Nuclear functions of catenin subfamilies

描述(由申请人提供)：脊椎动物连环蛋白在细胞核中的作用是什么，它们如何对共同或不同的发育或疾病结果做出贡献？与现有文献中对β-连环蛋白的主要关注形成鲜明对比的是，我们将探索 P120-连环蛋白和蛋白亲和素3-连环蛋白的核作用。尽管它们在发育和人类病理学中发挥了关键作用，但人们对它们知之甚少。我们最近发现，p120和其他连环蛋白是通过Wnt途径作用于β-连环蛋白来调节的。因此，我们问Wnt(或其他)信号是否可能涉及更大的连环蛋白网络，其核活动尚未确定。为这些国家的核功能提供了强有力的切入点 “其他连环蛋白”，我们最近发现了两个新的复合体，分别涉及p120-连环蛋白和蛋白亲和素3-连环蛋白。第一个是p120-连环蛋白与REST/COREST的复合体(目标1)，第二个是PLAKAPILIN 3-连环蛋白与ETV1的复合体(目标2)。鉴于REST/COREST和ETV1在干细胞、发育和病理学中的重要性，对这些复合体的了解将对多个科学领域产生影响。最后，为了向科学界提供一个亟需但目前缺乏的连环蛋白核功能概述，我们将对来自三个不同亚家族的代表性连环蛋白进行第一次全基因组范围的比较评估(目标3)。我们将在AIMS 1和AIMS 2中使用非洲爪哇胚胎和哺乳动物细胞系进行机制和功能研究，并使用小鼠胚胎干细胞(MESCs)在AIMS 3中对核连环蛋白进行全基因组分析。我们的假设是，p120和PLAK亲和素亚家族的连环蛋白与更好地了解的β-连环蛋白一样，在脊椎动物的发育和疾病过程中发挥网络核能力。目的1.揭示新的p120-连环蛋白的核功能：REST/COREST复合体。目的2.揭示新的Pkp3-catenin：ETV1复合体的核功能。目的3.全基因组分析p120-、PLAK-3-和β-连环蛋白的核功能。β-连环蛋白和经典的Wnt信号在发育和人类疾病中的关键性质已经确定，然而，同样在人类胚胎发育和疾病中发挥关键作用的额外连环蛋白的核贡献却知之甚少。通过深入研究我们发现的两个新的连环蛋白复合体(分别涉及p120-和Pkp3-连环蛋白)的核作用，以及在更广泛的全基因组水平上揭示这些连环蛋白的核作用，我们将产生第一个理解，即我们假设的是维持健康所需的连环蛋白功能的整合网络。

DESCRIPTION (provided by applicant): What are the roles of vertebrate catenins in the nucleus, and how do they contribute to shared or distinct developmental or disease outcomes? In sharp contrast to the dominant focus upon beta-catenin in the existing literature, we will probe the nuclear roles of p120-catenin and plakophilin3-catenin. Each is poorly understood despite playing key roles in development and human pathology. We recently revealed that p120 and additional catenins are regulated via Wnt-pathway mechanisms known to act upon beta-catenin. We thus ask if Wnt (or other) signals may involve a larger catenin network whose nuclear activities have yet to be defined. Providing a strong entry point to the nuclear functions of these "other catenins", we recently discovered two novel complexes that respectively involve p120-catenin and plakophilin3-catenin. The first complex is of p120-catenin with REST/CoREST (Aim 1), and the second is of plakophilin3-catenin with ETV1 (Aim 2). Given the importance of REST/CoREST and ETV1 in stem cells, development and pathology, an understanding of these complexes will have an impact upon multiple scientific fields. Finally, to provide the scientific community with a much needed but currently absent overview of catenin nuclear functions, we will undertake the first genome-wide comparative evaluation of representative catenins from three distinct subfamilies (Aim 3). We will employ Xenopus embryos and mammalian cell lines for mechanistic and functional studies in Aims 1 and 2, and mouse embryo stem cells (mESCs) for our genome wide analysis of nuclear catenins in Aim 3. Our Hypothesis is that catenins of the p120- and plakophilin-subfamilies, in common with the much better known beta-catenin, act in networked nuclear capacities during vertebrate development and disease. Aim 1. Reveal nuclear functions of the novel p120-catenin:REST/CoREST complex. Aim 2. Reveal nuclear functions of the novel Pkp3-catenin:ETV1 complex. Aim 3. Genome-wide analysis of p120-, plakophilin3-, and beta-catenin nuclear functions. The key nature of beta-catenin and canonical Wnt signaling in development and human disease is firmly established, yet the nuclear contributions of additional catenins, that likewise play key roles in human embryogenesis and disease, is in contrast poorly understood. By in-depth examination of the nuclear roles of two novel catenin complexes we have discovered (respectively involving p120- and Pkp3-catenin), as well as revealing these catenins' nuclear roles on a much wider whole-genome level, we will produce the first understanding of what we hypothesize is an integrated network of catenin functions needed to maintain health.