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)

Ras p21 in the GTP-bound form was shown to act as an upstream activator for mitogen-activated protein (MAP) kinase kinase (MAPKK) and MAP kinase, and Raf-1 was reported to act as a MAPKK kinase. Further, physical association between Ras and Raf-1 was demonstrated. Here we have shown that incubation of Xenopus immature oocyte extracts with Ras enhances the ability of endogenous Raf-1 to activate MAPKK. Moreover, a dominant negative form of Raf-1 blocked the Ras-induced activation of MAPKK and MAP kinase in the extracts, but not the cyclin A-dependent activation of MAP kinase. When the extracts were depleted of 45-kDa MAPKK with polyclonal anti-MAPKK antibody, no activation of MAP kinase occurred even after incubation with Ras. These results suggest that Ras can activate the MAPKK kinase activity of Raf-1 in the extracts and that MAPKK is indispensable for the Ras-induced MAP kinase activation. It is well known that Ras can induce oocyte maturation when injected into immature Xenopus oocytes. Co-injection of Ras with an anti-MAPKK antibody that inhibits the MAPKK activity prevented the Ras-induced germinal vesicle breakdown, suggesting that MAPKK mediates, at least, one of cellular functions of Ras.
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PMID:Analysis of the Ras p21/mitogen-activated protein kinase signaling in vitro and in Xenopus oocytes. 780 37

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

Up-regulation of ERK (extracellular signal-regulated kinase or MAP kinase) and MEK (ERK kinase or MAPK kinase) expression after rat facial nerve injury was demonstrated by in situ hybridization histochemistry and immunohistochemistry. These two enzymes play roles in one of the major intracellular signal cascade pathways involving receptor tyrosine kinase common to growth factor receptors, and transcription factors. Significant increases in ERK1 mRNA levels were observed from day 3 after facial nerve transection, with the highest level of expression from 1 to 2 weeks after the operation. This high level of mRNA expression then decreased gradually to the normal level. ERK1-like immunoreactivity showed a similar time course to that of its mRNA expression; however, the decay profile was more prolonged. The up-regulation of MEK, the ERK kinase/MAPK kinase, was also detected by immunohistochemistry. The protein expression profiles were almost equivalent, but the MEK expression was slightly advanced, suggesting that the observed up-regulation of MEK was not due to that of ERK. The receptor tyrosine kinase signal transduction pathway via MEK-ERK located downstream of growth factor receptors seems vital as a regulator of the synthesis of molecules that play important roles in the recovery process following injury or/and regeneration.
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PMID:Up-regulation of ERK (MAP kinase) and MEK (MAP kinase kinase) transcription after rat facial nerve transection. 783 28

Mammalian mitogen-activated protein (MAP) kinases include extracellular signal-regulated protein kinase (ERK), c-Jun amino-terminal kinase (JNK), and p38 subgroups. These MAP kinase isoforms are activated by dual phosphorylation on threonine and tyrosine. Two human MAP kinase kinases (MKK3 and MKK4) were cloned that phosphorylate and activate p38 MAP kinase. These MKK isoforms did not activate the ERK subgroup of MAP kinases, but MKK4 did activate JNK. These data demonstrate that the activators of p38 (MKK3 and MKK4), JNK (MKK4), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways.
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PMID:Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. 783 44

Saccharomyces cerevisiae FUS3/DAC2 protein kinase, a homolog of mammalian mitogen-activated protein (MAP) kinase, inactivates a G1 cyclin encoded by the CLN3 gene to arrest cell division in the G1 phase and activates a transcriptional factor STE12 in response to mating pheromone during sexual conjugation. To elucidate the role of the FUS3/DAC2 gene product in the mating process, I constructed and characterized dac2 cln3 double mutants. Here, I show that FUS3/DAC2 is required for completion of cell fusion even in the dac2 cln3 double mutants in which the pheromone response is restored, suggesting that FUS3/DAC2 plays a positive role in cell fusion during conjugation. In addition, the cdc dac2 and cdc37 ste double mutants were constructed and investigated for their phenotypes to clarify the relationship between FUS3/DAC2, STE7 or STE11 and CDC gene products (CDC28, 36, 37 and 39). The results indicate that FUS3/DAC2 may act upstream of CDC28 and provide evidence that the G1 arrest and morphological changes conferred by the cdc37 mutation may require FUS3/DAC2 (MAP kinase), STE7(MEK) and STE11 (MEK kinase).
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PMID:Yeast homolog of mammalian mitogen-activated protein kinase, FUS3/DAC2 kinase, is required both for cell fusion and for G1 arrest of the cell cycle and morphological changes by the cdc37 mutation. 784 75

