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 kinase (MAPK) cascade is an evolutionarily conserved signal transduction pathway that is involved in plant development and stress responses. As the first component of this phosphorelay cascade, mitogen-activated protein kinase kinase kinases (MAPKKKs) act as adaptors linking upstream signaling steps to the core MAPK cascade to promote the appropriate cellular responses; however, the functions of MAPKKKs in maize are unclear. Here, we identified 71 MAPKKK genes, of which 14 were novel, based on a computational analysis of the maize (Zea mays L.) genome. Using an RNA-seq analysis in the leaf, stem and root of maize under well-watered and drought-stress conditions, we identified 5,866 differentially expressed genes (DEGs), including 8 MAPKKK genes responsive to drought stress. Many of the DEGs were enriched in processes such as drought stress, abiotic stimulus, oxidation-reduction, and metabolic processes. The other way round, DEGs involved in processes such as oxidation, photosynthesis, and starch, proline, ethylene, and salicylic acid metabolism were clearly co-expressed with the MAPKKK genes. Furthermore, a quantitative real-time PCR (qRT-PCR) analysis was performed to assess the relative expression levels of MAPKKKs. Correlation analysis revealed that there was a significant correlation between expression levels of two MAPKKKs and relative biomass responsive to drought in 8 inbred lines. Our results indicate that MAPKKKs may have important regulatory functions in drought tolerance in maize.
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PMID:RNA-Seq Analysis Reveals MAPKKK Family Members Related to Drought Tolerance in Maize. 2659 13

Overexpression of human epidermal growth factor receptor 2 (HER2) drives the biology of 30% of breast cancer cases. As a transducer of HER2 signaling, RAS/RAF/MAPK pathway plays a pivotal role in the development of breast cancer. In this study, we examined the molecular mechanisms underlying the chemopreventive effects of black rice anthocyanins (BRACs) extract and identified their molecular targets in HER2(+) breast cancer cells. Treatment of MDA-MB-453 cells (HER2(+)) with BRACs inhibited cell migration and invasion, suppressed the activation of mitogen-activated protein kinase kinase kinase (RAF), mitogen-activated protein kinase kinase (MEK), and c-Jun N-terminal kinase (JNK), and downregulated the secretion of matrix metalloproteinase 2 (MMP2) and MMP9. BRACs also weakened the interactions of HER2 with RAF, MEK, and JNK proteins, respectively, and decreased the mRNA expression of raf, mek, and jnk. Further, we found combined treatment with BRACs and RAF, MEK, or JNK inhibitors could enhance the antimetastatic activity, compared with that of each treatment. Transient transfection with small interfering RNAs (siRNAs) specific for raf, mek, and jnk inhibited their mRNA expression in MDA-MB-453 cells. Moreover, cotreatment with BRACs and siRNA induces a more remarkable inhibitory effect than that by either substance alone. In summary, our study suggested that BRACs suppress metastasis in breast cancer cells by targeting the RAS/RAF/MAPK pathway.
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PMID:Black Rice Anthocyanins Suppress Metastasis of Breast Cancer Cells by Targeting RAS/RAF/MAPK Pathway. 2664 2

Apoptosis signal-regulating kinase I (ASK1) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates the downstream MAP kinase kinases (MKKs) from two MAP kinase cascades: c-Jun N-terminal kinase (JNK) and p38. The essential physiological functions of ASK1 have attracted extensive attention. However, our understanding of the molecular mechanisms of ASK1, including the activation mechanism of ASK1 and the catalytic mechanism of ASK1-mediated MKK phosphorylation, remain unclear. The lack of purified ASK1 protein has hindered the elucidation of ASK1-initiated signal transduction mechanisms. Here, we report a one-step chromatography method for the expression and purification of functional full-length ASK1 from Escherichia coli. The purified ASK1 demonstrates auto-phosphorylation activity. The kinase activity of auto-phosphorylated ASK1 (pASK1) was also evaluated on two MKK substrates, MKK4 and 7, from the JNK cascades. Our results show that MKK7 can be phosphorylated by pASK1 more effectively than MKK4. The steady-state kinetic analysis demonstrates that MKK7 is a better ASK1 substrate than MKK4. These observations are further confirmed by direct pull-down assays which shows ASK1 binds MKK7 significantly stronger than MKK4. Furthermore, robust phospho-tyrosine signal is observed in MKK4 phosphorylation by pASK1 in addition to the phospho-serine and phospho-threonine. This study provides novel mechanistic and kinetic insights into the ASK1-initiated MAPK signal transduction via highly controlled reconstructed protein systems.
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PMID:Purification, auto-activation and kinetic characterization of apoptosis signal-regulating kinase I. 2808 61

