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MBC in Press, published online ahead of print October 18, 2006
Mol. Biol. Cell 10.1091/mbc.E06-08-0740

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Submitted on August 23, 2006
Revised on September 22, 2006
Accepted on October 5, 2006

Cell Surface Collagenolysis Requires Homodimerization of the Membrane-bound Collagenase MT1-MMP

Yoshifumi Itoh,* Noriko Ito,* Hideaki Nagase,* Richard D. Evans,* Sarah A. Bird,* and Motoharu Seiki{dagger}

*Department of Matrix Biology, Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College London, London W6 8LH, United Kingdom; {dagger}Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

Monitoring Editor: Jean Schwarzbauer

Pericellular degradation of interstitial collagens is a crucial event for cells to migrate through the dense connective tissue matrices, where collagens exist as insoluble fibers. A key proteinase that participates in this process is considered to be membrane-type 1 matrix metalloproteinase (MT1-MMP or MMP-14), but little is known about the mechanism by which it cleaves the insoluble collagen. Here we report that homodimerization of MT1-MMP through its hemopexin (Hpx) domain is essential for cleaving type I collagen fibers at the cell surface. When dimerization was blocked by coexpressing either a membrane-bound or a soluble form of the Hpx domain, cell surface collagenolytic activity was inhibited in a dose-dependent manner. When MMP-13, a soluble collagenase active as a monomer in solution, was expressed as a membrane-anchored form on the cell surface, homodimerization was also required to cleave collagen. Our results introduce a new concept in that pericellular collagenolysis is regulated by correct molecular assembly of the membrane-anchored collagenase, thereby governing the directionality of the cell to migrate in tissue.

Address correspondence to: Yoshifumi Itoh (y.itoh{at}imperial.ac.uk)




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