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J. Biol. Chem., Vol. 279, Issue 10, 8592-8601, March 5, 2004

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Differential Inhibition of Membrane Type 3 (MT3)-Matrix Metalloproteinase (MMP) and MT1-MMP by Tissue Inhibitor of Metalloproteinase (TIMP)-2 and TIMP-3 Regulates Pro-MMP-2 Activation^*

Huiren Zhao, M. Margarida Bernardo, Pamela Osenkowski, Anjum Sohail, Duanqing Pei, Hideaki Nagase¶, Masahide Kashiwagi¶, Paul D. Soloway||, Yves A. DeClerck**, and Rafael Fridman

From the Department of Pathology, School of Medicine, Wayne State University, Detroit, Michigan 48201, the Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, the ^¶Kennedy Institute of Rheumatology Division, Imperial College London, London W6 8LH, United Kingdom, the ^||Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, and the ^**Division of Hematology-Oncology and Department of Pediatrics, Children's Hospital Los Angeles, University of Southern California, Los Angeles, California 90027

The membrane type (MT)-matrix metalloproteinases (MMPs) constitute a subgroup of membrane-anchored MMPs that are major mediators of pericellular proteolysis and physiological activators of pro-MMP-2. The MT-MMPs also exhibit differential inhibition by members of the tissue inhibitor of metalloproteinase (TIMP) family. Here we investigated the processing, catalytic activity, and TIMP inhibition of MT3-MMP (MMP-16). Inhibitor profile and mutant enzyme studies indicated that MT3-MMP is regulated on the cell surface by autocatalytic processing and ectodomain shedding. Inhibition kinetic studies showed that TIMP-3 is a high affinity inhibitor of MT3-MMP when compared with MT1-MMP (K_i = 0.008 nM for MT3-MMP versus K_i = 0.16 nM for MT1-MMP). In contrast, TIMP-2 is a better inhibitor of MT1-MMP. MT3-MMP requires TIMP-2 to accomplish full pro-MMP-2 activation and this process is enhanced in marimastatpretreated cells, consistent with regulation of active enzyme turnover by synthetic MMP inhibitors. TIMP-3 also enhances the activation of pro-MMP-2 by MT3-MMP but not by MT1-MMP. TIMP-4, in contrast, cannot support pro-MMP-2 activation with either enzyme. Affinity chromatography experiments demonstrated that pro-MMP-2 can assemble trimolecular complexes with a catalytic domain of MT3-MMP and TIMP-2 or TIMP-3 suggesting that pro-MMP-2 activation by MT3-MMP involves ternary complex formation on the cell surface. These results demonstrate that TIMP-3 is a major regulator of MT3-MMP activity and further underscores the unique interactions of TIMPs with MT-MMPs in the control of pericellular proteolysis.

Received for publication, August 6, 2003 , and in revised form, December 1, 2003.

^* This work was supported by National Institutes of Health Grants NCI-CA61986 and NCI-CA100475 (to R. F.), and AR39198 (to H. N.), and Wellcome Trust Grant 057508 (to H. N.). 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: Dept. of Pathology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201. Tel.: 313-577-1218, Fax: 313-577-8180; E-mail: rfridman{at}med.wayne.edu.

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