Prolonged exposure to high concentrations of glutamate leads to cell type specific glutathione depletion and resulting oxidative stress, known as oxytosis. As a result of glutathione depletion, accumulation of reactive oxygen species and Ca2+ influx are increased; however, the specific target of oxytosis has yet to be identified. In the present study, we focused on the effect of glutamate-induced oxidative stress on the extracellular-regulated protein kinase (ERK) pathway using the murine hippocampal HT22 cell line. Although the contribution of the ERK pathway to glutamate-induced oxytosis in HT22 cells is controversial, Western blot analysis revealed that glutamate caused down-regulation of mitogen-activated protein kinase kinase kinase (c-Raf) and a resulting decrease in the phosphorylation of c-Raf, as well as of mitogen-activated protein kinase kinase1/2 (MEK1/2) and ERK1/2, downstream components of the c-Raf/MEK/ERK pathway. Furthermore, neuroprotective (arylthio)cyclopentenone prostaglandins prevented glutamate-induced c-Raf down-regulation and consequently maintained the basal activity of c-Raf and its downstream signaling components. A pull-down assay using biotin-labeled cyclopentenone prostaglandins revealed that they preferentially bound to c-Raf relative to other signaling molecules of the ERK pathway, including Ras, MEK1/2, and ERK. These results suggest that neuroprotective (arylthio)cyclopentenone prostaglandins directly bind to c-Raf protein and protect cells from down-regulation of the c-Raf protein itself, resulting in neuroprotection against oxidative stress.
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PMID:Prevention of oxytosis-induced c-Raf down-regulation by (arylthio)cyclopentenone prostaglandins is neuroprotective. 2888 48

Plant mitogen-activated protein kinase (MAPK) cascades play important roles in development and stress responses. In previous studies, we have systematically investigated the mitogen-activated protein kinase kinase (MKK) and MAPK gene families in cotton. However, the complete interactions between MAPK gene family members in MAPK signaling cascade is poorly characterized. Herein, we investigated the mitogen-activated protein kinase kinase kinase (MAPKKK) family members and identified a total of 89 MAPKKK genes in the Gossypium raimondii genome. We cloned 51 MAPKKKs in G. hirsutum and investigated the interactions between MKK and MAPKKK proteins through yeast-two hybrid assays. A total of 18 interactive protein pairs involved in 14 MAPKKKs and six MKKs were found. Among these, 13 interactive pairs had not been reported previously. Gene expression patterns revealed that 12 MAPKKKs were involved in diverse signaling pathways triggered by hormone treatments or abiotic stresses. By combining the MKK-MAPK and MKK-MAPKKK protein interactions with gene expression patterns, 38 potential MAPK signaling modules involved in the complicated cross-talks were identified, which provide a basis on elucidating biological function of the MAPK cascade in response to hormonal and/or stress responses. The systematic investigation in MAPK signaling cascades will lay a foundation for understanding the functional roles of different MAPK cascades in signal transduction pathways, and for the improvement of various defense responses in cotton.
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PMID:Identification on mitogen-activated protein kinase signaling cascades by integrating protein interaction with transcriptional profiling analysis in cotton. 2980 1

As upstream components of MAPK cascades, mitogen-activated protein kinase kinase kinases (MAPKKKs) act as adaptors linking upstream signaling steps to the core MAPK cascades. MAPK cascades are universal modules of signal transduction in eukaryotic organisms and play crucial roles in plant development processes and in responses to biotic and abiotic stress and signal transduction. Members of the MAPKKK gene family have been identified in several plants,however, MAPKKKs have not been systematically studied in bermudagrass (Cynodon dactylon L.). In this study, 55 potential CdMAPKKKs were produced from bermudagrass transcriptome data, of which 13 belonged to the MEKK, 38 to the Raf, and 4 to the ZIK subfamily. Multiple alignment and conserved motif analysis of CdMAPKKKs supported the evolutionary relationships inferred from phylogenetic analyses. Moreover, the distribution pattern in Poaceae species indicated that members of the MAPKKK family were conserved among almost all diploid species, and species-specific polyploidy or higher duplication ratios resulted in an expansion of the MAPKKK family. In addition, 714 co-functional links which were significantly enriched in signal transduction, responses to temperature stimuli, and other important biological processes of 55 CdMAPKKKs were identified using co-functional gene networks analysis; 30 and 19 co-functional genes involved in response to cold or heat stress, respectively, were also identified. Results of promoter analyses, and interaction network investigation of all CdMAPKKKs based on the rice homologs suggested that CdMAPKKKs are commonly associated with regulation of numerous biological processes. Furthermore, 12 and 13 CdMAPKKKs were significantly up- and downregulated, respectively, in response to low temperature stress; among them, six CdMAPKKKs were significantly induced by low temperature stress, at least at one point in time. This is the first study to conduct identification and functional analysis of the MAPKKK gene family in bermudagrass, and our results provide a foundation for further research on the functions of CdMAPKKKs in response to low temperature stress.
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PMID:Transcriptome-wide identification of MAPKKK genes in bermudagrass (Cynodon dactylon L.) and their potential roles in low temperature stress responses. 3319 98


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