Yoshifumi Itoh - Overview

Our research goal is to understand the molecular mechanism of cellular invasion and migration in conjunction with extracellular matrix (ECM) receptors, re-organisation of the cytoskelton, and matrix metalloproteinases (MMPs). So far 23 MMPs have been identified, and these can be divided into soluble MMPs and membrane-type MMPs (MT-MMPs). Soluble MMPs are readily secreted into extracellular space, whereas MT-MMPs are bound to the plasma membrane through the transmembrane domain or GPI-anchor at the C-terminus. MT1-MMP was the first membrane-bound MMPs to be discovered and is highly expressed in many motile cells including invasive cancer cells. As MT1-MMP acts at the cell surface, it degrades the ECM attached to the cell surface. This breakdown in turn modifies the signals given by the ECM to the cells through various ECM receptors. Our recent findings also suggest that MT1-MMP degrades not only ECM molecules, but also cleaves CD44 resulting in increased cellular motility. Another recent finding we made suggests that not only the gross amount of the enzyme expressed on the cell surface, but also molecular arrangement of MT1-MMP is critical to express its biological activities. Given these observations, it is important to elucidate the regulation of MT1-MMP activity on the cell surface during migration as well as invasion in tissues.