Smad2 functions as a co-activator of canonical Wnt/β-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300
Smad2 functions as a co-activator of canonical Wnt/β-catenin signaling pathway independent of Smad4 through histone acetyltransferase activity of p300
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DOI：
10.1016/j.cellsig.2008.05.003
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发表时间：
2008-09-01
影响因子：
4.8
通讯作者：
Salomon, David S.
中科院分区：
文献类型：
--
作者：
Hirota, Morihisa;Watanabe, Kazuhide;Salomon, David S.
经典的Wnt/β-连环蛋白和TGF β/Smad信号传导途径在胚胎发生以及肿瘤进展期间协调调节模式形成。这两种途径之间的串扰的证据已被报道。在这里，我们证明了激活素样激酶4（Alk 4）/Smad 2途径通过一种新的Smad 4独立机制促进致癌Wnt/β-连环蛋白/Tcf 4途径的转录活性。激活后，Smad 2与Tcf 4、β-连环蛋白和共激活因子p300物理相互作用，通过p300的组蛋白乙酰转移酶活性增强β-连环蛋白/Tcf 4的转录活性。由Smad 2的反式激活是独立的Smad-binding元件（SBE）和Smad 4。事实上，β-连环蛋白/Tcf 4转录活性的增强激活Smad 2的Smad 4的存在下负调控。此外，Smad 2的肿瘤衍生的错义突变体，缺乏与Smad 4结合的能力，仍然能够在β-连环蛋白和Tcf 4存在下增强Tcf 4转录报告基因。我们的研究结果表明，Smad 2可能作为一个典型的Wnt/β-catenin/Tcf 4信号通过SBE/Smad 4非依赖性途径的激活剂。爱思唯尔公司出版
Both canonical Wnt/beta-catenin and TGF beta/Smad signaling pathways coordinately regulate pattern formation during embryogenesis as well as tumor progression. Evidence of cross-talk between these two pathways has been reported. Here we demonstrated that the Activin-like kinase 4 (Alk4)/Smad2 pathway facilitates the transcriptional activity of the oncogenic Wnt/beta-catenin/Tcf4 pathway through a novel Smad4-independent mechanism. Upon activation, Smad2 physically interacted with Tcf4, beta-catenin and the co-activator p300 to enhance transcriptional activity of beta-catenin/Tcf4 through the histone acetyltransferase activity of p300. Transactivation by Smad2 was independent of a Smad-binding element (SBE) and Smad4. Indeed, the enhancement of beta-catenin/Tcf4 transcriptional activity by activated Smad2 was negatively regulated by the presence of Smad4. Moreover, a tumor-derived missense mutant of Smad2, lacking the ability to bind to Smad4 was still able to enhance the Tcf4 transcriptional reporter in the presence of p-catenin and Tcf4. Our findings suggest that Smad2 may function as an activator of canonical Wnt/beta-catenin/Tcf4 signaling through a SBE/Smad4-independent pathway. Published by Elsevier Inc.