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

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。核心参与者是一种被称为膜型1基质金属蛋白酶（MT1-MMP）的酶，它是负责重塑ECM的酶家族的成员。与细胞运动一样，这些酶在发育和疾病中发挥重要作用，但在成人组织中相对安静。MT1-MMP是独一无二的。它是开发过程中绝对需要的唯一家庭成员。它有一个结构，它位于细胞膜上。在这里，它既可以重塑ECM，但同样重要的是，它可以与细胞外的信号分子结合，并将这些信号传递到细胞内，以改变迁移机制。此外，MT1-MMP可以结合几十个外部分子，并启动几个细胞内过程。我们的目标是观察不同的外部分子如何与MT1-MMP结合以触发不同的运动机制（发送细胞突起，或降解局部ECM等）。虽然细胞运动在胚胎发生过程中至关重要，但胚胎中发现的众多细胞类型使得检测单个细胞中的MT1-MMP信号变得困难。因此，我们将使用培养的细胞；有MT1-MMP的细胞，缺乏MT1-MMP的细胞，或有突变的MT1-MMP不能向细胞发出信号的细胞。这些细胞将用于研究MT1-MMP在协调外部信号以调节胚胎发生的基本细胞运动事件中所起的作用。

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.