Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.25 (MEKK1)
 1,856 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the p38 mitogen-activated protein kinase (MAPK) has been implicated in signal transduction events, its role in regulating the Mr 92,000 type IV collagenase matrix metalloprotease-9 (MMP-9) and in vitro invasiveness in cancer has not yet been determined. We made the surprising observation that, in a human squamous cell carcinoma cell line (UM-SCC-1), phorbol ester-enhanced MMP-9 secretion and in vitro invasiveness were associated with a strong activation of the p38 MAPK and its downstream target, MAPK-activated protein kinase-2. To determine the role of p38 activation in these events, we investigated the effect of SB 203580, a novel specific p38 inhibitor, on protease expression and in vitro invasion of these cells. We found that inhibition of p38 by SB 203580 resulted in the almost complete reduction of phorbol myristate acetate-induced MMP-9 secretion but not of urokinase-type plasminogen activator secretion. In contrast, the activation of a transiently transfected wild-type MMP-9 promoter by MEKK-1, a specific c-Jun NH2-terminal kinase activator, was only marginally inhibited by the compound, arguing for the specificity of SB 203580. Moreover, phorbol myristate acetate-enhanced in vitro invasion was completely blocked by SB 203580, whereas p38 inhibition had little effect on growth. These findings suggest that activation of p38 may contribute to a more invasive phenotype in vitro, possibly via the expression of MMP-9, and that targeting of p38 using SB 203580 may provide a novel means of controlling invasion of cancers in which this MAPK is activated.
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PMID:Inhibition of the p38 mitogen-activated protein kinase by SB 203580 blocks PMA-induced Mr 92,000 type IV collagenase secretion and in vitro invasion. 951 96

Trophoblast differentiation during placentation involves an epithelial-mesenchymal transition (EMT) with loss of E-cadherin and gain of trophoblast invasiveness. Mice harboring a point mutation that renders inactive the mitogen-activated protein kinase kinase kinase MEKK4 exhibit dysregulated placental development with increased trophoblast invasion. Isolated MEKK4 kinase-inactive trophoblast stem (TS) cells cultured under undifferentiating, self-renewing conditions in the presence of fibroblast growth factor 4 (FGF4) display increased expression of Slug, Twist, and matrix metalloproteinase 2 (MMP2), loss of E-cadherin, and hyperinvasion of extracellular matrix, each a hallmark of EMT. MEKK4 kinase-inactive TS cells show a preferential differentiation to Tpbp alpha- and Gcm1-positive trophoblasts, which are indicative of spongiotrophoblast and syncytiotrophoblast differentiation, respectively. FGF4-stimulated Jun N-terminal kinase (JNK) and p38 activity is markedly reduced in MEKK4 kinase-inactive TS cells. Chemical inhibition of JNK in wild-type TS cells induced a similar EMT response as loss of MEKK4 kinase activity, including inhibition of E-cadherin expression and increased expression of Slug, MMP2, Tpbp alpha, and Gcm1. Chromatin immunoprecipitation analyses revealed changes in AP-1 composition with increased Fra-2 and decreased Fra-1 and JunB binding to the regulatory regions of Gcm1 and MMP2 genes in MEKK4 kinase-inactive TS cells. Our results define MEKK4 as a signaling hub for FGF4 activation of JNK that is required for maintenance of TS cells in an undifferentiated state.
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PMID:Trophoblast stem cell maintenance by fibroblast growth factor 4 requires MEKK4 activation of Jun N-terminal kinase. 1928 95

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