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

---

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

c-Jun NH2-terminal protein kinase (JNK), a distant member of the mitogen-activated protein (MAP) kinase family, regulates gene expression in response to various extracellular stimuli. JNK is activated by JNK-activating kinase 1 (JNKK1), a dual specificity protein kinase that phosphorylates JNK on threonine 183 and tyrosine 185 residues. Here we show that JNKK2, a novel member of the MAP kinase kinase family, was phosphorylated and activated by MEKK1, a MAP kinase kinase kinase in the JNK signaling cascade. JNKK2 activity was also stimulated by constitutively active forms of Rac and Cdc42Hs, members of the Rho small GTP-binding protein family. Unlike JNKK1 that activates both JNK and p38 MAP kinases, JNKK2 stimulated only JNK. Transient transfection assays demonstrated that JNKK2 potentiated the stimulation of c-Jun transcriptional activity by MEKK1. The existence of multiple JNK-activating kinases may contribute to the specificity of the JNK signaling cascade.
...
PMID:Identification of c-Jun NH2-terminal protein kinase (JNK)-activating kinase 2 as an activator of JNK but not p38. 931 68

The Schizosaccharomyces pombe wis1(+) gene is essential for cell survival under stress conditions. The MAPKK homologue Wis1 is required for activation of the MAPK homologue Spc1, and integrity of the Wis1-Spc1 pathway is required for survival in extreme conditions of heat, osmolarity, oxidation or limited nutrition. We show here that Wis4, a protein kinase of a new MAPKKK class, phosphorylates Wis1 in vitro and activates it in vivo. Win1 is also required for full activation of Wis1, and Win1 rather than Wis4 mediates the osmotic stress signal. Surprisingly, the pathway can still be activated by heat or oxidative stress independently of the phosphorylation of two conserved Wis1 residues. Evidence is presented that the Pyp1 protein tyrosine phosphatase, which dephosphorylates Spc1, is central to this alternative activation mechanism.
...
PMID:Multiple modes of activation of the stress-responsive MAP kinase pathway in fission yeast. 932 95

Mitogen-activated protein kinases function in signal transduction pathways that are involved in controlling key cellular processes in many organisms. A mammalian member of this kinase family, MKK4/JNKK1/SEK1, has been reported to link upstream MEKK1 to downstream stress-activated protein kinase/JNK1 and p38 mitogen-activated protein kinase. This mitogen-activated protein kinase pathway has been implicated in the signal transduction of cytokine- and stress-induced apoptosis in a variety of cell types. Here, we report that two human tumor cell lines, derived from pancreatic carcinoma and lung carcinoma, harbor homozygous deletions that eliminate coding portions of the MKK4 locus at 17p, located approximately 10 cM centromeric of p53. In addition, in a set of 88 human cancer cell lines prescreened for loss of heterozygosity, we detected two nonsense and three missense sequence variants of MKK4 in cancer cell lines derived from human pancreatic, breast, colon, and testis cells. In vitro biochemical assays revealed that, when stimulated by MEKK1, four of the five altered MKK4 proteins lacked the ability to phosphorylate stress-activated protein kinase. Thus, the incidence of coding mutations of MKK4 in the set of cell lines is 6 of 213 (approximately 3%). These findings suggest that MKK4 may function as a suppressor of tumorigenesis or metastasis in certain types of cells.
...
PMID:Human mitogen-activated protein kinase kinase 4 as a candidate tumor suppressor. 933 Oct 70

Ste5 is essential for the yeast mating pheromone response pathway and is thought to function as a scaffold that organizes the components of the mitogen-activated protein kinase (MAPK) cascade. A new method was developed to isolate missense mutations in Ste5 that differentially affect the ability of Ste5 to interact with either of two MAPK cascade constituents, the MEKK (Ste11) and the MEK (Ste7). Mutations that affect association with Ste7 or with Ste11 delineate discrete regions of Ste5 that are critical for each interaction. Co-immunoprecipitation analysis, examining the binding in vitro of Ste5 to Ste11, Ste7, Ste4 (G protein beta subunit), and Fus3 (MAPK), confirmed that each mutation specifically affects the interaction of Ste5 with only one protein. When expressed in a ste5 delta cell, mutant Ste5 proteins that are defective in their ability to interact with either Ste11 or Ste7 result in a markedly reduced mating proficiency. One mutation that clearly weakened (but did not eliminate) interaction of Ste5 with Ste7 permitted mating at wild-type efficiency, indicating that an efficacious signal is generated even when Ste5 associates with only a small fraction of (or only transiently with) Ste7. Ste5 mutants defective in association with Ste11 or Ste7 showed strong interallelic complementation when co-expressed, suggesting that the functional form of Ste5 in vivo is an oligomer.
...
PMID:Mutational analysis of STE5 in the yeast Saccharomyces cerevisiae: application of a differential interaction trap assay for examining protein-protein interactions. 933 87

