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)

The mitogen-activated protein (MAP) kinases are serine-threonine protein kinases that are activated by tyrosine and threonine phosphorylation by the dual specificity protein kinase MEK (MAP kinase/ERK kinase). The present report describes the purification to near homogeneity and characterization of a protein tyrosine phosphatase from Xenopus laevis eggs that dephosphorylates MAP kinase phosphorylated by MEK. Bacterially expressed Xenopus MAP kinase phosphorylated by purified Xenopus MEK was used as substrate throughout the purification. The purification procedure included anion-exchange, cation-exchange, gel filtration, heparin-Sepharose, and chromatography on a column of thiophosphorylated MAP kinase-Sepharose, resulting in a > 3000-fold purification. Upon analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, a protein of 47 kDa correlated with activity. The phosphatase showed absolute specificity toward phosphotyrosine and no activity toward phosphothreonyl-phosphoseryl residues of MAP kinase. The pH optimum of the enzyme was 7.0 with a Km of 9.0 microM for phosphorylated MAP kinase. The phosphatase was inhibited by ammonium molybdate (IC50, 2 microM), vanadate (IC50, 250 microM), millimolar concentrations of MnCl2, ZnCl2 and p-nitrophenylphosphate but not by okadaic acid or microcystin. This tyrosine phosphatase may be involved in deactivating MAP kinase in vivo.
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PMID:Purification and characterization of a mitogen-activated protein kinase tyrosine phosphatase from Xenopus eggs. 822 71

The extracellular signal-regulated kinases ERK1 and ERK2 are 43- and 41-kd enzymes activated by many extracellular cues. They lie within a protein kinase cascade that is used to achieve many cellular responses. In addition to the wide variety of regulatory contexts in which they are activated, they phosphorylate important regulatory proteins, including receptors, transcription factors, cytoskeletal proteins, and other protein kinases. Thus, the stimulation of this kinase cascade is thought to have a pleiotropic action. ERK1 and ERK2 are controlled by phosphorylation on threonine and tyrosine. To understand the regulatory mechanisms, wild-type and mutant ERKs were expressed in bacteria and phosphorylated with MEK, the enzyme that is upstream of ERKs. Wild-type proteins could be activated 500- to 1,000-fold in vitro by MEK. ERK3, an enzyme of 62 kd and only 50% identical to ERK1 and ERK2 in the catalytic core, was also phosphorylated by MEK in vitro. This suggests that all three of these enzymes are targets of common signaling pathways.
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PMID:Regulation and properties of extracellular signal-regulated protein kinases 1, 2, and 3. 830 37

Activation of the Saccharomyces cerevisiae MAP kinase Fus3 is thought to occur via a linear pathway involving the sequential action of three proteins: Ste5, a protein of unknown function, Ste11, a MAPKK kinase homolog, and Ste7, a MAPK kinase homolog which phosphorylates and activates Fus3. In this report, we present evidence for a novel mechanism of Fus3 activation that involves a direct association with Ste5, a protein not predicted to interact with Fus3. First, overexpression of Ste5 suppresses fus3 point mutations in an allele-specific manner and increases Fus3 kinase activity in vitro. Second, Ste5 associates with Fus3 in vivo as demonstrated by the two-hybrid system and by two methods of copurification. Third, Ste5 and Fus3 associate prior to pheromone stimulation even when Fus3 is inactive, and in strains lacking Ste7 and Ste11. Fourth Ste5 is phosphorylated by Fus3 in purified complexes and copurifies with an additional protein kinase(s). These observations suggest the possibility that Ste5 promotes signal transduction by tethering Fus3 to its activating protein kinase(s).
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PMID:The MAP kinase Fus3 associates with and phosphorylates the upstream signaling component Ste5. 831 85

