Individual timp deficiencies differentially impact pro-MMP-2 activaiton

doi:10.1074/jbc.M512009200

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Papers In Press, published online ahead of print February 9, 2006
J. Biol. Chem, 10.1074/jbc.M512009200
Submitted on November 8, 2005
Revised on February 7, 2006
Accepted on February 9, 2006

Individual timp deficiencies differentially impact pro-MMP-2 activaiton

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

Onatrio Cancer Institute, Room# 10-330, Toronto, Ontario M5G 2M9

Corresponding Author: rkhokha{at}uhnres.utoronto.ca

Membrane-type matrix metalloproteinases (MT-MMPs) have emerged as key enzymes in tumour 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 show 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 (WT) 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-/- cells 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, while 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.

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