MEKK-1, a Component of the Stress (Stress-activated Protein Kinase/c-Jun N-terminal Kinase) Pathway, Can Selectively Activate Smad2-mediated Transcriptional Activation in Endothelial Cells
| Autor: | Michael A. Gimbrone, Maria R. DiChiara, James N. Topper, Keith R. Anderson, Jonathan D. Brown |
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| Rok vydání: | 1999 |
| Předmět: |
Transcriptional Activation
animal structures MAP Kinase Kinase 4 MAP Kinase Kinase 1 Smad2 Protein Protein Serine-Threonine Kinases Mitogen-activated protein kinase kinase Biochemistry MAP2K7 Genes Reporter Transforming Growth Factor beta Animals ASK1 c-Raf Phosphorylation Promoter Regions Genetic Molecular Biology Cells Cultured Mitogen-Activated Protein Kinase Kinases MAP kinase kinase kinase biology Akt/PKB signaling pathway Chemistry Cyclin-dependent kinase 2 JNK Mitogen-Activated Protein Kinases Cell Biology Protein-Tyrosine Kinases Immunohistochemistry Cell biology DNA-Binding Proteins Trans-Activators biology.protein Cattle Cyclin-dependent kinase 9 Endothelium Vascular Protein Kinases Signal Transduction Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 274:8797-8805 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.274.13.8797 |
| Popis: | Smad proteins are essential components of the intracellular signaling pathways utilized by members of the transforming growth factor-beta (TGF-beta) superfamily of growth factors. Certain Smad proteins (e.g. Smad1, -2, and -3) can act as regulated transcriptional activators, a process that involves phosphorylation of these proteins by activated TGF-beta superfamily receptors. We demonstrate that the intracellular kinase mitogen-activated protein kinase kinase kinase-1 (MEKK-1), an upstream activator of the stress-activated protein kinase/c-Jun N-terminal kinase pathway, can participate in Smad2-dependent transcriptional events in cultured endothelial cells. A constitutively active form of MEKK-1 but not mitogen-activated protein kinase kinase-1 (MEK-1) or TGF-beta-activated kinase-1, two distinct intracellular kinases, can specifically activate a Gal4-Smad2 fusion protein, and this effect correlates with an increase in the phosphorylation state of the Smad2 protein. These effects do not require the presence of the C-terminal SSXS motif of Smad2 that is the site of TGF-beta type 1 receptor-mediated phosphorylation. Activation of Smad2 by active MEKK-1 results in enhanced Smad2-Smad4 interactions, nuclear localization of Smad2 and Smad4, and the stimulation of Smad protein-transcriptional coactivator interactions in endothelial cells. Overexpression of Smad7 can inhibit the MEKK-1-mediated stimulation of Smad2 transcriptional activity. A physiological level of fluid shear stress, a known activator of endogenous MEKK-1 activity in endothelial cells, can stimulate Smad2-mediated transcriptional activity. These data demonstrate a novel mechanism for activation of Smad protein-mediated signaling in endothelial cells and suggest that Smad2 may act as an integrator of diverse stimuli in these cells. |
| Databáze: | OpenAIRE |
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