early steps in LPS signal transduction involve the tyrosine phosphorylation and activation of a number of kinases of the src family, and inhibition of this pathway causes a severe impairment in the production of the cytokines TNF-alpha and IL-1 beta. We find that LPS-induced macrophages activation also involves the Raf-1 kinase, a key component in mitogenic signal transduction. Treatment of BAC-1.2F5 macrophages with LPS causes phosphorylation and activation of Raf-1. This is paralleled by the stimulation of MEK-1 and MAP-kinase activity and by the phosphorylation of the transcription factor Elk-1, a nuclear target of MAP-kinase. Activation of the Raf/MAP-kinase pathway was inhibited upon pretreatment of the cells with genistein, a tyrosine kinase inhibitor. Raf-1 must thus lie downstream of tyrosine kinase in LPS signal transduction. However, Raf-1 is not a direct substrate of a LPS-induced tyrosine kinase, because Raf-1 immunoisolated from LPS-induced cells contains only phosphoserine. This resembles the situation after CSF-1-stimulation of macrophages, in which Raf-1 clearly transduces a signal generated by the CSF-1 receptor kinase, but is phosphorylated exclusively in serine. Phosphopeptide maps of Raf-1 immunoprecipitated from LPS- or CSF-1-treated cells are indistinguishable, suggesting that these agents activate Raf-1 by similar mechanisms. Finally, v-raf-infected BAC-1.2F5 macrophages were found to constitutively express low levels of IL-1 beta and TNF-alpha. These data argue that Raf-1 functions downstream of tyrosine kinases in LPS-mediated macrophage activation and cytokine production.
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PMID:Lipopolysaccharide induces activation of the Raf-1/MAP kinase pathway. A putative role for Raf-1 in the induction of the IL-1 beta and the TNF-alpha genes. 798 71

Numerous studies have been published these last few years on the involvement of MAP kinases in signal transduction reflecting their importance in cell cycle and cell growth controls. The identification and the characterization of their direct upstream activator has considerably enlarged our understanding of the phosphorylation network. The MAP kinase kinases (MAPKKs) are dual-specificity protein kinases which phosphorylate and activate MAP kinases. To date, MAPKK homologues have been found in yeast, invertebrates, amphibians, and mammals. Moreover, the MAPKK/MAPK phosphorylation switch constitutes a basic module activated in distinct pathways in yeast and in vertebrates. MAPKK regulation studies have led to the discovery of at least four MAPKK convergent pathways in higher organisms. One of these is similar to the yeast pheromone response pathway which includes the ste11 protein kinase. Two other pathways require the activation of either one or both of the serine/threonine kinase-encoded oncogenes c-Raf-1 and c-Mos. Additionally, recent studies suggest a possible effect of the cell cycle control regulator cyclin-dependent kinase 1 (cdc2) on MAPKK activity. Finally, MAPKKs seem to be essential transducers through which signals must pass before reaching the nucleus.
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PMID:MAP kinase kinase: a node connecting multiple pathways. 800 6

Src homology/collagen (SHC) proteins are thought to participate in signaling through both receptor tyrosine kinases, such as the insulin receptor and the EGF (epidermal growth factor) receptor, and cytoplasmic tyrosine kinases, such as v-src and v-fps. Here we approached the insulin-induced and the insulin-like-growth-factor-I-induced (IGF-I-induced) phosphorylation of SHC proteins, and the possible role of these proteins in insulin and IGF-I signaling. First, we showed that SHC proteins are phosphorylated on tyrosine residues upon insulin and IGF-I treatment of fibroblasts transfected with a SHC cDNA construct. More important, ligand-activated insulin and IGF-I receptors phosphorylate SHC proteins in vitro, indicating that SHC proteins could be direct substrates for insulin and IGF-I receptors. Further, insulin or IGF-I treatment of SHC-transfected fibroblasts leads to immunoprecipitation of SHC proteins with insulin-receptor substrate 1 (IRS-1). We next looked at the possible effect of SHC proteins on biological responses in SHC-transfected fibroblasts. We found that the expression of exogenous SHC proteins results in an increased basal MEK (MAPK/ERK-activating kinase) activity. Further, neither the basal nor the insulin-induced or IGF-I-induced PtdIns-3-kinase activity were modified by expression of exogenous SHC proteins. These results illustrate that SHC proteins are implicated in the MAP (mitogen-activated protein)-kinase pathway, but not in that of PtdIns-3-kinase. Finally, we show that SHC-transfected cells, unlike control cells, are able to advance into the early phases of the cell cycle, and are more sensitive to the growth-promoting effect of insulin. In conclusion, SHC proteins are substrates for insulin and IGF-I receptors, and would appear to function as early post-receptor signaling components.
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PMID:Involvement of Src-homology/collagen (SHC) proteins in signaling through the insulin receptor and the insulin-like-growth-factor-I-receptor. 803 92


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