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J. Biol. Chem., Vol. 280, Issue 12, 10974-10980, March 25, 2005

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Furin Directly Cleaves proMMP-2 in the trans-Golgi Network Resulting in a Nonfunctioning Proteinase^*

Jian Cao, Alnawaz Rehemtulla¶, Maria Pavlaki, Pallavi Kozarekar, and Christian Chiarelli||

From the Department of Medicine, School of Medicine, State University of New York at Stony Brook, Stony Brook, New York 11794, the ^¶Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109 and the ^||Department of Research, Veterans Affairs Medical Center, Northport, New York 11768

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 leading to an inactive form of matrix metalloproteinase-2 (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 mass 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-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 tissue inhibitor of metalloproteinase-2, which binds to the active site of membrane type 1-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 trans-Golgi network. 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.

Received for publication, December 2, 2004 , and in revised form, January 5, 2005.

^* This work was supported by a Scientist Development grant from the American Heart Association and a New Investigator grant from the United States Army Medical Research and Materiel Command (to J. C.) and a Research Enhancement Award Program grant from the Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Rm. 004, Life Sciences, SUNY at Stony Brook, Stony Brook, NY 11794-5200. Tel.: 631-632-1815; E-mail: jian.cao{at}sunysb.edu.

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