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:2.7.12.2 (MEK)
18,161 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In PC12 cells, cAMP stimulates the MAP kinase pathway by an unknown mechanism. Firstly, we examined the role of calcium ion mobilization and of protein kinase C in cAMP-stimulated MAP kinase activation. We show that cAMP stimulates p44mapk independently of these events. Secondly, we studied the role of B-Raf in this process. We observed that NGF, PMA and cAMP induce the phosphorylation of B-Raf as well as an upward shift in its electrophoretic mobility. We show that B-Raf is activated following NGF and PMA treatment of PC12 cells, and that it can phosphorylate and activate MEK-1. However, cAMP inhibits B-Raf autokinase activity as well as its ability to phosphorylate and activate MEK-1. This inhibition is likely to be due to a direct effect since we found that PKA phosphorylates B-Raf in vitro. Further, we show that B-Raf binds to p21ras, but more important, this binding to p21ras is virtually abolished with B-Raf from PC12 cells treated with CPT-cAMP. Hence, these data indicate that the PKA-mediated phosphorylation of B-Raf hampers its interaction with p21ras, which is responsible for the PKA-mediated decrease in B-Raf activity. Finally, our work suggests that in PC12 cells, cAMP stimulates MAP kinase through the activation of an unidentified MEK kinase and/or the inhibition of a MEK phosphatase.
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PMID:Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP. 783 30

Several members of the tumour-necrosis/nerve-growth factor (TNF/NGF) receptor family activate the transcription factor NF-kappaB through a common adaptor protein, Traf2 (refs 1-5), whereas the interleukin 1 type-I receptor activates NF-kappaB independently of Traf2 (ref. 4). We have now cloned a new protein kinase, NIK, which binds to Traf2 and stimulates NF-kappaB activity. This kinase shares sequence similarity with several MAPKK kinases. Expression in cells of kinase-deficient NIK mutants fails to stimulate NF-kappaB and blocks its induction by TNF, by either of the two TNF receptors or by the receptor CD95 (Fas/Apo-1), and by TRADD, RIP and MORT1/FADD, which are adaptor proteins that bind to these receptors. It also blocked NF-kappaB induction by interleukin-1. Our findings indicate that NIK participates in an NF-kappaB-inducing signalling cascade common to receptors of the TNF/NGF family and to the interleukin-1 type-I receptor.
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PMID:MAP3K-related kinase involved in NF-kappaB induction by TNF, CD95 and IL-1. 902 Mar 61

The mitogen-activated protein kinase (MAP kinase) is a key participant in growth factor-stimulated intracellular events such as proliferation and differentiation. We and others have previously described a cross-talk between the MAP kinase pathway and the cAMP pathway. Indeed, in several cell lines and, in particular in fibroblasts, an increase in the level of cAMP produced an inhibition of MAP kinase together with decreased cell proliferation. In contrast, in PC12 cells, cAMP induced an increase in the NGF-induced activation of MAP kinase concomitantly with augmented NGF-induced differentiation. Therefore, it has been proposed that the cellular context is important for the nature of the cAMP effects on growth factor-stimulated MAP kinase activity. Here we show that the type of tyrosine kinase receptor stimulated also participates in the nature of the cAMP effect. Thus, in NIH3T3 fibroblasts expressing NGF receptors (NIH3T3/trk cells) we found that cAMP potentiates NGF-stimulated ERK1 and MEK1 activities, whereas in NIH3T3 fibroblasts expressing insulin receptors (NIH3T3/IR cells) we saw no effect of cAMP on the activation of insulin-stimulated ERK1 and MEK1. In PC12 cells and in Rat1 fibroblasts expressing insulin receptors (PC12/IR and Rat1/IR cells) we observed, respectively, a potentiation and an inhibition of insulin-stimulated ERK1 activity. In addition, cAMP does not seem to modify the basal nor growth factor-stimulated She or IRS-1 tyrosine phosphorylation in the different cell lines studied. Finally, we observed that cAMP inhibited serum- and insulin-induced, but not NGF-induced, cell proliferation in NIH3T3 cells. However, cAMP potentiated insulin-stimulated cell differentiation in PC12/IR cells. These results led us to conclude that the cAMP effect on cell proliferation in NIH3T3 fibroblasts and PC12/IR cells appears to be correlated, in part, with the effect of cAMP on the MAP kinase pathway, but by itself this pathway cannot fully account for these observations.
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PMID:The effect of cyclic adenosine monophosphate on the mitogen-activated protein kinase pathway depends on both the cell type and the type of tyrosine kinase-receptor. 904 17

