Understanding mechanisms that regulate ECM degradation is of paramount importance, not only to biochemistry and cell biology, but also to the treatment of malignancies. Our studies will provide information about mechanisms involved in the control of ECM proteolysis. Our hypothesis is that there are specific interactions of MMPs with molecular receptors on cell surfaces. Our data suggest that MT1-MMP, TIMP-2, and alphavbeta3 integrin could jointly control activation and docking of secretory MMP-2. MT1-MMP initiates activation of MMP-2 and the alphavbeta3 integrin governs further autocatalytic maturation of MMP-2. A disulfide bridge with an intracellular, presumably cytoskeleton, protein can direct MT1-MMP to discrete regions on the cell surface in an immediate proximity of alphavbeta3. This could be a link between continually changing cell shape, cytoskeleton and focal proteolysis of the ECM. Since docking co-exists with MMP-2 activation at the cell surface, the identified mechanisms illustrate how latent MMP-2 produced by the stroma could be specifically localized at tumors as the mature enzyme. Furthermore, MT1-MMP-mediated cleavage generates the modified, shorter beta3 integrin subunit that can facilitate migration of cells. We suggest that these are basic mechanisms to spatially and temporally control focal proteolysis. These mechanisms can enable tumor cells to separate active MMP-2 from an excess of its zymogen and specifically increase levels of the active enzyme on tumor cell surfaces, thereby facilitating directional invasion of the cells.
Our aims are: 1) To enzymologically characterize MT1-MMP and to complete the characterization of the MMP-2 activation cascade; 2) To functionally and structurally characterize MT1-MMP-mediated modifications of the alphavbeta3 in malignant progression and identify novel targets for prognosis and inhibition of malignancies; 4) To identify critical functional and structural elements of the C-terminal hemopexin-like domains of MMP-2 and MT1-MMP and to test peptide inhibitors derived from their sequences. We anticipate that novel methods of tumor prognosis and therapy will emerge from our studies.
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