PDF(Pubmed)
Abstract：
The transmembrane E3 ligases RNF43 and ZNRF3 perform key tumour suppressor roles by inducing endocytosis of members of the Frizzled (FZD) family, the primary receptors for WNT. Loss-of-function mutations in RNF43 and ZNRF3 mediate FZD stabilisation and a WNT-hypersensitive growth state in various cancer types. Strikingly, RNF43 and ZNRF3 mutations are differentially distributed across cancer types, raising questions about their functional redundancy. Here, we compare the efficacy of RNF43 and ZNRF3 of targeting different FZDs for endocytosis. We find that RNF43 preferentially down-regulates FZD1/FZD5/FZD7, whereas ZNRF3 displays a preference towards FZD6. We show that the RNF43 transmembrane domain (TMD) is a key molecular determinant for inducing FZD5 endocytosis. Furthermore, a TMD swap between RNF43 and ZNRF3 re-directs their preference for FZD5 down-regulation. We conclude that RNF43 and ZNRF3 preferentially down-regulate specific FZDs, in part by a TMD-dependent mechanism. In accordance, tissue-specific expression patterns of FZD homologues correlate with the incidence of RNF43 or ZNRF3 cancer mutations in those tissues. Consequently, our data point to druggable vulnerabilities of specific FZD receptors in RNF43- or ZNRF3-mutant human cancers.
摘要：
跨膜E3连接酶RNF43和ZNRF3通过诱导Frizzled（FZD）家族成员的内吞作用来发挥关键的肿瘤抑制作用，WNT的主要受体。RNF43和ZNRF3中的功能丧失突变在各种癌症类型中介导FZD稳定和WNT超敏生长状态。引人注目的是，RNF43和ZNRF3突变在癌症类型中差异分布。对它们的功能冗余提出质疑。这里,我们比较了RNF43和ZNRF3靶向不同FZD内吞的疗效。我们发现RNF43优先下调FZD1/FZD5/FZD7，而ZNRF3则显示出对FZD6的偏好。我们表明RNF43跨膜结构域（TMD）是诱导FZD5内吞的关键分子决定因素。此外，RNF43和ZNRF3之间的TMD交换重新引导了他们对FZD5下调的偏好。我们得出结论，RNF43和ZNRF3优先下调特定的FZDs，部分是由TMD依赖机制。InAccording,FZD同源物的组织特异性表达模式与这些组织中RNF43或ZNRF3癌症突变的发生率相关。因此,我们的数据表明RNF43或ZNRF3突变人类癌症中特定FZD受体的药物易损性.