In this study we examined the contribution of MAPK1 and 2 [also known as extracellular signal-regulated kinases (ERK)-1 and 2] to the induction of zif268 mRNA in PC12D cells by using two methods to block the activation of these kinases. In one set of experiments, we inhibited the activation of MAPK by pretreating cells with PD098059, a specific inhibitor of MEK (MAPKK), the immediate upstream activator of MAPK. In the second set of experiments, we blocked the activation of MAPK by overexpressing N17Ras, a dominant-negative form of Ha-Ras. These two approaches yielded similar results and showed that inhibition of MAPK blocks less than half of the induction of zif268 mRNA by NGF. Much of the residual induction of zif268 mRNA is blocked by low concentrations of wortmannin, an inhibitor of phosphatidylinositol (PI) 3-kinase. Since PI 3-kinase was previously shown to function upstream in epidermal growth factor (EGF)-mediated activation of c-Jun N-terminal kinase (JNK), and JNK is known to phosphorylate and activate transcription factors that regulate the expression of zif268, we investigated the role of JNK in the induction of zif268 mRNA by NGF. Stimulation of PC12D cells with NGF weakly activates JNK, but this activation is enhanced rather than inhibited by pretreatment with wortmannin, suggesting that JNK does not function downstream of PI 3-kinase in the induction of zif268 mRNA. A role for JNK in the induction of the zif268 gene is indicated, however, by the fact that cotransfection of expression vectors encoding JIP-1 or the JNK binding domain of JIP-1, which act as dominant-negative inhibitors of JNK, partially blocks the NGF-mediated induction of a luciferase reporter gene linked to the zif268 promoter. Together, these results suggest that MAPK, PI-3 kinase and JNK each play a role in the induction of zif268 gene expression by NGF in PC12D cells.
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PMID:Nerve growth factor induces zif268 gene expression via MAPK-dependent and -independent pathways in PC12D cells. 1005 43

The role of signal transducer and activator of transcription (STAT) signaling pathways in the interleukin-6 (IL-6)-induced morphological differentiation of PC12-E2 cells was assessed using wild type and dominant negative mutants of Stat1 and Stat3, containing Tyr --> Phe (YF), Ser --> Ala (SA), and the double mutations (DM), respectively. FS3-YF or FS3-DM markedly inhibited the IL-6-induced response, but overexpression of FS3-SA caused only a modest inhibition. Expression of all Stat3 mutants had no effect on NGF-induced neurite outgrowth. Overexpression of wild type Stat1 protein inhibited IL-6 activated DNA binding complexes containing Stat3 homodimers, which may explain the partial negative effect of Stat1 on IL-6-induced neurite outgrowth. Specificity of these STAT constructs was confirmed using luciferase reporter gene assays, which showed that IL-6-activated transcription was blocked by expression of FS3-YF and FS3-DM and that FS1 enhanced the interferon gamma-activated transcription. Thus, in PC12-E2 cells, Stat3 homodimers are preferentially activated by IL-6, indicating a role for Stat3 in the regulation of cellular differentiation. Furthermore, IL-6 induced robust neurite outgrowth in PC12-E2 cells expressing dominant negative forms of RAS or SHC or in cells pretreated with the mitogen-activated protein kinase mitogen-activated protein kinase kinase inhibitor, PD98059. Thus, activation of the Stat3 signaling pathway, but not RAS/ERK dependent pathways, is essential for differentiation of PC12-E2 cells by IL-6.
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PMID:Activation of the Stat3 signaling pathway is required for differentiation by interleukin-6 in PC12-E2 cells. 1063 20

In PC12 phaeochromocytoma cells, protein synthesis is activated by epidermal and nerve growth factors (EGF and NGF). EGF and NGF also regulate a number of components of the translational machinery in these cells. Here we show that the ability of EGF and NGF to induce the phosphorylation of the 70 kDa ribosomal protein, S6 kinase, and the eukaryotic initiation factor (eIF), 4E-binding protein 1, is dependent upon the presence of amino acids (but not glucose) in the medium. This resembles the regulation of these proteins by insulin, which also requires amino acids. Glucose, but not amino acids, is required for the activation of eIF2B by EGF and NGF. In contrast, EGF and NGF can still activate protein synthesis in the absence of nutrients, suggesting that other regulatory events are important in this. In nutrient-deprived cells, an increase in the phosphorylation of eIF4E, and the assembly of the eIF4F complex by EGF and NGF, coincided with the activation of protein synthesis. In serum-starved cells, activation of protein synthesis, phosphorylation of eIF4E, and formation of the eIF4F complex, were blocked by inhibition of MEK, a component of the extracellular regulated kinase (ERK) signalling pathway. Thus the ERK pathway plays a key role in the regulation of protein synthesis in PC12 cells.
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PMID:Glucose and amino acids modulate translation factor activation by growth factors in PC12 cells. 1074 69

To investigate the influence of AT(2) receptor stimulation on the ERK pathway and elucidate potential mechanisms of angiotensin II (ANG II)-mediated neuronal differentiation, we analysed tyrosine phosphorylation and activity of ERK after ANG II treatment of both quiescent and NGF-treated PC12W cells. Tyrosine phosphorylation of ERK1 and ERK2 corresponded with the activity of ERK. While ANG II induced an initial activation of ERK in quiescent cells, the NGF-mediated plateau of ERK-stimulation was lowered by costimulation with ANG II. All effects of ANG II were sensitive to AT(2) - but not AT(1) receptor blockade. Ang II-mediated neurite outgrowth in PC12W cells was inhibited by co-treatment with the MEK inhibitor PD 098059. These findings demonstrate that the AT(2) receptor modulates ERK activity depending on the overall cellular input. The distinct regulation of ERK by ANG II and NGF further indicates basic differences in AT(2) receptor- and NGF-induced neuronal differentiation.
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PMID:Angiotensin AT(2) receptor stimulates ERK1 and ERK2 in quiescent but inhibits ERK in NGF-stimulated PC12W cells. 1089 97

