Abstract

The long-term goal of the research in our group is to understand the mechanism of cell migration in tissue. In particular, we are studying one of the key cell surface proteinases, MT1 -MMP, during cell migration. ECM plays a major role to maintain the architecture of tissues by filling the gap between cells, to provide survival signals and differentiation signals to cells, to provide growth factor pools and scaffoldings for migration. On the other hand, ECM is also a physical barrier for migrating cells in tissues and needs to be degraded in order for cells to migrate through. Because cells require ECM as scaffolding, degradation of the barrier ECM needs to occur specifically at the direction of the migration. To degrade ECM barrier, cells utilise proteinases, and one of the plasma membrane-bound metalloproteinase, membrane-type 1 matrix metalloproteinase (MT1-MMP) is thought to be a critical enzyme for this process. MT1 -MMP is a type I transmembrane proteinase and it degrades various ECM components such as collagens type-I, -II, -III, fibronectin, laminins, fibrin, aggrecan and so on. It also activates other matrix metalloproteinases (MMPs) namely MMP -2 and MMP13 that have different array of substrate specificities. Therefore, expression of MT1 -MMP can create multiple enzyme activities.

MT1 -MMP is implicated in many physiological processes and diseases such as wound healing, bone development, angiogenesis, atherosclerosis, cancer progression, and rheumatoid arthritis. A common feature of these events is a cellular migration/invasion in tissues, and MT1 -MMP is playing a major role. Such event can be recapiturated by overexpressing the enzyme in the cells which results in enhanced cell motility. MT1 -MMP activity on the cell surface is precisely regulated not only as a proteinase but also as a membrane protein. We have demonstrated that such cellular regulation is essential for MT1 -MMP to promote cellular invasion. Disturbing one of the mechanisms supporting its function is enough to inactivate its cell migration promoting activity.

Therefore, our group is currently focusing on critical cellular mechanisms that control MT1 -MMP in the hope that we would find new means to regulate MT1 -MMP function and new treatment of the diseases such as cancer and rheumatoid arthritis. We employ biochemical, molecular biological, cell biological and structural techniques and insights to attack these problems.