Tissue inhibitor of metalloproteinase (TIMP)-2 acts synergistically with synthetic matrix metalloproteinase (MMP) inhibitors but not with TIMP-4 to enhance the (membrane type 1)-MMP-dependent activation of pro-MMP-2

The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been shown to be a key enzyme in tumor angiogenesis and metastasis. MT1-MMP hydrolyzes a va riety of extracellular matrix components and is a physiological activator o f pro-MMP-2, another MMP involved in malignancy. Pro-MMP-2 activation by MT 1-MMP involves the formation of an MT1-MMP tissue inhibitors of metalloprot einases 2 (TIMP-2) pro-MMP-2 complex on the cell surface that promotes the hydrolysis of pro-MMP-2 by a neighboring TIMP-2-free MT1-MMP. The MT1-MMP T IMP-2 complex also serves to reduce the intermolecular autocatalytic turnov er of MT1-MMP, resulting in accumulation of active MT1-MMP (57 kDa) on the cell surface. Evidence shown here in Timp2-null cells demonstrates that pro -MMP-2 activation by MT1-MMP requires TIMP-2. In contrast, a C-terminally d eleted TIMP-2 (Delta -TIMP-2), unable to form ternary complex, had no effec t, However, Delta -TIMP-2 and certain synthetic MMP inhibitors, which inhib it MT1-MMP autocatalysis, can act synergistically with TIMP-2 in the promot ion of pro-MMP-2 activation by MT1-MMP. In contrast, TIMP-4, an efficient M T1-MMP inhibitor, had no synergistic effect, These studies suggest that und er certain conditions the pericellular activity of MT1-MMP in the presence of TIMP-2 can be modulated by synthetic and natural (TIMP-4) MMP inhibitors .