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.
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.
Mesh Terms:
Animals, Cattle, Cells, Cultured, DNA-Binding Proteins, Endothelium, Vascular, Genes, Reporter, Immunohistochemistry, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 1, MAP Kinase Kinase 4, Mitogen-Activated Protein Kinase Kinases, Phosphorylation, Promoter Regions, Genetic, Protein Kinases, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Signal Transduction, Smad2 Protein, Trans-Activators, Transcription Factors, Transcriptional Activation, Transforming Growth Factor beta
Animals, Cattle, Cells, Cultured, DNA-Binding Proteins, Endothelium, Vascular, Genes, Reporter, Immunohistochemistry, JNK Mitogen-Activated Protein Kinases, MAP Kinase Kinase 1, MAP Kinase Kinase 4, Mitogen-Activated Protein Kinase Kinases, Phosphorylation, Promoter Regions, Genetic, Protein Kinases, Protein-Serine-Threonine Kinases, Protein-Tyrosine Kinases, Signal Transduction, Smad2 Protein, Trans-Activators, Transcription Factors, Transcriptional Activation, Transforming Growth Factor beta
J. Biol. Chem.
Date: Mar. 26, 1999
PubMed ID: 10085121
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