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J. Biol. Chem., Vol. 281, Issue 10, 6826-6840, March 10, 2006

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Type I Collagen Abrogates the Clathrin-mediated Internalization of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) via the MT1-MMP Hemopexin Domain^*

Marc A. Lafleur, Francesca A. Mercuri, Neeracha Ruangpanit, Motoharu Seiki^¶, Hiroshi Sato^||, and Erik W. Thompson¹

From the VBCRC Invasion and Metastasis Group, St. Vincent's Institute, Fitzroy, Victoria 3065, Australia, the Department of Surgery, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia, the ^¶Department of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, and the ^||Department of Molecular Virology and Oncology, Kanazawa University, Kanazawa 920-0934, Japan

Type I collagen (Col I)-stimulated matrix metalloproteinase-2 (MMP-2) activation via membrane type 1 MMP (MT1-MMP) involves both a transcriptional increase in MT1-MMP expression and a nontranscriptional response mediated by preexisting MT1-MMP. In order to identify which MT1-MMP domains were required for the nontranscriptional response, MCF-7 cells that lack endogenous MT1-MMP were transfected with either wild type or domain mutant MT1-MMP constructs. We observed that mutant constructs lacking the MT1-MMP cytoplasmic tail were able to activate MMP-2 in response to Col I but not a construct lacking the MT1-MMP hemopexin domain. Col I did not alter total MT1-MMP protein levels; nor did it appear to directly induce MT1-MMP oligomerization. Col I did, however, redistribute preexisting MT1-MMP to the cell periphery compared with unstimulated cells that displayed a more diffuse staining pattern. In addition, Col I blocked the internalization of MT1-MMP in a dynamin-dependent manner via clathrin-coated pit-mediated endocytosis. This mechanism of impaired internalization is different from that reported for concanavalin A, since it is not mediated by the cytoplasmic tail of MT1-MMP but rather by the hemopexin domain. In summary, upon Col I binding to its cell surface receptor, MT1-MMP internalization via clathrin-coated pit-mediated endocytosis is impaired through interactions with the hemopexin domain, thereby regulating its function and ability to activate MMP-2.

Received for publication, December 7, 2005

^* This work was supported by the Victorian Breast Cancer Research Consortium and the National Health and Medical Research Council of Australia. 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: St. Vincent's Institute of Medical Research, 9 Princes St., Fitzroy, Victoria 3065, Australia. Tel.: 61-3-9288-2569; Fax: 61-3-9416-2676; E-mail: rik{at}medstv.unimelb.edu.au.

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