Reciprocal regulation between beta TrCP and Smurf1 suppresses proliferative capacity of liver cancer cells
Reciprocal regulation between beta TrCP and Smurf1 suppresses proliferative capacity of liver cancer cells
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βTrCP 和 Smurf1 之间的相互调节抑制肝癌细胞的增殖能力
DOI：
10.1002/jcp.25780
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发表时间：
2017
影响因子：
5.6
通讯作者：
Wang Jiayi
中科院分区：
文献类型：
--
作者：
Zhang Yue;Wang Wenhua;Cai Si;Chen Yan;Wang Qinwan;Pan Qiuhui;Sun Fenyong;Wang Jiayi
我们之前报道过，泛素E3连接酶βTrCP（含β-转导素重复序列的E3泛素蛋白连接酶）和Smurf 1（SMAD特异性E3泛素蛋白连接酶1）在肝癌细胞中发挥相似的抗肿瘤作用。然而，它们是否以及如何受到严格管制仍然是一个谜。在这里，我们表明βTrCP通过7 ×色氨酸（W）天冬氨酸（D）（WD）40和与E6-AP羧基末端（HECT）结构域同源的区域与Smurf 1相互作用，这两个结构域分别是βTrCP和Smurf 1的E3连接酶结构域。βTrCP和Smurf 1的E3连接酶结构域对于维持Smurf 1和βTrCP的蛋白表达也是至关重要的。此外，组织芯片分析也显示βTrCP和Smurf 1之间存在正相关，表明这种关系在肝癌中可能是重要的。此外，我们发现Smurf 1可能通过减少βTrCP的自动喹啉化来增加β TrCP的蛋白稳定性，反之亦然。有趣的是，这种效应依赖于E3连接酶结构域的存在。重要的是，Smurf 1或βTrCP增强的肝癌细胞增殖能力的耗竭可以通过野生型βTrCP或Smurf 1的过表达而不是其E3连接酶死亡突变体来部分逆转。总的来说，在这项研究中发现了βTrCP和Smurf 1之间的相互翻译后调节。同时增强βTrCP和Smurf 1的功能可能有助于肝癌的治疗。
We previously reported that both the ubiquitin E3 ligases βTrCP (beta‐transducin repeat‐containing E3 ubiquitin protein ligase) and Smurf1 (SMAD‐specific E3 ubiquitin protein ligase 1) play similar antitumorigenic roles in liver cancer cells. However, whether and how they are reciprocally regulated remains elusive. Here, we show that βTrCP interacts with Smurf1 through the 7 × tryptophan (W) aspartic acid (D)(WD) 40 and the region homologous to the E6‐AP carboxyl terminus (HECT) domains, which are the E3 ligase domains of βTrCP and Smurf1, respectively. The E3 ligase domains of βTrCP and Smurf1 are also critical for maintaining the protein expressions of Smurf1 and βTrCP. Moreover, a positive correlation between βTrCP and Smurf1 was also revealed by tissue microarray analysis, indicating that this relationship might be important in liver cancer. Further, we found that Smurf1 increases the protein stability of βTrCP, possibly by reducing autoubiquitination of βTrCP, and vice versa. Interestingly, such effects depended on the presence of E3 ligase domains. Importantly, depletion of Smurf1‐ or βTrCP‐enhanced proliferative capacity of liver cancer cells could be partially reversed by overexpression of wild‐type βTrCP or Smurf1 but not their E3 ligase‐dead mutants. Collectively, a reciprocal post‐translational regulation between βTrCP and Smurf1 has been uncovered in this study. Simultaneous enhancement of βTrCP and Smurf1 functions might be helpful in the treatment of liver cancer.