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© The Rockefeller University Press, 0021-9525/2000//615 $5.00
The Journal of Cell Biology, Volume 148, Number 3, , 2000 615-624

Original Article

Role of Cell Surface Metalloprotease Mt1-Mmp in Epithelial Cell Migration over Laminin-5



Naohiko Koshikawaa,b, Gianluigi Giannellia, Vincenzo Cirullic, Kaoru Miyazakib, and Vito Quarantaa

a The Scripps Research Institute, Department of Cell Biology, La Jolla, California 92037
b Division of Cell Biology, Kihara Institute for Biological Research, Yokohama City University, 641-12, Maioka-cho, Totsuka-ku, Yokohama 244-0813, Japan
c The Islet Research Laboratory at The Whittier Institute for Diabetes, Department of Pediatrics, University of California San Diego, La Jolla, California 92037
The Scripps Research Institute, SBR-12, 10550 North Torrey Pines Road, La Jolla, CA 92037.858-784-2246858-784-8793

quaranta{at}scripps.edu

Laminin-5 (Ln-5) is an extracellular matrix substrate for cell adhesion and migration, which is found in many epithelial basement membranes. Mechanisms eliciting migration on Ln-5 need to be elucidated because of their relevance to tissue remodeling and cancer metastasis. We showed that exogenous addition of activated matrix metalloprotease (MMP) 2 stimulates migration onto Ln-5 in breast epithelial cells via cleavage of the {gamma}2 subunit. To investigate the biological scope of this proteolytic mechanism, we tested a panel of cells, including colon and breast carcinomas, hepatomas, and immortalized hepatocytes, selected because they migrated or scattered constitutively in the presence of Ln-5. We found that constitutive migration was inhibited by BB94 or TIMPs, known inhibitors of MMPs. Limited profiling by gelatin zymography and Western blotting indicated that the ability to constitutively migrate on Ln-5 correlated with expression of plasma membrane bound MT1-MMP metalloprotease, rather than secretion of MMP2, since MMP2 was not produced by three cell lines (one breast and two colon carcinomas) that constitutively migrated on Ln-5. Moreover, migration on Ln-5 was reduced by MT1-MMP antisense oligonucleotides both in MMP2+ and MMP2– cell lines. MT1-MMP directly cleaved Ln-5, with a pattern similar to that of MMP2. The hemopexin-like domain of MMP2, which interferes with MMP2 activation, reduced Ln-5 migration in MT1-MMP+, MMP2+ cells, but not in MT1-MMP+, MMP2– cells. These results suggest a model whereby expression of MT1-MMP is the primary trigger for migration over Ln-5, whereas MMP2, which is activated by MT1-MMP, may play an ancillary role, perhaps by amplifying the MT1-MMP effects. Codistribution of MT1-MMP with Ln-5 in colon and breast cancer tissue specimens suggested a role for this mechanism in invasion. Thus, Ln-5 cleavage by MMPs may be a widespread mechanism that triggers migration in cells contacting epithelial basement membranes.

Key Words: migration • extracellular matrix • epithelial cell • invasion

© 2000 The Rockefeller University Press

Abbreviations used in this paper: AS, antisense oligonucleotide; BM, basement membrane; CM, conditioned medium; ECM, extracellular matrix; HLD, hemopexin-like domain; Ln-5, laminin-5; MMP, matrix metalloprotease; MT1-MMP, membrane type 1-MMP; TIMP, tissue inhibitor of metalloprotease.


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