Morphine sulfate causes immunomodulatory and immunosuppressive effects in human. In this study, the signaling pathway involved in these morphine effects was studied. Addition of morphine sulfate to human CEMx174 lymphocytic cells resulted in increased expression of mitogen-activated protein kinase cascade proteins. Morphine enhanced the cellular levels of ERK1 (44 kDa), ERK2 (42 kDa), a 54-kDa ERK, MEK1 (45 kDa), and MEKK (78 kDa). A time-dependent increase in the activated (Thr and Tyr dually phosphorylated) state of ERK1 and ERK2 was also observed. Naloxone, a morphine antagonist, reversed the observed morphine effects, implicating a micro opioid receptor-mediated process. These findings suggest that mitogen-activated protein kinases are important intermediates in signal transduction pathways initiated by morphine receptors in immune cells.
...
PMID:Induction and activation of mitogen-activated protein kinases of human lymphocytes as one of the signaling pathways of the immunomodulatory effects of morphine sulfate. 934 Nov 10

We previously reported that both hypoxia and hypoxia followed by reoxygenation (hypoxia/reoxygenation) rapidly activate Src family tyrosine kinases and p21ras in cultured rat cardiac myocytes. This was followed by the sequential activation of mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1, MAP kinase kinase (MAPKK), MAPKs (p44mapk and p42mapk, also called extracellular signal-regulated protein kinase [ERK]1 and ERK2, respectively), and S6 kinase (p90rsk). In this study, we demonstrated that both hypoxia and hypoxia/reoxygenation caused rapid activation of stress-activated MAPK signaling cascades involving p65PAK, p38MAPK, and SAPK. These stimuli also caused phosphorylation of activating transcription factor (ATF)-2. Because p65PAK is known to be upstream of p38MAPK and also be a target of p21rac-1, which belongs to the rho subfamily of p21ras-related small GTP-binding proteins, these results strongly suggested that two different stress-activated MAPK pathways distinct from the classical MAPK pathway were activated in response to hypoxia and hypoxia/reoxygenation in cardiac myocytes.
...
PMID:Hypoxia and hypoxia/reoxygenation activate p65PAK, p38 mitogen-activated protein kinase (MAPK), and stress-activated protein kinase (SAPK) in cultured rat cardiac myocytes. 936 56

MEK kinases (MEKKs) are serine-threonine kinases that regulate sequential protein phosphorylation pathways involving mitogen-activated protein kinases (MAPKs), including members of the Jun kinase (JNK) family. MEKK1 is a 196 kDa protein that when cleaved by caspase-3-like proteases generates an active COOH-terminal kinase domain. Expression of the MEKK1 kinase domain is sufficient to induce apoptosis. Mutation of MEKK1 to prevent its proteolytic cleavage protects cells from MEKK1-mediated cell death even though the JNK pathway is still activated, indicating that JNK activation is not sufficient to induce cell death. The inducible acute expression at modest levels of the activated MEKK1 kinase domain can be used to potentiate the apoptotic response to low dose ultraviolet irradiation and cisplatin. Similarly, in L929 fibrosarcoma cells inducible acute expression of the kinase domain of MEKK1 markedly increased the cell death response to tumor necrosis factor alpha (TNF alpha). The findings demonstrate that acute expression of an active form of MEKK1 can potentiate the cell death response to external stress stimuli. Manipulation of MEKK1 proteolysis and its regulation of signal pathways involved in apoptosis has significant potential for anticancer therapies when used in combination with therapeutic agents at doses that alone have little or modest effects on cell viability.
...
PMID:Potentiation of apoptosis by low dose stress stimuli in cells expressing activated MEK kinase 1. 939 40