The kinase Raf-1 can be activated by treatment of cells with mitogens and by the protein kinase C (PKC) activator 12-O-tetradecanoyl-phorbol-13-acetate (TPA) (reviewed in refs 1,2). Activated Raf-1 triggers a protein kinase cascade by direct phosphorylation of MAP kinase kinase, resulting in phosphorylation of ternary complex factor and Jun by MAP kinase. Here we investigate the molecular mechanism and biological consequences of PKC alpha-mediated Raf-1 activation in NIH3T3 fibroblasts. PKC alpha directly phosphorylates and activates Raf-1 both in vitro and in vivo. PKC alpha induces Raf-1 phosphorylation at several sites, including a serine residue at position 499. Mutation of serine at this position or at residue 259 does not abrogate Raf-1 stimulation by a combination of Ras plus the src tyrosine kinase Lck, but severely impedes Raf-1 activation by PKC alpha. Consistent with such a direct interaction is the observation that Raf-1 and PKC alpha cooperate in the transformation of NIH3T3 cells. The Ser499 phosphorylation site is necessary for this synergism.
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PMID:Protein kinase C alpha activates RAF-1 by direct phosphorylation. 832 21

We used a Saccharomyces cerevisiae genetic system to detect the physical interaction of RAS and RAF oncoproteins. We also observed interaction between RAS and byr2, a protein kinase implicated as a mediator of the Schizosaccharomyces pombe ras1 protein. Interaction with RAS required only the N-terminal domains of RAF or byr2 and was disrupted by mutations in either the guanine nucleotide-binding or effector-loop domains of RAS. We observed interaction between MEK (a kinase that phosphorylates mitogen-activated protein kinases) and the catalytic domain of RAF. RAS and MEK also interacted but only when RAF was overexpressed.
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PMID:Complex formation between RAS and RAF and other protein kinases. 832 1

Intracellular signalling from receptor tyrosine kinases in mammalian cells involves the activation of a signal cascade which includes p21ras and the protein kinases p74raf-1, MAP kinase kinase and MAP kinases. In the yeasts Schizosaccharomyces pombe and Saccharomyces cerevisiae the response to mating pheromones requires the Spk1 and KSS1/FUS3 kinases, which have sequence homology to vertebrate MAP kinases. The recent cloning of complementary DNAs for mammalian and frog MAP kinase kinases has shown that they are homologous to the S. pombe Byr1 (ref. 17) and S. cerevisiae STE7 (ref. 18) kinases, which have been proposed to function upstream of Spk1 and KSS1/FUS3, respectively. We have investigated whether these apparently similar kinase pathways are functionally conserved between vertebrates and S. pombe. We report here that expression of mammalian MAP kinase kinase alone fails to complement a byr1 mutant of S. pombe. When coexpressed with Raf kinase, however, MAP kinase kinase is activated by phosphorylation and the mating defect of the byr1 mutant is rescued. This suggests that the pathways are functionally homologous and that Raf kinase may directly phosphorylate and activate MAP kinase kinase.
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PMID:Complementation of byr1 in fission yeast by mammalian MAP kinase kinase requires coexpression of Raf kinase. 833 94

Mitogen-activated protein kinases (MAP kinases) or meiosis-activated myelin basic protein kinase (p44mpk) are known to be activated by a mechanism involving dual phosphorylation at both tyrosine and serine/threonine in response to many extracellular stimuli. There has been considerable speculation as to whether MAP kinases are autophosphorylated and activated by an upstream protein kinase (MAP kinase kinase) or an activator of autophosphorylation or both. Here we report that the ets-related proteins elk-1 and delta elk-1 to be potential physiological substrates and activators of MAP kinases. Our results demonstrate for the first time that MAP kinase activators can also be non-kinase proteins that enhance the autophosphorylation and activation of MAP kinase. These findings could establish a general mechanism wherein specific MAP kinase activator protein(s) may function by interacting with MAP kinases ensuring a conformational change and stimulating their autophosphorylation and activation property. Our results also suggest that the amino-terminal truncated elk-1 proteins are better activators of MAP kinase than full length proteins indicating the presence of a potential negative regulatory region which may control the kinase activator function of elk-1 proteins. Our results suggest differential regulation of elk-1 and delta elk-1 proteins in fibroblasts stimulated by epidermal growth factor implicating a key role for these proteins in the signal transduction pathway. These results establish the presence of an alternative pathway for activation of MAP kinases. Thus we propose that elk-1 proteins may represent key intermediates which would transmit signals arriving at the surface of the cell from activated receptors to downstream MAP kinases in the cytoplasm to reach the transcriptional factors in the nucleus.
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PMID:Elk-1 proteins are phosphoproteins and activators of mitogen-activated protein kinase. 833 45

