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

被引:303
作者
Sano, Y
Harada, J
Tashiro, S
Gotoh-Mandeville, R
Maekawa, T
Ishii, S
机构
[1] RIKEN, Tsukuba Life Sci Ctr, Mol Genet Lab, Ibaraki, Osaka 3050074, Japan
[2] Japan Sci & Technol Corp, Core Res Evolut Sci & Technol, Osaka, Japan
关键词
D O I
10.1074/jbc.274.13.8949
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页码:8949 / 8957
页数:9
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