ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-β signaling
ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-β signaling
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DOI：
10.1074/jbc.274.13.8949
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发表时间：
1999-03-26
影响因子：
4.8
通讯作者：
Ishii, S
中科院分区：
文献类型：
--
作者：
Sano, Y;Harada, J;Ishii, S
在转化生长因子-β（TGF-β）与其同源受体结合后，Smad 3和Smad 4形成异二聚体并将TGF-β信号传递到细胞核。除了Smad途径之外，涉及促分裂原活化蛋白激酶家族的成员TGF-β活化激酶-1（TAK 1）的另一途径是TGF-β信号传导所需的。然而，目前尚不清楚这些途径如何共同发挥作用，以协同放大TGF-β信号传导。在这里，我们报告说，转录因子ATF-2（也称为CRE-BP 1）结合的Smad 3和Smad 4在TGF-β刺激的异源寡聚体。ATF-2是ATF/CREB家族的一个成员，与cAMP反应元件结合，其活性在应激活化蛋白激酶如c-Jun N-末端激酶和p38磷酸化后增强。ATF-2和Smad 3/4之间的结合通过Smad蛋白的MH 1区域和ATF-2的碱性亮氨酸拉链区域介导。TGF-β信号还通过TAK 1和p38诱导ATF-2的磷酸化。这两种作用被证明是负责ATF-2反式激活能力的协同刺激。这些结果表明，ATF-2通过作为Smad和TAK 1途径的共同核靶点在TGF-β信号传导中发挥核心作用。
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.