MAP kinases p42mapk and p44mapk participate in a protein kinase cascade(s) important for signaling in many cell types and contexts. Both MAP kinases are activated in vitro by MAP kinase kinase, a protein-tyrosine and threonine kinase. A MAP kinase kinase cDNA was isolated from a rat kidney library by using peptide sequence data we obtained from MAP kinase kinase isolated from rabbit skeletal muscle. The deduced sequence, containing 393 amino acids (predicted mass, 43.5 kDa), is most similar to byr1 (Bypass of ras1), a yeast protein kinase functioning in the mating pathway induced by pheromones in Schizosaccharomyces pombe. An unusually large insert is present in MAP kinase kinase between domains IX and X and may contribute to protein-protein interactions with MAP kinase. Major (2.7 kilobases) and minor (1.7 kilobases) transcripts are widely expressed in rat tissues and appear to be derived from a single gene.
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PMID:Molecular structure of a protein-tyrosine/threonine kinase activating p42 mitogen-activated protein (MAP) kinase: MAP kinase kinase. 838 Apr 94

Mitogen-activated protein kinases (MAPKs) are rapidly phosphorylated and activated in response to various extracellular stimuli in many different cell types. Such regulation of MAPK results from sequential activation of a series of protein kinases. The kinases that phosphorylate MAPKs, the MAP kinase kinases (MEKs) are also activated by phosphorylation. MEKs are related in sequence to the yeast protein kinases Byr1 (from Schizosaccharomyces pombe) and Ste7 (from Saccharomyces cerevisiae), which function in the pheromone-induced signaling pathway that results in mating. Byr1 and Ste7 are in turn regulated by the protein kinases Byr2 and Ste11. The amino acid sequence of the mouse homolog of Byr2 and Ste11, denoted MEKK (MEK kinase), was elucidated from a complementary DNA sequence encoding a protein of 672 amino acid residues (73 kilodaltons). MEKK was expressed in all mouse tissues tested, and it phosphorylated and activated MEK. Phosphorylation and activation of MEK by MEKK was independent of Raf, a growth factor-regulated protein kinase that also phosphorylates MEK. Thus, MEKK and Raf converge at MEK in the protein kinase network mediating the activation of MAPKs by hormones, growth factors, and neurotransmitters.
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PMID:A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. 838 2

The PKC1 gene of Saccharomyces cerevisiae encodes a homolog of mammalian protein kinase C that is required for normal growth and division of yeast cells. We report here the isolation of the yeast MKK1 and MKK2 (for mitogen-activated protein [MAP] kinase-kinase) genes which, when overexpressed, suppress the cell lysis defect of a temperature-sensitive pkc1 mutant. The MKK genes encode protein kinases most similar to the STE7 product of S. cerevisiae, the byr1 product of Schizosaccharomyces pombe, and vertebrate MAP kinase-kinases. Deletion of either MKK gene alone did not cause any apparent phenotypic defects, but deletion of both MKK1 and MKK2 resulted in a temperature-sensitive cell lysis defect that was suppressed by osmotic stabilizers. This phenotypic defect is similar to that associated with deletion of the BCK1 gene, which is thought to function in the pathway mediated by PCK1. The BCK1 gene also encodes a predicted protein kinase. Overexpression of MKK1 suppressed the growth defect caused by deletion of BCK1, whereas an activated allele of BCK1 (BCK1-20) did not suppress the defect of the mkk1 mkk2 double disruption. Furthermore, overexpression of MPK1, which encodes a protein kinase closely related to vertebrate MAP kinases, suppressed the defect of the mkk1 mkk2 double mutant. These results suggest that MKK1 and MKK2 function in a signal transduction pathway involving the protein kinases encoded by PKC1, BCK1, and MPK1. Genetic epistasis experiments indicated that the site of action for MKK1 and MKK2 is between BCK1 and MPK1.
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PMID:MKK1 and MKK2, which encode Saccharomyces cerevisiae mitogen-activated protein kinase-kinase homologs, function in the pathway mediated by protein kinase C. 838 20


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