Inhibition of MMP activity

Inhibition/deactivation of MMPs can be accomplished by several factors including a-2-mac-roglobulin, tissue inhibitors of metalloproteinases (TIMPs), small molecules with TIMP-like domains, and the membrane-bound inhibitor RECK (reversion-inducing cysteine-rich protein with kazal motifs) (Sasahara et al., 2002). In tissue fluids, a2-macroglobulin forms a complex with MMPs that can bind to a scavenger receptor. Endocytosis removes the trimer-ic complex, a2-macroglobulin-MMP-scavenger receptor, in an irreversible manner. The activity of MMPs is regulated by the presence of endogenous protein inhibitors, Tissue Inhibitors of Metalloproteinases (TIMP). Four TIMPs (TIMPs1-4) have been identified, each with a specific function (Gomez et al., 1997). TIMPs inhibit tumorigenesis, cell invasion, metastasis and angiogenesis. A fine balance between MMPs and TIMPs regulates tumor progression. TIMP binds to the active site of MMP, leading to a conformational change in the enzyme. The ratio of MMP to its specific TIMP determines the metastatic potential of a tumor cell. Recent evidence suggests that an increase in MMP2 to TIMP2 ratio is associated with high-grade and high-stage prostate tumors (Still et al., 2000).

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