Membrane Type 1 Matrix Metalloproteinase Digests Interstitial Collagens and Other Extracellular Matrix Macromolecules
Open accessAbstract
Membrane type 1 matrix metalloproteinase (MT1-MMP) is expressed on cancer cell membranes and activates the zymogen of MMP-2 (gelatinase A). We have recently isolated MT1-MMP complexed with tissue inhibitor of metalloproteinases 2 (TIMP-2) and demonstrated that MT1-MMP exhibits gelatinolytic activity by gelatin zymography (Imai, K., Ohuchi, E., Aoki, T., Nomura, H., Fujii, Y., Sato, H., Seiki, M., and Okada, Y. (1996) Cancer Res. 56, 2707-2710). In the present study, we have further purified to homogeneity a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) and native MT1-MMP secreted from a human breast carcinoma cell line (MDA-MB-231 cells) and examined their substrate specificities. Both proteinases are active, without any treatment for activation, and digest type I (guinea pig), II (bovine), and III (human) collagens into characteristic 3/4 and 1/4 fragments. The cleavage sites of type I collagen are the Gly775-Ile776 bond for alpha1(I) chains and the Gly775-Leu776 and Gly781-Ile782 bonds for alpha2(I) chains. DeltaMT1 hydrolyzes type I collagen 6.5- or 4-fold more preferentially than type II or III collagen, whereas MMP-1 (tissue collagenase) digests type III collagen more efficiently than the other two collagens. Quantitative analyses of the activity of DeltaMT1 and MMP-1 indicate that DeltaMT1 is 5-7.1-fold less efficient at cleaving type I collagen. On the other hand, gelatinolytic activity of DeltaMT1 is 8-fold higher than that of MMP-1. DeltaMT1 also digests cartilage proteoglycan, fibronectin, vitronectin and laminin-1 as well as alpha1-proteinase inhibitor and alpha2-macroglobulin. The activity of DeltaMT1 on type I collagen is synergistically increased with co-incubation with MMP-2. These results indicate that MT1-MMP is an extracellular matrix-degrading enzyme sharing the substrate specificity with interstitial collagenases, and suggest that MT1-MMP plays a dual role in pathophysiological digestion of extracellular matrix through direct cleavage of the substrates and activation of proMMP-2.
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MMP-14 is highly expressed on osteoclast podosomes and digests interstitial collagen and other ECM molecules.
“MMP-14 is highly expressed on osteoclast podosomes,149 and it digests interstitial collagen as well as other ECM molecules.150”
From Bone remodeling: an operational process ensuring survival and bone mechanical competence (2022) · cites this paper as [150]
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- Authors
- Ohuchi, E., Imai, K., Fujii, Y., Sato, H., Seiki, M., & Okada, Y.
- Affiliations
- Kanazawa University (JP)
- Corresponding author
- Okada, Yasunori
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1997-01
- Volume
- 272
- Issue
- 4
- Pages
- 2446-2451
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2043068076
- Cited by
- 938
- References
- 35
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 8 · 2023: 14 · 2022: 14 · 2021: 15 · 2020: 20 · 2019: 19 · 2018: 19 · 2017: 30 · 2016: 23 · 2015: 23 · 2014: 27 · 2013: 33 · 2012: 28
- FWCI
- 23.97
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Health Sciences › Medicine › Oncology › Peptidase Inhibition and Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- MT1-MMP, MMP-1, MMP-2, extracellular matrix degradation, cartilage proteoglycans, fibronectin, vitronectin, laminin-1, alpha 1-proteinase inhibitor, alpha2-macroglobulin, synergistic enzyme activity, breast cancer cells, MDA-MB-231 cells
- MeSH terms
- Collagen, Electrophoresis, Polyacrylamide Gel, Extracellular Matrix, Fibronectins, Gelatin, Glycoproteins, Humans, Laminin, Protease Inhibitors, Proteins, Substrate Specificity, Vitronectin, Tissue Inhibitor of Metalloproteinases, Tissue Inhibitor of Metalloproteinase-2, Matrix Metalloproteinase Inhibitors
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