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Papers In Press, published online ahead of print January 6, 2005
Medicine, SUNY at Stony Brook, Stony Brook, NY 11794-5200
Corresponding Author: jian.cao{at}sunysb.edu
Proprotein convertases play an important role in tumorigenesis and invasiveness. Here, we report that a dibasic amino acid convertase, furin, directly cleaves proMMP-2 within the trans Golgi network (TGN) leading to an inactive form of MMP-2. Co-transfection of COS-1 cells with both proMMP-2 and furin cDNAs resulted in the cleavage of the N-terminal propeptide of proMMP-2. The molecular weight of cleaved MMP-2 (63 kDa), detected in both cell lysates and conditioned medium, is between the intermediate and fully activated forms of MMP-2 induced by membrane type 1-matrix metalloproteinase (MT1-MMP). Furin-cleaved MMP-2 does not possess proteolytic activity as examined in a cell-free assay. Treatment of transfected cells with a furin inhibitor resulted in a dose-dependent inhibition of proMMP-2 cleavage; recombinant TIMP-2, which binds to the active site of MT1-MMP, had no inhibitory effect. Site-directed mutagenesis of amino acids in the furin consensus recognition motif of proMMP-2(R69KPR72) prevented propeptide cleavage, thereby identifying the scissile bond and characterizing the basic amino acids required for cleavage. Other experimental observations were consistent with intracellular furin cleavage of proMMP-2 in the TGN. The furin cleavage site in other proMMPs was examined. MMP-3, which contains the RXXR furin consensus sequence was cleaved in furin co-transfected cells, whereas MMP-1, which lacks an RXXR consensus sequence, was not cleaved. In conclusion, we report the novel observation that furin can directly cleave the RXXR amino acid sequence in the propeptide domain of proMMP-2 leading to inactivation of the enzyme.
J. Biol. Chem, 10.1074/jbc.M412370200
Submitted on November 2, 2004
Revised on January 5, 2005
Accepted on January 6, 2005
Furin directly cleaves proMMP-2 in the trans-golgi network resulting in a non-functioning proteinase
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