ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signaling.

Upon transforming growth factor-beta (TGF-beta) binding to its cognate receptor, Smad3 and Smad4 form heterodimers and transduce the TGF-beta signal to the nucleus. In addition to the Smad pathway, another pathway involving a member of the mitogen-activated protein kinase kinase kinase family of kinases, TGF-beta-activated kinase-1 (TAK1), is required for ...
TGF-beta signaling. However, it is unknown how these pathways function together to synergistically amplify TGF-beta signaling. Here we report that the transcription factor ATF-2 (also called CRE-BP1) is bound by a hetero-oligomer of Smad3 and Smad4 upon TGF-beta stimulation. ATF-2 is one member of the ATF/CREB family that binds to the cAMP response element, and its activity is enhanced after phosphorylation by stress-activated protein kinases such as c-Jun N-terminal kinase and p38. The binding between ATF-2 and Smad3/4 is mediated via the MH1 region of the Smad proteins and the basic leucine zipper region of ATF-2. TGF-beta signaling also induces the phosphorylation of ATF-2 via TAK1 and p38. Both of these actions are shown to be responsible for the synergistic stimulation of ATF-2 trans-activating capacity. These results indicate that ATF-2 plays a central role in TGF-beta signaling by acting as a common nuclear target of both Smad and TAK1 pathways.
Mesh Terms:
Activating Transcription Factor 2, Animals, Cells, Cultured, Cyclic AMP Response Element-Binding Protein, DNA-Binding Proteins, Leucine Zippers, MAP Kinase Kinase Kinases, Mammals, Phosphorylation, Protein Binding, Protein-Serine-Threonine Kinases, Recombinant Fusion Proteins, Signal Transduction, Smad3 Protein, Trans-Activators, Transcription Factors, Transforming Growth Factor beta
J. Biol. Chem.
Date: Mar. 26, 1999
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