The Drosophila F-box protein Slimb controls dSmurf protein turnover to regulate the Hippo pathway
The Drosophila F-box protein Slimb controls dSmurf protein turnover to regulate the Hippo pathway
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果蝇 F-box 蛋白 Slimb 控制 dSmurf 蛋白更新以调节 Hippo 通路
DOI：
10.1016/j.bbrc.2016.11.061
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发表时间：
2017
影响因子：
3.1
通讯作者：
Wu Shian
中科院分区：
文献类型：
--
作者：
Hu Liangchang;Wang Ping;Zhao Runan;Li Shanshan;Wang Feng;Li Chaojie;Cao Lei;Wu Shian
SMAD 泛素化调节因子 1 和 2 (Smurf1/2) 是 HECT 结构域 E3 连接酶家族的成员，在细胞周期进程、平面细胞极性、癌症转移和细胞凋亡的调节中发挥着至关重要的作用。我们最近表明，果蝇同源物 dSmurf 控制 Warts 激酶的稳定性，从而调节 Hippo 通路。在目前的研究中，我们发现F-box蛋白Slimb控制dSmurf蛋白水平来调节Hippo通路。 S2 细胞中的免疫共沉淀分析显示，Slimb 与 dSmurf 存在物理关联。 Slimb 的 C 端 WD40 重复序列（188-510 个氨基酸）和 dSmurf 的 C 端 HECT 结构域（723-1061 个氨基酸）对于它们的结合是必需的。与 Slimb 的相互作用导致 dSmurf 泛素化和降解，从而对 dSmurf 介导的 Yki 磷酸化和 Hippo 途径活性进行负调节。因此，我们的研究揭示了 Hippo 通路的一种新的调节机制，这可能为肿瘤治疗的发展提供启示。
SMAD ubiquitination regulatory factors 1 and 2 (Smurf1/2) are members of the HECT domain E3 ligase family which play crucial roles in the regulation of cell cycle progression, planar cell polarity, cancer metastasis and cell apoptosis. We recently showed that theDrosophilahomolog dSmurf controls the stability of Warts kinase to regulate the Hippo pathway. In the current study, we found that the F-box protein Slimb controls dSmurf protein level to regulate the Hippo pathway. Slimb physically associates with dSmurf as revealed by co-immunoprecipitation assay in S2 cells. The C-terminal WD40 repeats of Slimb (188-510 amino acid) and the C-terminal HECT domain of dSmurf (723-1061 amino acid) are necessary for their binding. Interaction with Slimb leads to the ubiquitination and degradation of dSmurf, resulting in negative regulation of dSmurf-mediated Yki phosphorylation and activity in the Hippo pathway. Thus our study revealed a new regulatory mechanism of the Hippo pathway which may provide implications for developing tumor treatment.