The role of E-cadherin in regulating signalling pathways

E-钙粘蛋白在调节信号通路中的作用

• 批准号: RGPIN-2019-05220
• 负责人: Wang, Lisheng
• 金额: $ 2.33万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=684462
• 关键词: role; cadherin; regulating; signalling; pathways

Novelty, research program and short-term goal E-cadherin exhibits broad biological functions and is crucial during embryonic development, reprogramming of adult cells to embryonic stem-like cells and adult tissue maintenance/homeostasis. While the majority of studies thus far focus on how growth factors, extracellular signals, transcriptional factors, and intracellular signaling pathways regulate E-cadherin expression, a fundamental question that has been largely overlooked and yet to be answered is whether and to what extent the dynamic E-cadherin expression and its intracellular partners, in turn, affect their regulators to co-control embryonic development and adult cell homeostasis and functions. This will be the long-term goal of our research program. The short-term goal of this proposed project (and hypothesis) will determine whether intracellular partners of E-cadherin and Rap1-regulated E-cadherin recycling differentially affect NF-kB, Wnt and AKT signaling activities and adult cell functions (Fig 1).******Our recent progress and preliminary work related to this proposed research project The trainees in my lab have demonstrated that E-cadherin is capable of actively regulating Wnt signaling in embryonic stem cells (Stem Cells 2010 and 2015, Mol Cell Proteomics 2011, etc.). We recently observed that E-cadherinhigh adult cells markedly inhibits NF-kB whereas upregulating Wnt and Akt activity; Wnt inhibition differentially affects other signaling pathways and the expression of stem cell-associated proteins (preliminary data). ******Short term objectives Adult cells, gain- and loss-of-function and multidisciplinary approaches will be used in three aims. In Aim 1, group 1 trainees will determine which intracellular partners of E-cadherin (-catenin, -catenin, and p120) affect NF-kB, Wnt, and AKT activities, stem cell-associated genes/proteins and cell functions (proliferation, apoptosis, migration and cell cycle). In Aim 2, group 2 trainees will determine the extent by which Rap1-regulated E-cadherin recycling affects three signaling activity. In Aim 3, trainees will determine whether inhibition or activation of one signaling (using gene overexpression, siRNA/shRNA knockdown, and small-molecule activators/inhibitors) differentially affects other two pathways and cell functions in an E-cadherin-intracellular partners-dependent manner.******Significance As part of our research program, knowledge gained from this proposed project will provide new insights into the currently unknown roles of intracellular partners of E-cadherin and Rap1-regulated E-cadherin cycling in the regulation of NF-kB, Wnt, and Akt signaling pathways that are crucial for adult cell functions. This will have broad impacts in cell biology, and will also offer an excellent platform for trainees to prepare their careers for academia or biotechnology companies.**

新奇、研究计划和短期目标E-钙粘蛋白具有广泛的生物学功能，在胚胎发育、成体细胞向胚胎干细胞样细胞重编程和成体组织维持/稳态过程中至关重要。虽然迄今为止大多数研究都集中在生长因子、细胞外信号、转录因子和细胞内信号通路如何调节E-钙粘蛋白表达，但一个基本问题在很大程度上被忽视，尚未得到回答，即动态E-钙粘蛋白表达及其细胞内伴侣是否以及在多大程度上反过来，影响它们的调节因子，共同控制胚胎发育和成体细胞的稳态和功能。这将是我们研究计划的长期目标。本项目的短期目标（和假设）将确定E-cadherin和Rap 1调节的E-cadherin再循环的细胞内伴侣是否差异地影响NF-κ B，Wnt和AKT信号传导活性和成体细胞功能（图1）。我们最近的进展和初步工作与这个拟议的研究项目有关，我实验室的学员已经证明，E-钙粘蛋白能够积极调节胚胎干细胞中的Wnt信号（干细胞2010和2015，分子细胞蛋白质组学2011等）。我们最近观察到，E-cadherinhigh成人细胞显着抑制NF-κ B，而上调Wnt和Akt活性; Wnt抑制差异影响其他信号通路和干细胞相关蛋白的表达（初步数据）。** 短期目标成年细胞、功能获得和丧失以及多学科方法将用于三个目标。在目标1中，第1组受训者将确定哪些E-钙粘蛋白的细胞内伴侣（-catenin，-catenin和p120）影响NF-κ B，Wnt和AKT活性，干细胞相关基因/蛋白和细胞功能（增殖，凋亡，迁移和细胞周期）。在目标2中，第2组学员将确定Rap 1调节的E-钙粘蛋白再循环影响三种信号传导活性的程度。在目标3中，学员将确定一种信号传导的抑制或激活（使用基因过表达，siRNA/shRNA敲低和小分子激活剂/抑制剂）是否以E-钙粘蛋白-细胞内伴侣依赖性方式差异影响其他两种途径和细胞功能。意义作为我们研究计划的一部分，从这个拟议的项目中获得的知识将提供新的见解，目前未知的作用，细胞内的合作伙伴的E-钙粘蛋白和Rap 1调节的E-钙粘蛋白循环的调节NF-κ B，Wnt和Akt信号通路，是至关重要的成人细胞功能。这将对细胞生物学产生广泛的影响，也将为学员提供一个很好的平台，为学术界或生物技术公司的职业生涯做好准备。