Activation of MMPs

While transcriptional regulation is important in determining MMP synthesis, activation of MMPs is a key factor in regulating proteolysis of specific substrates. Newly synthesized MMPs are secreted into the extracellular space in zymogen form. Outside the cell, other MMPs, serine proteinases, growth factors, and chemical/physical reagents can activate the latent MMP. Proteolytic enzymes such as urokinase, plasmin, and cathepsins are known to activate MMPs. In addition, organomercurials (APMA) are used routinely to activate MMPs under experimental conditions. MMP activity in vivo has been associated with the interstitial form urokinase plasminogen activator (uPA). Recent evidence has shown that latent MMP-2 is activated at the cell surface in a highly regulated pathway involving tissue inhibitors of metalloproteinases-2 (TIMP-2) and MT1-MMP (Hernandez-Barrantes et al., 2000). TIMP-2 binds MT1-MMP at its N-terminus and proMMP-2 at its C-terminus. Another free MT1-MMP molecule cleaves the bound proMMP-2, leading to partial activation of MMP-2. Another fully activated MMP-2 is required to remove a residual portion of the MMP-2 propeptide (Deryugina, 2001). At low concentrations, TIMP-2 stimulates proMMP-2 activation; at high concentrations, it inhibits MMP-2 activation.

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