Cancer cells invade surrounding tissues and metastasize 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 cancer progression 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-MMP), was identified and shown to be expressed at heightened levels in a variety of human carcinomas. Based on the ability of MT-MMP to activate progelatinase A (an additional member of the MMP family with broad spectrum, matrix-degrading activity), it has been postulated that this new metalloproteinase may act as the master switch that regulates the expression of the tissue-invasive phenotype in cancer cells. However, like all members of the MMP family, MT-MMP itself is synthesized as a zymogen that must be processed to its active form in order to express catalytic activity. Presently, the factors regulating MT-MMP activation are unknown as are the molecular characteristics of the MT-MMP progelatinase A interaction. Furthermore, technical complexities associated with the purification of transmembrane enzymes have precluded efforts to determine whether active MT-MMP (or its active derivatives) expresses additional proteolytic activities that affect or regulate the tissue-invasive properties of cancer cells. To address these issues, the applicant proposes to use a series of molecular, biochemical and cellular approaches to I) characterize the regulatory processes that control the processing of the MT-MMP zymogen to its active form, ii) define the molecular basis of MT-MMP-dependent progelatinase A activation, iii) characterize the enzymic properties of membrane-anchored and soluble forms of MT-MMP and iv) assess the ability of MT-MMP to regulate the behavior of cancer cells in an in vivo-like model of the extracellular matrix. These studies should not only provide new insights into the role of MT-MMP in cancer progression, but also its potential importance as a target for novel therapeutic interventions.
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