β-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis.
β-Catenin destruction complex-independent regulation of Hippo-YAP signaling by APC in intestinal tumorigenesis.
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DOI：
10.1101/gad.264515.115
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发表时间：
2015-07-15
影响因子：
10.5
通讯作者：
Pan D
中科院分区：
文献类型：
--
作者：
Cai J;Maitra A;Anders RA;Taketo MM;Pan D
蔡等人。结果表明，除了在Wnt-β-catenin信号转导中发挥作用外，APC还发挥支架蛋白的作用，通过与Sav1和Lats1相互作用促进河马激活级联反应。他们还发现，YAP对于APC缺陷性腺瘤的发展是绝对必要的。家族性腺瘤性息肉病(FAP)是一种以大肠息肉广泛发展为特征的遗传性癌症综合征。APC是β-连环蛋白破坏复合体中的一种支架蛋白，其活性被典型的Wnt信号拮抗。其他效应通路是否介导APC的肿瘤抑制功能尚不清楚。在此，我们报告，河马信号通路下游效应物YAP的激活是FAP患者管状腺瘤的一个普遍特征。我们证明了APC作为一种支架蛋白，通过与Sav1和Lats1相互作用促进河马激酶级联反应。与APC和河马信号通路之间的分子联系一致，遗传分析表明YAP在APC缺陷性腺瘤的发展中是绝对必要的。这些发现证实了河马-YAP信号是APC下游的一个关键效应通路，独立于它对β-连环蛋白破坏复合体的参与。
Cai et al. show that, besides its role in Wnt–β-catenin signaling, APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. They also find that YAP is absolutely required for the development of APC-deficient adenomas. Mutations in Adenomatous polyposis coli (APC) underlie familial adenomatous polyposis (FAP), an inherited cancer syndrome characterized by the widespread development of colorectal polyps. APC is best known as a scaffold protein in the β-catenin destruction complex, whose activity is antagonized by canonical Wnt signaling. Whether other effector pathways mediate APC's tumor suppressor function is less clear. Here we report that activation of YAP, the downstream effector of the Hippo signaling pathway, is a general hallmark of tubular adenomas from FAP patients. We show that APC functions as a scaffold protein that facilitates the Hippo kinase cascade by interacting with Sav1 and Lats1. Consistent with the molecular link between APC and the Hippo signaling pathway, genetic analysis reveals that YAP is absolutely required for the development of APC-deficient adenomas. These findings establish Hippo–YAP signaling as a critical effector pathway downstream from APC, independent from its involvement in the β-catenin destruction complex.