Sano Y, Harada J, Tashiro S, Gotoh-Mandeville R, Maekawa T, Ishii S
Laboratory of Molecular Genetics, Tsukuba Life Science Center, RIKEN, 3-1-1 Koyadai, Tsukuba, Ibaraki 305-0074, Japan.
J Biol Chem. 1999 Mar 26;274(13):8949-57. doi: 10.1074/jbc.274.13.8949.
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.
转化生长因子-β（TGF-β）与其同源受体结合后，Smad3和Smad4形成异源二聚体，并将TGF-β信号转导至细胞核。除了Smad信号通路外，TGF-β信号传导还需要另一条涉及丝裂原活化蛋白激酶激酶激酶家族成员TGF-β活化激酶1（TAK1）的信号通路。然而，尚不清楚这些信号通路如何共同发挥作用以协同放大TGF-β信号。在此，我们报告转录因子ATF-2（也称为CRE-BP1）在TGF-β刺激后与Smad3和Smad4的异源寡聚体结合。ATF-2是ATF/CREB家族中与cAMP反应元件结合的成员之一，其活性在被应激激活蛋白激酶如c-Jun N端激酶和p38磷酸化后增强。ATF-2与Smad3/4之间的结合是通过Smad蛋白的MH1区域和ATF-2的碱性亮氨酸拉链区域介导的。TGF-β信号传导还通过TAK1和p38诱导ATF-2的磷酸化。这两种作用均被证明对协同刺激ATF-2的反式激活能力起作用。这些结果表明，ATF-2作为Smad和TAK1信号通路的共同核靶点，在TGF-β信号传导中发挥核心作用。
