名校学者解读Wnt/β连环蛋白

Wnt/β连环蛋白信号肽在癌症中扮演了关键的角色，研究表明β-catenin 在癌症的引发和发展进程中起到关键作用。一个由哈佛大学、斯坦福大学等机构的科研人员在这一方面的研究上取得新突破，相关论文发表在2012年12月13日的Cell杂志上。

Wnt/β-连环蛋白信号途径在动物生长发育过程中发挥了重要作用。一旦该通路中相关信号传递发生异常改变, 就可能导致该通路异常活化, 从而影响生物的胚胎发育、能量代谢等一系列生理过程, 甚至会导致肿瘤的发生及恶化。

YAP（Yes—assoeiatedprotein）即Yes相关蛋白，是一种连接蛋白和转录共激活因子，在正常机体细胞内发挥着信号转导和基因转录调节的作用。近年研究发现，YAP是Hippo通路中的靶因子，该通路通过抑制YAP的活性调控细胞增生和凋亡间平衡，抑制组织细胞过度生长。

为破解β-catenin的具体作用机制，研究人员对85种癌细胞中β-catenin的活化进行分类，结果发现了YAP1的调整作用在β-catenin活化癌细胞信号网络中起到关键作用，YAP1和TBX5转录因子和β-catenin形成复合体。Yap 1通过酪氨酸激酶YES1磷酸化，结果推动BCL2L1和BIRC5等细胞抗凋亡基因定位。这样一个小分子抑制剂阻碍扩散癌症细胞系和动物模型中β- catenin依赖的癌细胞增殖。这些结果表明β- catenin-yap1-tbx5复合体是β- catenin活化癌细胞中起到至关重要的作用。

原文摘要：

β-Catenin-Driven Cancers Require a YAP1 Transcriptional Complex for Survival and Tumorigenesis

Wnt/β-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for cancer initiation and progression. To decipher the role of β-catenin in transformation, we classified β-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that β-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with β-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of β-catenin-dependent cancers in both cell lines and animal models. These observations define a β-catenin-YAP1-TBX5 complex essential to the transformation and survival of β-catenin-driven cancers.