Cross-linked fibrin is deposited in tissues surrounding wounds, inflammatory sites, or tumors and serves not only as a supporting substratum for trafficking cells, but also as a structural barrier to invasion. While the plasminogen activator-plasminogen axis provides cells with a powerful fibrinolytic system, plasminogen-deleted animals use alternate proteolytic processes that allow fibrin invasion to proceed normally. Using fibroblasts recovered from wild-type or gene-deleted mice, invasion of three-dimensional fibrin gels proceeded in a matrix metalloproteinase (MMP)-dependent fashion. Consistent with earlier studies supporting a singular role for the membrane-anchored MMP, MT1-MMP, in fibrin-invasive events, fibroblasts from MT1-MMP–null mice displayed an early defect in invasion. However, MT1-MMP–deleted fibroblasts circumvented this early deficiency and exhibited compensatory fibrin-invasive activity. The MT1-MMP–independent process was sensitive to MMP inhibitors that target membrane-anchored MMPs, and further studies identified MT2-MMP and MT3-MMP, but not MT4-MMP, as alternate pro-invasive factors. Given the widespread distribution of MT1-, 2-, and 3-MMP in normal and neoplastic cells, these data identify a subset of membrane-anchored MMPs that operate in an autonomous fashion to drive fibrin-invasive activity.
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4 February 2002
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January 28 2002
Matrix Metalloproteinases (MMPs) Regulate Fibrin-invasive Activity via MT1-MMP–dependent and –independent Processes
Kevin B. Hotary,
Kevin B. Hotary
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Ikuo Yana,
Ikuo Yana
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Farideh Sabeh,
Farideh Sabeh
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Xiao-Yan Li,
Xiao-Yan Li
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Kenn Holmbeck,
Kenn Holmbeck
2National Institutes of Health/National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
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Henning Birkedal-Hansen,
Henning Birkedal-Hansen
2National Institutes of Health/National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
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Edward D. Allen,
Edward D. Allen
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Nobuaki Hiraoka,
Nobuaki Hiraoka
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Stephen J. Weiss
Stephen J. Weiss
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
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Kevin B. Hotary
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
Ikuo Yana
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
Farideh Sabeh
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
Xiao-Yan Li
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
Kenn Holmbeck
2National Institutes of Health/National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
Henning Birkedal-Hansen
2National Institutes of Health/National Institute of Dental and Craniofacial Research, Bethesda, MD 20892
Edward D. Allen
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
Nobuaki Hiraoka
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
Stephen J. Weiss
1University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109
Address correspondence to Stephen J. Weiss, 5220 MSRB III, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-0640. Phone: 734-764-0030; Fax: 734-764-0101; E-mail: [email protected]
K.B. Hotary, I. Yana, and F. Sabeh contributed equally to this work.
*
Abbreviations used in this paper: H and E, hematoxylin and eosin; MMP, matrix metalloproteinase; PDGF, platelet-derived growth factor; RT, reverse transcription; SF/HFG, scatter factor/hepatocyte growth factor; TIMP, tissue inhibitor of metalloproteases.
Received:
May 14 2001
Revision Received:
October 18 2001
Accepted:
December 11 2001
Online ISSN: 1540-9538
Print ISSN: 0022-1007
The Rockefeller University Press
2002
J Exp Med (2002) 195 (3): 295–308.
Article history
Received:
May 14 2001
Revision Received:
October 18 2001
Accepted:
December 11 2001
Citation
Kevin B. Hotary, Ikuo Yana, Farideh Sabeh, Xiao-Yan Li, Kenn Holmbeck, Henning Birkedal-Hansen, Edward D. Allen, Nobuaki Hiraoka, Stephen J. Weiss; Matrix Metalloproteinases (MMPs) Regulate Fibrin-invasive Activity via MT1-MMP–dependent and –independent Processes . J Exp Med 4 February 2002; 195 (3): 295–308. doi: https://doi.org/10.1084/jem.20010815
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