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J. Biol. Chem., Vol. 281, Issue 15, 10337-10346, April 14, 2006

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Individual Timp Deficiencies Differentially Impact Pro-MMP-2 Activation^*

Jane L. English, Zamaneh Kassiri, Ilpo Koskivirta, Susan J. Atkinson^¶, Marco Di Grappa, Paul D. Soloway^||, Hideaki Nagase^**, Eero Vuorio, Gillian Murphy^¶, and Rama Khokha¹

From the Ontario Cancer Institute, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada, Department of Medical Biochemistry and Molecular Biology, University of Turku, Kiinamyllynkatu 10, FI-20520 Turku, Finland, ^¶Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council Building, Cambridge University, Cambridge CB2 2XY, United Kingdom, ^||Division of Nutritional Sciences, Cornell University, Ithaca, New York 14853, and the ^**Kennedy Institute of Rheumatology Division, Imperial College, London W6 8LH, United Kingdom

Membrane-type matrix metalloproteinases (MT-MMPs) have emerged as key enzymes in tumor cell biology. The importance of MT1-MMP, in particular, is highlighted by its ability to activate pro-MMP-2 at the cell surface through the formation of a trimolecular complex comprised of MT1-MMP/tissue inhibitor of metalloproteinase-2 (TIMP-2)/pro-MMP-2. TIMPs 1-4 are physiological MMP inhibitors with distinct roles in the regulation of pro-MMP-2 processing. Here, we have shown that individual Timp deficiencies differentially affect MMP-2 processing using primary mouse embryonic fibroblasts (MEFs). Timp-3 deficiency accelerated pro-MMP-2 activation in response to both cytochalasin D and concanavalin A. Exogenous TIMP-2 and N-TIMP-3 inhibited this activation, whereas TIMP-3 containing matrix from wild-type MEFs did not rescue the enhanced MMP-2 activation in Timp-3^-/- cells. Increased processing of MMP-2 did not arise from increased expression of MT1-MMP, MT2-MMP, or MT3-MMP or altered expression of TIMP-2 and MMP-2. To test whether increased MMP-2 processing in Timp-3^-/- MEFs is dependent on TIMP-2, double deficient Timp-2^-/-/-3^-/- MEFs were used. In these double deficient cells, the cleavage of pro-MMP-2 to its intermediate form was substantially increased, but the subsequent cleavage of intermediate-MMP-2 to fully active form, although absent in Timp-2^-/- MEFs, was detectable with combined Timp-2^-/-/-3^-/- deficiency. TIMP-4 associates with MMP-2 and MT1-MMP in a manner similar to TIMP-3, but its deletion had no effect on pro-MMP-2 processing. Thus, TIMP-3 provides an inherent regulation over the kinetics of pro-MMP-2 processing, serving at a level distinct from that of TIMP-2 and TIMP-4.

Received for publication, November 8, 2005 , and in revised form, February 7, 2006.

^* This work was supported by funding from the Canadian Institutes of Health Research (to R. K.). 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.

¹ To whom correspondence should be addressed. Tel.: 416-946-2501; Fax: 416-946-2984; E-mail: rkhokha{at}uhnres.utoronto.ca.

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