Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer.
Distinct Interactions of EBP1 Isoforms with FBXW7 Elicits Different Functions in Cancer.
复制标题
EBP1 同工型与 FBXW7 的独特相互作用在癌症中引发不同的功能
DOI：
10.1158/0008-5472.can-16-2246
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发表时间：
2017-04-15
期刊：
影响因子：
11.2
通讯作者：
Wei G
中科院分区：
文献类型：
--
作者：
Wang Y;Zhang P;Wang Y;Zhan P;Liu C;Mao JH;Wei G
ErbB 3受体结合蛋白EBP 1编码两种可变剪接的同种型p48和p42。虽然有证据表明这些亚型在肿瘤发生中的不同作用，但对其潜在机制知之甚少。在这里，我们证明了EBP 1亚型与SCF型泛素连接酶FBXW 7以不同的方式相互作用，在肿瘤发生中发挥相反的作用。EBP 1 p48作为FBXW 7的致癌底物与FBXW 7的WD结构域结合。EBP 1 p48结合使FBXW 7 α与胞质溶胶隔离，调节其在蛋白质降解中的作用并减弱其肿瘤抑制功能。相比之下，EBP 1 p42既与FBXW 7的F-box结构域结合，也与FBXW 7底物结合。EBP 1 p42的这种衔接子功能稳定了FBXW 7与其底物的相互作用，并促进了FBXW 7介导的致癌靶点降解，增强了其整体肿瘤抑制功能。总的来说，我们的研究结果建立了FBXW 7和EBP 1亚型之间不同的物理和功能相互作用，这些相互作用产生了EBP 1在癌症中独特的亚型特异性功能。
The ErbB3 receptor binding protein EBP1 encodes two alternatively spliced isoforms p48 and p42. While there is evidence of differential roles for these isoforms in tumorigenesis, little is known about their underlying mechanisms. Here we demonstrate that EBP1 isoforms interact with the SCF-type ubiquitin ligase FBXW7 in distinct ways to exert opposing roles in tumorigenesis. EBP1 p48 bound to the WD domain of FBXW7 as an oncogenic substrate of FBXW7. EBP1 p48 binding sequestered FBXW7α to the cytosol, modulating its role in protein degradation and attenuating its tumor suppressor function. In contrast, EBP1 p42 bound to both the F-box domain of FBXW7 as well as FBXW7 substrates. This adapter function of EBP1 p42 stabilized the interaction of FBXW7 with its substrates and promoted FBXW7-mediated degradation of oncogenic targets, enhancing its overall tumor suppressing function. Overall, our results establish distinct physical and functional interactions between FBXW7 and EBP1 isoforms which yield their mechanistically unique isoform-specific functions of EBP1 in cancer.