Mechanisms for pro matrix metalloproteinase activation

The activation of pro matrix metalloproteinases (MMPs) by sequential proteo lysis of the propeptide blocking the active site cleft is regarded as one o f the key levels of regulation of these proteinases. Potential physiologica l mechanisms including cell-associated plasmin generation by urokinase-like plasminogen activator, or the action of cell surface MT1-MMPs appear to be involved in the initiation of cascades of pro MMP activation. Gelatinase A , collagenase 3 and gelatinase B may be activated by MT-MMP based mechanism s, as evidenced by both biochemical and cell based studies. Hence the regul ation of MT-MMPs themselves becomes critical to the determination of MMP ac tivity. This includes activation, assembly at the cell surfaces as TIMP-2 c omplexes and subsequent inactivation by proteolysis or TIMP inhibition.