Grant: Discovery Grants Program - Individual

During embryogenesis different species utilize a variety of conserved strategies that facilitate novel cell signaling events. As cell divide within an embryo they are held together by many secreted proteins which need to be altered when cells need to migrate. Guidance by these secreted extracellular matrix (ECM) proteins is fundamental to development, as changes in the ECM facilitates needed novel cell-cell interactions. Matrix metalloproteinases (MMPs) are secreted enzymes that cleave the ECM and thus influence numerous cell migration and signalling events. MMP function is regulated in a number of ways, including the use of secreted inhibitors (tissue inhibitors of MMPs [TIMPs]) and the secretion of most MMPs as zymogens that need to be activated extracellularly through the removal of a pro-peptide. The activation of pro-MMPs is complex and often brought about by other already active MMPs. Membrane type (MT) MMPs are a sub-family of MMPs that are secreted in an active form. Paradoxically, TIMPs work with MT-MMPs to activate pro-MMPs. However the microenvironment is which MMPs are activated is further complicated by the involvement of other cell surface proteins, such as RECK, and, whose actions can also regulate MMP activity. We will use frog embryos to understand how MMPS are regulated directly by TIMPs, as they inhibit their catalytic activity, and indirectly, as TIMPs can regulate other cellular processes that then have secondary effects on MMP functions. As TIMPs have two distinct domains, one that binds MMPs, and the other that binds to cell surface molecules, we will investigate how these domains work together in vivo - in a whole embryo. Other in vitro cell culture work has shown that MMP dependent and independent functions are crucial in regulating proper MMP activity and as such are required in many developmental processes. Using the development of frog as a model system we will generate meaningful data that will contribute much to our understanding the fundamental mechanisms involved in cell migration and signalling as these play many important biological roles.