Extracellular Matrix Regulations of Membrane Type 1 - Matrix Metalloproteinasis (MT1-MMP) and Matrix Metalloproteinase-2 (MMP-2) in Human Breast Fibroblasts

摘要

The tissue inhibitors of metalloproteinases (TIMPs) are specific inhibitors of MMP enzymatic activity. However, TlMP-2 can promote the activation of pro-MMP-2 by MTl-MMP. This process is mediated by the formation of a complex between MTl-MMP, TIMP-2, and pro-MMP-2. Binding of TIMP-2 to active MTl- MMP also inhibits the autocatalytic turnover of MT1 MMP on the cell surface. Thus, under certain conditions, TIMP-2 is a positive regulator of MMP activity. TIMP- 4, a close homologue of TIMP-2 also binds to pro-MMP- 2 and can potentially participate in pro-MMP-2 activation. We coexpressed MTl-MMP with TIMP-4 and investigated its ability to support pro-MMP-2 activation. TIMP-4, unlike TlMP-2, does not promote pro-MMP-2 activation by MTl-MMP. However, TIMP-4 binds to MTl- MMP inhibiting its autocatalytic processing. When coexpressed with TIMP-2, TIMP- 4 competitively reduced pro-MMP-2 activation by MTl-MMP. A balance between TIMP- 2 and TIMP-4 may be a critical factor in determining the degradative potential of cells in normal and pathological conditions.