Normal as well as neoplastic cells invade surrounding tissues by controlling the expression of proteolytic enzymes that allow them to degrade the structural barriers established by the extracellular matrix. One group of proteinases, known as the matrix-degrading metalloproteinases or MMPs, is currently believed to play a prominent role in matrix remodeling events since these enzymes can, in concert, degrade all of the major proteinaceous components of the extracellular matrix including collagens, elastin and proteoglycans. Recently, the first membrane-anchored member of the MMP family, termed the membrane-type MMP (MT 1-MMP), was identified and shown to be expressed not only in normal mesenchymal/epithelial cell types, but also at heightened levels in a variety of human carcinomas. Based on the ability of MT1-MMP to activate progelatinase A and/or collagenase-3, it has been postulated that this metalloproteinase axis may act as the """"""""master switch"""""""" that regulates the expression of the tissue-invasive phenotype. However, the role that MTIMMP, and a structurally related proteinase, termed MT2-MMP, play in regulating cell-matrix interactions alone or in combination with progelatinase A or collagenase-3 remains the subject of controversy. Likewise, the mechanisms by which cells use these proteinases, control proliferative responses or regulate their activity at the cell surface have not been clarified. To address these issues, we propose to use a series of molecular, biochemical and cellular approaches to i) characterize the role that MT1-MMP and MT2-MMP play in controlling cell motility and invasive processes, ii) define the molecular basis of MT1-MMP/MT2-MMPdependent regulation of cell growth, iii) characterize the trafficking of MT1-MMP and MT2-MMP from intracellular compartments to the cell surface and iv) determine the regulatory domains in the cytosolic tails of MT1-MMP and MT2-MMP that control proteolytic activity at the cell surface. These studies should provide new insights into the role of the MT-MMPs in normal and neoplastic cell populations and define their potential importance as targets for novel therapeutic interventions.
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