Malignancies are the second most common cause of death in the US. Membrane type-1 matrix metalloproteinase (MT1-MMP) is a key protease in cell migration/invasion. Its functional activity is directly associated with extensive tumor neovascularization, aggressive cell invasion and metastasis. MT1-MMP is ideally positioned for performing the focalized pericellular proteolysis. A better understanding of the functional role and the regulation of MT1-MMP in tumorigenesis is mandatory. The purpose of this application is to describe a program that will provide this required understanding. Achievement of the program's specific aims will determine: (I) the physiologically-relevant pathways of MT1-MMP activation and maturation, (II) how MT1-MMP regulates the functionality of integrin adhesion receptors in malignant cells, (III) how MT1-MMP stimulates signal transduction and activates transcription of the invasion associated genes, (IV) the trafficking and internalization pathways of MT1-MMP, and (V) the molecular mechanisms involving MT1-MMP in tumor immunity. Prior studies have revealed that MT1-MMP plays an integral role in carcinogenesis and is, in fact, a centerpiece of malignant transformation. We hypothesize that MT1-MMP contributes to cell invasion and tumorigenesis mostly via the proteolytic regulation of the cell surface-associated targets. The immediate goals of the program are to understand the mechanisms by which MT1-MMP interacts with cellular targets and modifies the functionality of these targets and to determine whether agents, which inhibit these interactions, can regulate the MT1-MMP function in vivo. Through the proteolytic modification of the cell receptor targets, which exhibit an extensive life span, short-lived MT1-MMP has a long-lasting effect on cell behavior. The research plan is focused on elucidating the fundamental biological mechanisms that regulate the expression, the structure and the function of MT1-MMP in cancer and endothelial cells. The results will provide the necessary knowledge to control MT1-MMP in a clinically advantageous manner. Given that MMPs are the promising subjects for anti-cancer therapy, the opportunity to specifically target the singular cell surface-associated MT1-MMP enzyme with a unique function rather than to deal with twenty three individual species of known human MMPs, will prove to be the correct and most effective means to extend the life of cancer patients. This program offers a comprehensive system approach with structural, enzymological, immunological, molecular/cell biological, computer modeling, and in vivo studies to acquire the essential knowledge of MT1-MMP. The better characterization of MT1-MMP accomplished through successful execution of this project will support the design of novel and directly applicable anti-cancer therapies. The results of these experiments have a very high probability of providing an effective means to regulate the MT1-MMP function in the setting of the disease.
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