Mechanism of YAP/TAZ crosstalk with Wnt signaling

总结 Hippo和Wnt信号通路与组织稳态和肿瘤发生密切相关。 然而，这两条通路如何相互影响仍然是一个难以捉摸的问题，一直是一个激烈的争论。两 Hippo信号转导的细胞内介质雅普/TAZ对Wnt信号转导的正向和负向调节， 已经报道，显然需要进一步的研究来解决关于功能和 这两个重要的信号通路之间的相互作用。在肠上皮中，Wnt信号传导 在控制干细胞更新和分化中起着关键作用，我们最近的工作表明Lats 1/2， 核心Hippo激酶是维持肠干细胞中Wnt信号传导所必需的。我们证明了Lats 1/2 去除以细胞自主方式抑制肠中APC/β-连环蛋白下游的Wnt途径。在 这项资助，我们将使用遗传学，蛋白质组学和化学方法的组合来剖析分子 肠中雅普/TAZ-Wnt串扰的基础。在具体目标1中，我们将检查雅普/TAZ的能力， 在野生型和APC突变的肠中抑制Wnt/TCF活化，使用两个新的条件等位基因， 我们最近生成的核雅普/TAZ。我们还将确定核反应的分子机制， 雅普/TAZ抑制APC下游的Wnt/TCF转录激活。在具体目标2中，我们定义Wnt- APC和Lats 1/2突变的肠上皮细胞中的非偶联TEAD依赖性下游程序， 使用动物模型探索TEAD在肠道肿瘤中的治疗靶向。

SUMMARY The Hippo and Wnt signaling pathways are intimately associated with tissue homeostasis and tumorigenesis. However, how these two pathways crosstalk remains elusive and has been a matter of intense debate. Both positive and negative regulation of Wnt signaling by YAP/TAZ, the intracellular mediators of Hippo signaling, has been reported, and further studies are clearly required to resolve the controversy regarding the functional and signaling interactions between these two important pathways. In the intestinal epithelium where Wnt signaling plays a pivotal role in controlling stem cell renewal and differentiation, our recent work demonstrated that Lats1/2, the core Hippo kinases, are required for sustaining Wnt signaling in intestinal stem cells. We showed that Lats1/2 removal inhibits Wnt pathway downstream of APC/β-Catenin in the intestine in a cell-autonomous manner. In this grant, we will use a combination of genetic, proteomic and chemical approaches to dissect the molecular basis of the YAP/TAZ-Wnt crosstalk in the intestine. In Specific Aim 1, we will examine the ability of YAP/TAZ to inhibit Wnt/TCF activation in both wild type and APC mutated intestine, using two new conditional alleles of nuclear YAP/TAZ we recently generated. We will also determine the molecular mechanism by which nuclear YAP/TAZ suppress Wnt/TCF transcriptional activation downstream of APC. In Specific Aim 2, we define the Wnt- uncoupled TEAD-dependent downstream programs in APC- and Lats1/2- mutated intestinal epithelium and explore therapeutic targeting TEAD in intestinal tumors using animal models.