Mechanism of YAP/TAZ crosstalk with Wnt signaling

YAP/TAZ 与 Wnt 信号的串扰机制

基本信息

批准号：
10328901
负责人：
Junhao Mao
金额：
$ 36.87万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10328901
关键词：
Address Alleles Animal Model Binding Cells Chemicals Critical Pathways Disease Event Excision Gastrointestinal tract structure Genes Genetic Genetic Transcription Genetic study Grant Growth Homeostasis Intestinal Neoplasms Intestines MYC gene Malignant Neoplasms Mediating Mediator of activation protein Molecular Mutate Nuclear Oncogenic Output Pathway interactions Phosphotransferases Play Proteins Proteomics Proto-Oncogenes Regulation Reporting Research Personnel Role Signal Pathway Signal Transduction Testing Therapeutic Time Tissues Transcription Factor AP-1 Transcription Repressor Transcriptional Activation Ubiquitination WNT Signaling Pathway Work beta catenin design in vivo insight intestinal crypt intestinal epithelium intestinal homeostasis intestinal tumorigenesis knockout animal novel novel therapeutic intervention palmitoylation progenitor programs small molecule inhibitor stem cell division stem cells therapeutic target transcription factor tumor growth tumorigenesis

项目摘要

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.

概括 Hippo 和 Wnt 信号通路与组织稳态和肿瘤发生密切相关。然而，这两种途径如何串扰仍然是一个难以捉摸的问题，并且一直是一个激烈争论的问题。 YAP/TAZ（Hippo 信号传导的细胞内介质）对 Wnt 信号传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有关功能和功能的争议这两个重要途径之间的信号相互作用在肠上皮细胞中存在 Wnt 信号传导。在控制干细胞更新和分化中发挥着关键作用，我们最近的工作表明，Lats1/2，核心 Hippo 激酶是维持肠道干细胞中 Wnt 信号传导所必需的。我们证明了 Lats1/2。去除以细胞自主方式抑制肠道中 APC/β-Catenin 下游的 Wnt 通路。这笔资助，我们将结合遗传、蛋白质组学和化学方法来剖析分子肠道中 YAP/TAZ-Wnt 串扰的基础在特定目标 1 中，我们将检查 YAP/TAZ 的能力。使用两个新的条件等位基因抑制野生型和 APC 突变肠道中的 Wnt/TCF 激活我们最近生成的核 YAP/TAZ 我们还将确定核的分子机制。 YAP/TAZ 抑制 APC 下游的 Wnt/TCF 转录激活。在特定目标 2 中，我们定义了 Wnt-。 APC 和 Lats1/2 突变肠上皮中解偶联的 TEAD 依赖性下游程序和使用动物模型探索针对肠道肿瘤的 TEAD 治疗。