Mitogen-activated protein kinase (MAPK) kinases (MKKs) are dual-specificity protein kinases that phosphorylate and activate MAPK. We have isolated a cDNA encoding a novel protein kinase that has significant homology to MKKs. The novel kinase MKK7 has a nucleotide sequence that encodes an open reading frame of 347 amino acids with 11 kinase subdomains. MKK7 is ubiquitously expressed in all adult and embryonic organs but displays high expression in epithelial tissues at later stages of fetal development. When transiently expressed in 293 cells, MKK7 specifically activated stress-activated protein kinases (SAPKs)/c-Jun N-terminal protein kinases (JNKs) but not extracellular-regulated kinase or p38 kinase. A kinase-negative mutant of MKK7 inhibits interleukin-1beta, lipopolysaccharide, and MEKK1-induced SAPK/JNK activation. Thus, MKK7 is a new member of the MAPK kinase family that functions upstream of SAPK/JNK in the SAPK/JNK signaling pathway.
...
PMID:Activation of stress-activated protein kinases/c-Jun N-terminal protein kinases (SAPKs/JNKs) by a novel mitogen-activated protein kinase kinase. 940 46

Mitogen-activated protein kinase kinases (MKKs or MEKs) are dual specificity tyrosine/threonine protein kinases that are activated by phosphorylation at two closely spaced serine residues (serines-218 and -222) by the c-mos and raf proto-oncogenes. This double phosphorylation is both necessary and sufficient for MEKs to activate the MAP kinase enzymes in vitro. The specificity or regulation of in vivo signaling to the mammalian MEKs (MEK1 and MEK2) was recently reported also to involve the differential phosphorylation of a proline-rich peptide located between the MEK kinase-subdomains IX and X. Here we report the purification and characterization of an auto-activating protein kinase from bovine brain that phosphorylates serine-298 of the MEK1 and MEK2 proline-rich insert peptides. The auto-activation of the MEK-S298 peptide kinase is the result of an intermolecular phosphorylation event that can be prevented by the peptide substrates. The inactive kinase migrates on gel filtration as a 90 kDa protein, and after activation as a 43 kDa phosphoprotein. Incorporation of 32P[phosphate] into 40-42 kDa proteins on SDS-PAGE parallels the activation of the enzyme, and dephosphorylation by protein phosphatase 2Ac reverses the activation. SDS-PAGE renaturation assays show that the 40 kDa protein has the capacity to autophosphorylate, and exhibits kinase activity towards myelin basic protein after activation. Phosphorylation of purified bovine brain MEK or recombinant MEK1 by the auto-activated kinase does not activate the enzyme, and does not interfere with the in vitro raf-mediated MEK activation. We conclude that still unknown kinases may control the MAP kinase pathway by targeting MEK.
...
PMID:Identification and characterization of an auto-activating MEK kinase from bovine brain: phosphorylation of serine-298 in the proline-rich domain of the mammalian MEKs. 941 3

The fission yeast Sty1 mitogen-activated protein (MAP) kinase (MAPK) and its activator the Wis1 MAP kinase kinase (MAPKK) are required for cell cycle control, initiation of sexual differentiation, and protection against cellular stress. Like the mammalian JNK/SAPK and p38/CSBP1 MAPKs, Sty1 is activated by a range of environmental insults including osmotic stress, hydrogen peroxide, UV light, menadione, heat shock, and the protein synthesis inhibitor anisomycin. We have recently identified two upstream regulators of the Wis1 MAPKK, namely the Wak1 MAPKKK and the Mcs4 response regulator. Cells lacking Mcs4 or Wak1, however, are able to proliferate under stressful conditions and undergo sexual differentiation, suggesting that additional pathway(s) control the Wis1 MAPKK. We now show that this additional signal information is provided, at least in part, by the Win1 mitotic regulator. We show that Wak1 and Win1 coordinately control activation of Sty1 in response to multiple environmental stresses, but that Wak1 and Win1 perform distinct roles in the control of Sty1 under poor nutritional conditions. Our results suggest that the stress-activated Sty1 MAPK integrates information from multiple signaling pathways.
...
PMID:The Win1 mitotic regulator is a component of the fission yeast stress-activated Sty1 MAPK pathway. 945 Sep 57


<< Previous 1 2 3 4 5 6 7 8 9 10

---