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

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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.