Transforming growth factor-beta-mediated signaling via the p38 MAP kinase pathway activates Smad-dependent transcription through SUMO-1 modification of Smad4.
Transforming growth factor-beta-mediated signaling via the p38 MAP kinase pathway activates Smad-dependent transcription through SUMO-1 modification of Smad4.
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发表时间：
2003
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通讯作者：
T. Ohshima;K. Shimotohno
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作者：
T. Ohshima;K. Shimotohno
泛素化、磷酸化和乙酰化等翻译后修饰在 Smad 介导的功能调节中发挥重要作用。在这里，我们证明 Smad4 被 SUMO-1 共价修饰，SUMO-1 最近被认为是许多转录因子的关键调节剂。 Sumoylation of Smad4 mainly occurs at lysine 159, located in the linker region, and facilitates Smad-dependent transcriptional activation. Furthermore, we show that the PIAS family proteins, PIAS1 and PIASx beta, function as E3 ligase factors for Smad4. Intriguingly, sumoylation of Smad4 was strongly enhanced by TGF-beta-induced activation of the p38 MAP kinase pathway but not the Smad pathway. p38 的激活不仅稳定了 PIASx β 蛋白，而且增强了 PIASx β 基因表达，表明 PIAS 介导的 Smad4 苏酰化受到 p38 MAP 激酶途径的调节。这些发现说明了一种新的调节机制，Smad 依赖性转录激活通过受体介导的磷酸化和苏酰化协同调节 Smad 蛋白。
Post-translational modifications such as ubiquitination, phosphorylation, and acetylation play important roles in the regulation of Smad-mediated functions. Here, we demonstrate that Smad4 is covalently modified by SUMO-1, which was characterized recently as a key modulator of many transcription factors. Sumoylation of Smad4 mainly occurs at lysine 159, located in the linker region, and facilitates Smad-dependent transcriptional activation. Furthermore, we show that the PIAS family proteins, PIAS1 and PIASx beta, function as E3 ligase factors for Smad4. Intriguingly, sumoylation of Smad4 was strongly enhanced by TGF-beta-induced activation of the p38 MAP kinase pathway but not the Smad pathway. Activation of p38 not only stabilized PIASx beta protein but also enhanced PIASx beta gene expression, suggesting that PIAS-mediated sumoylation of Smad4 is regulated by the p38 MAP kinase pathway. These findings illustrate a novel regulatory mechanism by which Smad-dependent transcriptional activation cooperatively modulates Smad proteins through receptor-mediated phosphorylation and sumoylation.