RT Journal Article SR Electronic T1 Direct Activation of Pro-Matrix Metalloproteinase-2 by Leukolysin/Membrane-type 6 Matrix Metalloproteinase/Matrix Metalloproteinase 25 at the Asn109-Tyr Bond JF Cancer Research JO Cancer Res FD American Association for Cancer Research SP 6758 OP 6762 VO 63 IS 20 A1 Nie, Jing A1 Pei, Duanqing YR 2003 UL http://cancerres.aacrjournals.org/content/63/20/6758.abstract AB Leukolysin/membrane-type 6 matrix metalloproteinase (leukolysin/MT6-MMP), a glycosylphosphatidylinositol-anchored neutrophil matrix metalloproteinase, is also abnormally expressed in brain cancer tissues. Yet, little is known about its role in cancer progression. Here we show that MT6-MMP is capable of activating proMMP-2, an enzyme implicated in tumor invasion and metastasis. Although MT6-MMP is only 10% as active as MT5-MMP in mediating proMMP-2 activation, it generates a higher ratio of mature/intermediate forms of MMP-2 than MT5-MMP. Consistently, purified CAT of MT6-MMP converts proMMP-2 into mostly the mature form. Using the catalytically inactive mutant MMP-2EA (the E404A mutant of proMMP-2), which cannot autocatalytically mature from the intermediate form into the mature one, we show that MT6-MMP cleaves not only the known MT-MMP-processing site at Asn66-Leu but also the previously unsuspected Asn109-Tyr to yield a fully mature molecule. Despite their difference in mediating proMMP-2 activation in transfected cells, the CAT of MT6-MMP appears to be as efficient as that of MT5-MMP in cleaving proMMP-2EA in buffer, suggesting that its CAT is a strong proMMP-2 activator. Indeed, the CAT of MT6-MMP can partially substitute the CAT of prototypical MT1-MMP in mediating proMMP-2 activation. Taken these facts together, we conclude that MT6-MMP may participate in tumor invasion and metastasis by directly converting proMMP-2 into active form. ©2003 American Association for Cancer Research.