Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1).
Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1).
复制标题
DOI：
--
复制
发表时间：
2004
期刊：
影响因子：
8
通讯作者：
A. Komuro;T. Imamura;M. Saitoh;Y. Yoshida;T. Yamori;K. Miyazono;K. Miyazawa
中科院分区：
文献类型：
--
作者：
A. Komuro;T. Imamura;M. Saitoh;Y. Yoshida;T. Yamori;K. Miyazono;K. Miyazawa
Smad7通过与激活的I型受体结合，从而阻止受体调节的Smads(R-Smads)的磷酸化，以及通过招募Hect型E3泛素连接酶通过泛素依赖的机制降解I型受体，从而负向调节转化生长因子-β超家族信号转导。为了阐明转化生长因子-β信号的调控机制，我们使用酵母双杂交系统寻找与Smad7相互作用的蛋白的新成员。WW结构域包含蛋白1(WWP1)在结构上与Smad泛素调节因子、Smads的E3泛素连接酶和转化生长因子-β超家族受体相关。在哺乳动物细胞中使用转化生长因子-β反应报告，我们发现WWP1抑制转化生长因子-β诱导的转录活性。与蓝精灵类似，WWP1与Smad7结合并诱导其核输出，并增强Smad7与转化生长因子-βI型受体的结合，导致该受体泛素化和降解。与这些结果一致的是，WWP1抑制了转化生长因子-β诱导的Smad2的磷酸化。因此，WWP1与Smad7合作，负向调节转化生长因子-β信号。然而，与蓝精灵不同的是，WWP1未能泛化R-SMADS和SnoN。重要的是，WWP1和蓝精灵在人体组织和癌细胞中以不同的模式表达，提示WWP1和蓝精灵具有独特的病理生理作用。
Smad7 negatively regulates transforming growth factor (TGF)-beta superfamily signaling by binding to activated type I receptors, thereby preventing the phosphorylation of receptor-regulated Smads (R-Smads), as well as by recruiting HECT-type E3 ubiquitin ligases to degrade type I receptors through a ubiquitin-dependent mechanism. To elucidate the regulatory mechanisms of TGF-beta signaling, we searched for novel members of proteins that interact with Smad7 using a yeast two-hybrid system. One of the proteins identified was the WW domain-containing protein 1 (WWP1) that is structurally related to Smad ubiquitin regulatory factors (Smurfs), E3 ubiquitin ligases for Smads and TGF-beta superfamily receptors. Using a TGF-beta-responsive reporter in mammalian cells, we found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, WWP1 inhibited phosphorylation of Smad2 induced by TGF-beta. WWP1 thus negatively regulates TGF-beta signaling in cooperation with Smad7. However, unlike Smurfs, WWP1 failed to ubiquitinate R-Smads and SnoN. Importantly, WWP1 and Smurfs were expressed in distinct patterns in human tissues and carcinoma cell lines, suggesting unique pathophysiological roles of WWP1 and Smurfs.