Direct activation of pro-matrix metalloproteinase-2 by leukolysin/membrane-type 6 matrix metalloproteinase/matrix metalloproteinase 25 at the asn(109)-Tyr bond.
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 Asn(66)-Leu but also the previously unsuspected Asn(109)-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.
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Jing
J
Nie
Duanqing
D
Pei
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002460:Cell Line; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D058851:GPI-Linked Proteins; D018093:Gelatinases / Q000378:metabolism*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000378:metabolism*; D008969:Molecular Sequence Data; D014162:Transfection
D004792:Enzyme Precursors; D058851:GPI-Linked Proteins; D018093:Gelatinases; C492243:MMP24 protein, human; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; C403928:matrix metalloproteinase 25; C069860:progelatinase