Regulation of Smad4 sumoylation and transforming growth factor-β signaling by protein inhibitor of activated STAT1
Regulation of Smad4 sumoylation and transforming growth factor-β signaling by protein inhibitor of activated STAT1
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DOI：
10.1074/jbc.m401554200
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发表时间：
2004-05-28
影响因子：
4.8
通讯作者：
Lin, X
中科院分区：
文献类型：
--
作者：
Liang, M;Melchior, F;Lin, X
肿瘤抑制因子Smad4/DPC4是转化生长因子-β信号转导通路中常见的信号转导分子。在这项研究中，我们证明了激活的STAT1蛋白抑制因子(PIAS1)通过苏莫化依赖的机制调节Smad4的信号潜能。体内外研究表明，PIAS1是Smad4苏甲基化的E3连接酶。PIAS1以转化生长因子-β诱导的方式与Smad4发生物理作用。在PIAS1蛋白上定义了一个最小的SUMO E3连接酶结构域和Smad4结合结构域。PIAS1的环指结构域是其E3连接酶功能所必需的。虽然PIAS1增强了Smad4依赖的转化生长因子-β信号的转录激活，但缺乏环区的突变体以显性负向方式抑制Smad4的总和基化，结果是取消了转化生长因子-β的转录反应。这些数据表明，作为Smad4的相扑E3连接酶，PIAS1蛋白正向调节了转化生长因子-β的反应。
The tumor suppressor, Smad4/DPC4, is a common signal transducer in transforming growth factor-beta (TGF-beta) signaling. In this study, we demonstrated that the protein inhibitor of activated STAT1 (PIAS1) regulates the signaling potential of Smad4 through a sumoylation-dependent mechanism. PIAS1 was shown to be an E3 ligase for Smad4 sumoylation in vitro and in vivo. PIAS1 physically interacted with Smad4 in a TGF-beta-inducible manner. A minimal SUMO E3 ligase domain and Smad4-binding domain were defined on PIAS1 protein. The RING finger domain of PIAS1 was essential for its E3 ligase function. Although PIAS1 enhanced the Smad4-dependent transcriptional activation of TGF-beta signaling, a mutant lacking the RING domain inhibited the sumoylation of Smad4 in a dominant negative manner and, as a result, abolished the transcriptional response of TGF-beta. These data demonstrate that PIAS1 protein positively modulates TGF-beta responses as a SUMO E3 ligase for Smad4.