Exposure of mesangial cells to platelet-derived growth factor (PDGF) BB caused a significant stimulation of cell proliferation and protein synthesis, as measured by [3H]thymidine incorporation and [3H]leucine incorporation respectively. In contrast, cells treated with angiotensin II had no significant increase in [3H]thymidine incorporation, but demonstrated a marked increase in [3H]leucine incorporation. Furthermore, angiotensin II significantly increased total protein content per cell. These data show that, whereas PDGF-BB is a mitogen and stimulates mesangial-cell hyperplasia, angiotensin II causes hypertrophy of the cells without hyperplasia. Treatment of mesangial cells with PDGF and angiotensin II rapidly and dose-dependently stimulated mitogen-activated protein (MAP) kinase activity, as shown by an assay for activity in vitro using myelin basic protein as a substrate, and by immunoprecipitation of 32P-labelled cells with specific antibodies against the 42 kDa and 44 kDa mitogen-activated protein kinases p42mapk and p44mapk, respectively. Whereas stimulation with PDGF-BB caused a potent and sustained (for more than 30 min) phosphorylation and activation of p42mapk and p44mapk, as well as of the upstream activators MAP kinase kinase and c-Raf, the effect of angiotensin II was less potent, reaching a peak at 5-10 min and thereafter declining rapidly. In summary, these results suggest that PDGF-BB and angiotensin II differ in their potency and duration of activation of the MAP kinase cascade, which may explain why PDGF-BB is a potent mitogen for mesangial cells, whereas angiotensin II only triggers mesangial-cell hypertrophy.
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PMID:Platelet-derived growth factor and angiotensin II stimulate the mitogen-activated protein kinase cascade in renal mesangial cells: comparison of hypertrophic and hyperplastic agonists. 784 76

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

ENGAGEMENT of the T-cell receptor (TCR) with cognate ligands provokes different outcomes depending on the developmental stage of the T cell and on the properties of the ligand. In immature thymocytes TCR stimulation may result in maturation (positive selection) or death (negative selection), whereas in mature T cells it may induce proliferation, death or unresponsiveness. To investigate the different signals involved in these processes, we have analysed the role of the MAP kinase (MAPK) cascade, which is required for growth-factor-stimulated replication and for differentiation in other cell types, by expressing a catalytically inactive form of MAPK kinase (MEK-1) in thymocytes, thereby blocking MAPK activation. We find that positive selection of these cells is inhibited but that negative selection and TCR-induced proliferation are unaffected. Our results indicate that the intracellular signals regulating lineage commitment in T cells parallel those in photoreceptor cell specification in Drosophila and vulval cell differentiation in Caenorhabditis elegans, suggesting that general rules for cell-type specification could apply among all metazoans.
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PMID:Selective requirement for MAP kinase activation in thymocyte differentiation. 785 19

Activation of the mitogen activated protein kinase (MAPK) plays essential roles in many signal transduction pathways. MAPK has been demonstrated to phosphorylate and regulate numerous cellular proteins, including growth factor receptor, transcription factors, cytoskeletal proteins, phospholipase and other protein kinases. Activation of MAPK requires phosphorylation of both threonine and tyrosine residues, which are catalysed by a single protein kinase known as MAPK kinase or MEK. MEK itself is activated by phosphorylation on two conserved serine residues. Three distinct mammalian Ser/Thr kinases, including Raf, Mos and MEKK (for MEK kinase), have been demonstrated to phosphorylate and activate MEK. The MAP kinase cascade is highly conserved in all eukaryotes and involved in numerous cellular responses. Activation of MAPK is a transient event that is tightly regulated by both kinases and phosphatases. A growth factor induced dual specific phosphatase is likely to play an important role in MAPK regulation.
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PMID:The mitogen activated protein kinase signal transduction pathway: from the cell surface to the nucleus. 785 62


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