Role of MT1-matrix metalloproteinase in regulating cell signalling and cell invasion.

MT1-基质金属蛋白酶在调节细胞信号传导和细胞侵袭中的作用。

• 批准号: RGPIN-2018-06665
• 负责人: Damjanovski, Sashko
• 金额: $ 2.33万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=713994
• 关键词: Role; MT1; matrix; metalloproteinase; regulating

Multicellular organisms are composed of trillions of cells held together by secreted proteins called the ECM. However, cells must move, as cell movement is fundamental to embryogenesis. Whether it is the global movements of many cells that shape our entire body plan, or the complicated folding of tissues to form a heart, or the extension of nerves from the central nervous system to innervate a muscle, the movement of groups of cells, individual cells, or even parts of cells, is essential. Cell movement requires the coordination of many biological events. The cells must be signalled when and where to go (get up, move in this direction), and then manifest these signals into the proper cellular machinery needed to facilitate movement. Cell movement involves changes in shape, as the cell pushes out membrane protrusions in a given direction, but movement may also require the passage through the ECM barrier. This passage requires the cells to remodel the ECM in a process termed invasion. Thus, movement must coordinate changes in cell shape, with invasion requiring the additional step of ECM remodelling. During embryogenesis cells elegantly communicate with each other to coordinate which cells move. Such cell movement is rare in adults, but does occur during wound healing, immune responses, pregnancy, and is problematic in disease, where unregulated movement by cells causes problems. The central focus of my research program is to understand how cells interpret extracellular signals to coordinate changes in cell shape and their ability to degrade the ECM. The central player is an enzyme called membrane type 1 matrix metalloproteinase (MT1-MMP), a member of the enzyme family responsible for remodelling the ECM. As with cell movement, these enzymes play important roles during development and disease, but are relatively quiet in adult tissues. MT1-MMP is uniquely special. It is the only family member that is absolutely required during development. And it has a structure whereby it sits on the membrane of a cell. Here it can both remodel the ECM but, as importantly, it can bind to signalling molecule outside of the cell and transmit these signals into the cell to alter the migration machinery. Also, MT1-MMP can bind dozens of external molecules, and turn on several intracellular processes. We aim to see how different external molecules bind to MT1-MMP to trigger different movement mechanisms (to send out a cell protrusion, or to degrade the local ECM etc). While cell movements are critical during embryogenesis, the numerous cell types found in an embryo make it difficult to examine MT1-MMP signals in individual cells. Thus, we will use cells grown in culture; cells that have MT1-MMP, lack MT1-MMP, or that have mutated MT1-MMP that cannot signal into the cell. These cells will be used to investigate the roles played by MT1-MMP in coordinating external signals to regulate cell movement events that are fundamental to embryogenesis.

多细胞生物是由数万亿个细胞组成的，这些细胞是由被称为ECM的分泌蛋白结合在一起的。然而，细胞必须运动，因为细胞运动是胚胎发生的基础。无论是形成我们整个身体结构的许多细胞的整体运动，还是形成心脏的组织的复杂折叠，还是从中枢神经系统延伸到支配肌肉的神经，细胞群、单个细胞甚至部分细胞的运动都是必不可少的。细胞运动需要许多生物事件的协调。细胞必须在何时何地得到信号（起身，朝这个方向移动），然后将这些信号显示到适当的细胞机制中，以促进运动。细胞运动包括形状的改变，因为细胞将膜突起向特定方向推出，但运动也可能需要通过ECM屏障。这一过程需要细胞在称为侵袭的过程中重塑ECM。因此，运动必须协调细胞形状的变化，入侵需要额外的ECM重塑步骤。在胚胎发生过程中，细胞之间优雅地相互沟通，协调哪个细胞移动。这种细胞运动在成人中很少见，但在伤口愈合、免疫反应、怀孕期间确实会发生，并且在疾病中是有问题的，在疾病中，细胞不受控制的运动会导致问题。我的研究计划的中心焦点是了解细胞如何解释细胞外信号，以协调细胞形状的变化及其降解ECM的能力。