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

Armus 对细胞粘附和细胞内运输的时空调节

• 批准号: BB/M022617/1
• 负责人: Vania Braga
• 金额: $ 47.11万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM022617%2F1
• 关键词: Spatial; temporal; regulation; cell; adhesion

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.

上皮细胞是体内许多不同组织和器官的重要组成部分，它们将任何腔体和外部表面包裹成单独的隔间，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相连。许多研究调查了这些细胞如何强烈地相互粘合，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，它们的附着是如何被操纵的。因此，细胞-细胞接触的破坏是上皮病理学的一个关键特征，必须受到严格的调控，以维持健康的组织和器官。保持上皮层完整的一个关键事件是细胞-细胞接触处的粘附性受体的数量。通过损害黏附受体在连接处的水平和定位，上皮的完整性受到损害，更容易被破坏。我们的建议将剖析在生长因子EGF刺激下，导致一种名为E-钙粘素的细胞-细胞黏附分子被移除和破坏的机制。虽然EGF对上皮的发育和维持很重要，但在包括癌症在内的不同病理情况下，EGF受体在细胞中的异常激活都被观察到。然而，EGF过度刺激导致E-钙粘附素降解的确切机制尚不清楚。Armus是我们实验室发现的一种蛋白质，它控制着E-钙粘附素在一个名为溶酶体的细胞室中的降解，在那里处理不需要的物质的降解。在这里，我们旨在剖析当EGF刺激细胞远离同行时Armus是如何被调控的，是什么控制了它在连接或溶酶体上的定位，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洞察力，即在稳态和刺激时，是什么控制同一蛋白质在细胞内的不同隔室中的分布和功能。通过研究Armus的调节机制，我们将找到潜在的方法来阻断Armus的功能，以削弱E-钙粘附素的降解。重要的是，这些知识将有助于我们的模型系统以外的治疗策略：(I)溶酶体功能的特定抑制剂不可用，(Ii)在许多病理情况下，细胞内物质的降解功能不正常，例如在神经退行性疾病、杀死内化细菌等方面。

项目成果

Rac1-PAK1 regulation of Rab11 cycling promotes junction destabilization.

RAC1-PAK1 RAB11循环的调节促进了连接处的稳定化。

• DOI: 10.1083/jcb.202002114
• 发表时间: 2021-06-07
• 期刊: The Journal of cell biology
• 作者: Erasmus JC;Smolarczyk K;Brezovjakova H;Mohd-Naim NF;Lozano E;Matter K;Braga VMM
• 通讯作者: Braga VMM

Intrinsic cell rheology drives junction maturation.

• DOI: 10.1038/s41467-022-32102-9
• 发表时间: 2022-08-17
• 期刊: Nature communications
• 影响因子: 16.6

Editorial Overview: Integration of dynamic processes in cell behaviour and tissue architecture.

编辑概述：细胞行为和组织结构中动态过程的整合。

• DOI: 10.1016/j.ceb.2018.09.005
• 发表时间: 2018
• 期刊: Current opinion in cell biology
• 影响因子: 7.5
• 作者: Braga VM

Defining functional interactions during biogenesis of epithelial junctions.

• DOI: 10.1038/ncomms13542
• 发表时间: 2016-12-06
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Erasmus, J. C.;Bruche, S.;Pizarro, L.;Maimari, N.;Pogglioli, T.;Tomlinson, C.;Lees, J.;Zalivina, I.;Wheeler, A.;Alberts, A.;Russo, A.;Braga, V. M. M.
• 通讯作者: Braga, V. M. M.