Differential roles of TIMP-4 and TIMP-2 in Pro-MMP-2 activation by MT1-MMP

The tissue inhibitors of metalloproteinases (TIMPs) are specific inhibitors of MMP enzymatic activity. However, TIMP-2 can promote the activation of p ro-MMP-2 by MT1-MMP. This process is mediated by the formation of a complex between MT1-MMP, TIMP-2, and pro-MMP-2. Binding of TIMP-2 to active MT1-MM P also inhibits the autocatalytic turnover of MT1-MMP on the cell surface. Thus, under certain conditions, TIMP-2 is a positive regulator of MMP activ ity. TIMP-4, a close homologue of TIMP-2 also binds to pro-MMP-2 and can po tentially participate in pro-MMP-2 activation. We coexpressed MT1-MMP with TIMP-4 and investigated its ability to support pro-MMP-2 activation. TIMP-4 , unlike TIMP-2, does not promote pro-MMP-2 activation by MT1-MMP. However, TIMP-4 binds to MT1-MMP inhibiting its autocatalytic processing, When coex pressed with TIMP-2, TIMP-4 competitively reduced pro-MMP-2 activation by M T1-MMP. A balance between TIMP-2 and TIMP-4 may be a critical factor in det ermining the degradative potential of cells in normal and pathological cond itions. (C) 2001 Academic Press.