Plasmin activates pro‐matrix metalloproteinase‐2 with a membrane‐type 1 matrix metalloproteinase‐dependent mechanism

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Abstract
Membrane‐type 1 matrix metalloproteinase (MT1‐MMP) has been implicated as a physiological activator of progelatinase A (MMP‐2). We previously reported that plasmin treatment of cells results in proMMP‐2 activation and increased type IV collagen degradation. Here, we analyzed the role of MT1‐MMP in plasmin activation of MMP‐2 using HT‐1080 cells transfected with MT1‐MMP sense or antisense cDNA. Control, vector‐transfected cells that expressed endogenous MT1‐MMP, and antisense cDNA transfectants with very low levels of MT1‐MMP did not activate proMMP‐2. Conversely, cells transfected with sense MT1‐MMP cDNA expressed high MT1‐MMP levels and processed proMMP‐2 to 68/66‐kDa intermediate activation products. Control cells and MT1‐MMP transfectants had much higher levels of cell‐associated MMP‐2 than antisense cDNA transfectants. Addition of plasmin(ogen) to control or MT1‐MMP‐transfected cells generated active, 62‐kDa MMP‐2, but was ineffective with antisense cDNA transfectants. The effect of plasmin(ogen) was prevented by inhibitors of plasmin, but not by metalloproteinase inhibitors, implicating plasmin as a mechanism for proMMP‐2 activation independent of the activity of MT1‐MMP or other MMPs. Plasmin‐mediated activation of proMMP‐2 did not result from processing of proMT1‐MMP and did not correlate with αvβ3 integrin or TIMP‐2 levels. Thus, plasmin can activate proMMP‐2 only in the presence of MT1‐MMP; however, this process does not require the catalytic activity of MT1‐MMP.

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