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

By N. Koshikawa, Gianluigi Giannelli, V. Cirulli, Kaoru Miyazaki, V. Quaranta. Journal of Cell Biology, 2000

670 citations recorded by the source corpus.

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 γ2 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.

Subfields: Cancer Research, Hematology, Immunology and Allergy

View Paper: https://www.semanticscholar.org/paper/cc627a354534bfba896295dd73a057a58d536fba

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In Cancer Research

1. Zena Werb
2. I. Stamenkovic
3. M. Egeblad
4. V. Martins
5. E. O’Toole
6. M. Caley
7. Jeremy S. Duffield
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In Hematology

1. I. Stamenkovic
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3. M. Egeblad

In Immunology and Allergy

1. Zena Werb
2. M. Egeblad
3. I. Stamenkovic
4. Jeremy S. Duffield

Citations in the corpus

• Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. (2009, background): “For example, cleavage of collagen IV and laminin-5 generates cryptic peptides that can in turn promote migration of tumor cells.(14,15) MMP substrates include nonECM molecules, ranging from growth factor precursors and cell surface adhesion molecules to angiogenic inhibitor precursors (Fig 2).”
• New functions for the matrix metalloproteinases in cancer progression (2002, background): “Cleavage of laminin-5 by MMP-2 and MMP-14 reveals a cryptic site that triggers cell motilit”
• Extracellular matrix remodelling: the role of matrix metalloproteinases (2003, background): “Thus, cleavage of laminin-5 by MMP-2 and -14 results in laminin fragments that trigger migration signals in cells [45,119], and cleavage of collagen IV discloses cryptic sites that are recognized by integrins and contribute to migration stimuli [46].”
• The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. (2001, background): “28 Koshikawa, N. et al. (2000) Role of cell surface metalloprotease”
• Matrix metalloproteinases: effectors of development and normal physiology. (2000, background): “In another system, breast epithelial cell migration on laminin-5 correlates with expression of MMP-14 (MT1–MMP) and MMP-2 (gelatinase A), and anti-sense oligodeoxynucleotides against MT1-MMP reduced their migration over this substrate (Koshikawa et al. 2000).”
• Regulation of Cell Invasion and Morphogenesis in a Three-Dimensional Type I Collagen Matrix by Membrane-Type Matrix Metalloproteinases 1, 2, and 3 (2000, background): “Thus, we favor a scenario in which distinct MT-MMPs promote invasive and/or morphogenic responses in a manner dictated by the enzymes’ proteolytic profile and the characteristics of the connective tissue barrier confronting the cell (e.g., Belien et al., 1999; Koshikawa et al., 2000).”
• Membrane-Type 1 Matrix Metalloproteinase Cleaves Cd44 and Promotes Cell Migration (2001, background): “MT1-MMP degrades collagen types I, II, and III, fibronectin, laminin 1 and 5, vitronectin, and aggrecan (d’Ortho et al., 1997; Ohuchi et al., 1997; Buttner et al., 1998; Fosang et al., 1998; Koshikawa et al., 2000).”
• Matrix MetalloProteinases (MMPs) andTissue Inhibitors of MetalloProteinases (TIMPs): positive and negative regulators intumor cell adhesion (2010, neutral): “Comprehensive analysis on the effects of MMPs-mediated ECM component degradation in various types of cancer systems is described elsewhere [59–64].”
• Metalloproteinases and Wound Healing (2015, background): “For example, within the wound environment, MT1MMP releases a fragment from the c-2 chain of laminin 332 (c-2 III domain) found within the skin basement membrane; this fragment contains multiple EGF-like repeats and promotes keratinocyte migration.(14,15) The role of specific MMPs in wound repair MMP”