MT1-MMP regulation of matrix degradation and cell movement.

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Multicellular organisms are composed of trillions of cells held together by secreted extracellular matrix (ECM) proteins. Cells movement thus requires an orchestrated effort that involves cell communication, re-arrangements, and possibly the degradation of the ECM. Cell invasion is a type of cell migration through tissues that requires the degradation of the ECM. Cell migration is often activated by surface receptor triggered signalling cascades and changes in cell shape. Cell invasion, which is rare in adults, but crucial during embryogenesis and plays critical roles in adult wound healing, pregnancy, and in many diseases, is enabled by ECM degradation brought about by a family of 24 secreted enzymes called matrix metalloproteinases (MMPs). MMPs are often expressed in both migrating and invading cells. But the movement of cells through tissues is not simply dependent on ECM degradation, as inhibiting MMP enzymatic activity is not always associated with impaired migration nor invasion. Our objectives are to identify the roles played by a key membrane type MMP, MT1-MMP in orchestrating the movement of cells. While lack of MMP presence during embryogenesis does results in inappropriate ECM remodelling and associated vascular and skeletal defects, only the lack of MT1-MMP is embryonic lethal. While most MMPs are released from the cell surface, membrane bound MT1-MMP can also transduce signals into the cell. This, and our more recent work in frog and with 2D and 3D cell cultures has demonstrated a fundamental role for MT1-MMP, one which we believe is key to governing cell movement. MT1-MMP can; 1) cleave the ECM, 2) regulate the activity of other MMPs, 3) binds in a receptor-like fashion to a variety of secreted molecule, 4) activate intracellular signalling cascades that regulates gene expression and cell morphology.