Epidermal and nerve growth factors (EGF and NGF) activate protein synthesis and initiation factor eIF2B in rat phaeochromocytoma (PC12) cells. The activation of protein synthesis by EGF or NGF depends upon extracellular regulated kinase kinase (MEK)/extracellular regulated kinase signalling. Here we show that PD98059, an inhibitor of MEK activation, blocks the activation of eIF2B by EGF or NGF. It is known that eIF2B activity can be inhibited by phosphorylation at Ser535 in its epsilon-subunit by glycogen synthase kinase (GSK)-3. We find that inactivation of GSK-3 by EGF or NGF is blocked by PD98059. However, neither EGF nor NGF caused a detectable change in phosphorylation of Ser535 of eIF2Bepsilon. Thus, the EGF- and NGF-induced activation of eIF2B in PC12 cells involves regulatory mechanisms distinct from dephosphorylation of the GSK-3 site.
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PMID:The activation of eukaryotic initiation factor (eIF)2B by growth factors in PC12 cells requires MEK/ERK signalling. 1091 25

Although it is well established that members of the Egr family of transcription regulatory factors are induced in many neuronal plasticity paradigms, it is still unclear what role, if any, they play in this process. Because NGF stimulation of pheochromocytoma 12 cells elicits a robust induction of Egr family members, we have investigated their role in mediating long-term effects elicited by NGF in these cells by using the Egr zinc finger DNA-binding domain as a selective antagonist of Egr family-mediated transcription. We report that expression of this Egr inhibitor construct suppresses neurite outgrowth elicited by NGF but not by dibutyryl cAMP. To check that this Egr inhibitor construct does not act by blocking the MEK/ERK pathway, which is known to mediate NGF-induced neurite outgrowth, we confirmed that the Egr inhibitor construct does not block NGF activation of Elk1-mediated transcription, a response that is dependent on this pathway. Conversely, inhibition of MEK does not impair Egr family-mediated transcription. Thus, we conclude (1) that induction of Egr family members and activation of the MEK/ERK pathway by NGF are mediated by separate signaling pathways and (2) that both are required to trigger neurite outgrowth induced by NGF.
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PMID:Blockade of NGF-induced neurite outgrowth by a dominant-negative inhibitor of the egr family of transcription regulatory factors. 1115 Mar 18

We have shown previously that BDNF, neurotrophin-3 (NT-3), chlorphenylthio-cAMP (cpt-cAMP) (a permeant cAMP analog), and membrane depolarization promote spiral ganglion neuron (SGN) survival in vitro in an additive manner, depolarization having the greatest efficacy. Expression of both BDNF and of NT-3 is detectable in cultured SGNs after plating in either depolarizing or nondepolarizing medium. These neurotrophins promote survival by an autocrine mechanism; TrkB-IgG or TrkC-IgG, which block neurotrophin binding to, respectively, TrkB and TrkC, partially inhibit the trophic effect of depolarization. The mitogen-activated protein kinase kinase inhibitor PD98059 and the phosphatidylinositol-3-OH kinase inhibitor LY294002 both abolish trophic support by neurotrophins but only partially inhibit support by depolarization. Inhibition by these compounds is not additive with inhibition by Trk-IgGs. The cAMP antagonist Rp-adenosine-3',5'-cyclic-phosphorothioate (Rp-cAMPS) abolishes survival attributable to cpt-cAMP but has no effect on that attributable to neurotrophins, nor do inhibitors of neurotrophin-dependent survival affect survival attributable to cpt-cAMP. However, Rp-cAMPS does partially inhibit depolarization-dependent survival, an inhibition that is additive with that by Trk-IgGs, PD98059, or LY294002. Moreover, Rp-cAMPS prevents depolarization-dependent survival of PC12 cells maintained in subthreshold levels of NGF. Inhibition of Ca(2+)/calmodulin-dependent protein kinases (CaMKs) with KN-62 reduces SGN survival independently of Rp-cAMPS, Trk-IgGs, and LY294002 and additively with them. Combined inhibition of Trk, cAMP, and CaMK signaling prevents depolarization-dependent survival. Thus, survival of SGNs under depolarizing conditions involves additivity among a depolarization-independent autocrine pathway, a cAMP-dependent pathway, and a CaMK-dependent pathway.
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PMID:Multiple distinct signal pathways, including an autocrine neurotrophic mechanism, contribute to the survival-promoting effect of depolarization on spiral ganglion neurons in vitro. 1126 1


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