Spatial and temporal regulation of cell adhesion and intracellular trafficking by Armus

上皮细胞形成体内许多不同组织和器官的重要组成部分，它们将任何腔和外表面包裹为单独的隔室，防止水分流失，病原体感染，并促进液体，空气和营养物质的交换。要做到这一点，上皮细胞必须彼此紧密附着。许多研究调查了这些细胞如何在它们之间牢固地粘合，以及当细胞分裂时，在伤口愈合迁移，病原体入侵和其他慢性疾病期间，它们的附着如何被操纵。因此，细胞-细胞接触的破坏是上皮病理学的一个关键特征，必须严格调控以维持健康的组织和器官。保持上皮片完整的一个关键事件是细胞-细胞接触处的粘附受体的量。通过损害连接处粘附受体的水平和定位，上皮完整性受损并且更容易破坏。我们的建议将解剖机制，导致删除和破坏的细胞间粘附分子命名为E-钙粘蛋白刺激生长因子EGF。虽然EGF对上皮的发育和维持很重要，但在不同的病理学中，包括癌症，都观察到其受体在细胞中的异常激活。然而，EGF过度刺激导致E-cadherin降解的确切机制尚不清楚。Armus是我们实验室鉴定的一种蛋白质，它控制着E-cadherin在称为溶酶体的细胞室中的降解，在那里处理不需要的材料。在这里，我们的目标是剖析当细胞受到EGF治疗刺激而远离它们的同伴时，Armus是如何被调节的，是什么控制了它在连接处或溶酶体的定位，以及对Armus在空间和时间上的精确激活至关重要的结合蛋白。我们的研究将为基本的生物学问题提供深入的见解，即在稳态和刺激时，是什么控制着相同蛋白质在细胞内不同隔室的分布和功能。通过研究Armus调节的机制，我们将确定潜在的方法来阻断Armus功能，以损害E-钙粘蛋白的降解。重要的是，这些知识将有益于我们的模型系统之外的治疗策略：（i）溶酶体功能的特异性抑制剂不可用，以及（ii）存在许多病理学，其中细胞内物质的降解是功能障碍的，例如在神经退行性疾病中，杀死内化的细菌等。

Epithelial cells form an important component of many different tissues and organs in the body, where they wrap up any cavity and external surfaces as separate compartments, protect against water loss, pathogen infection and facilitate the exchange of fluids, air and nutrients. To do so, epithelial cells must be tightly attached to each other. Many studies investigate how these cells glue strongly among themselves and how their attachment can be manipulated when cells divide, during wound healing migration, invasion by pathogens and other chronic diseases. Disruption of cell-cell contacts is thus a key feature of epithelial pathologies and must be tightly regulated to maintain healthy tissues and organs.A key event to keep epithelial sheets intact is the amount of adhesive receptors at cell-cell contacts. By impairing the levels and localization of adhesion receptors at junctions, epithelial integrity is compromised and easier to disrupt. Our proposal will dissect mechanisms leading to removal and the destruction of a cell-cell adhesion molecule named E-cadherin following stimulation with the growth factor EGF. Although EGF is important for epithelial development and maintenance, aberrant activation of its receptor in cells is observed in different pathologies, including cancer. Yet, the precise mechanisms via which EGF over-stimulation leads to E-cadherin degradation are not well understood.Armus is a protein identified in our lab that controls the degradation of E-cadherin in a cell compartment called lysosome, where degradation of unwanted material is processed. Here we aim to dissect how Armus is regulated when cells are stimulated to move away from their peers by EGF treatment, what controls its localization at junctions or lysosomes, and the binding proteins that are important for the precise activation of Armus in space and time. Our studies will provide insights into fundamental biological questions as to what controls the distribution and function of the same protein into different compartments inside the cell at steady-state and upon stimulation.By investigating the mechanisms of Armus regulation, we will identify potential ways to block Armus function to impair degradation of E-cadherin. Importantly, such knowledge will be beneficial in therapeutic strategies beyond our model system: (i) specific inhibitors of lysosomal function are not available and (ii) there are a number of pathologies where degradation of intracellular material is mal-functioning, such as in neurodegenerative diseases, killing internalised bacteria, etc.