Mechanism of YAP/TAZ crosstalk with Wnt signaling

YAP/TAZ 与 Wnt 信号的串扰机制

• 批准号: 10552565
• 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
• 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/10552565
• 关键词: 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; Molecular; Mutate; Nuclear; Oncogenic; Output; Pathway interactions; Phosphorylation; 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

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.

摘要 河马和Wnt信号通路与组织动态平衡和肿瘤发生密切相关。 然而，这两条道路的串扰如何仍然难以捉摸，也一直是一个激烈辩论的问题。两者都有 河马信号的细胞内介体YAP/TAZ对Wnt信号的正负调节 已经有报道，显然需要进一步的研究来解决关于功能性和 这两条重要通路之间的信号相互作用。在肠上皮细胞中，Wnt信号 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Lats1/2， 核心河马蛋白是肠道干细胞维持Wnt信号所必需的。我们展示了Lats1/2 清除以一种细胞自主的方式抑制肠道APC/β-连环蛋白下游的Wnt通路。在……里面 这笔赠款，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 肠道内YAP/TAZ-WNT串扰的基础。在具体目标1中，我们将审查YAP/TAZ的能力 使用两个新的条件等位基因抑制野生型和APC突变的肠道中Wnt/TCF的激活 我们最近产生的核YAP/TAZ。我们还将确定原子核的分子机制 YAP/TAZ抑制APC下游Wnt/Tcf转录激活。在具体目标2中，我们定义了WNT- APC和Lats1/2突变的肠上皮中依赖tead的解偶联下游程序和 利用动物模型探索肠道肿瘤的靶向治疗。