期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 288, 期 15, 页码 10195-10204出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.447169
关键词
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资金
- National Institutes of Health, NIDCR
- Danish Cancer Society
- Danish Medical Research Council
- Danish Cancer Research Foundation
- Lundbeck Foundation
- Novo Nordisk Foundation
- Danish National Research Foundation (Danish-Chinese Center for Proteases and Cancer)
- Fonds de la Recherche Scientifique - FNRS (F.R.S.-FNRS, Belgium)
- Foundation against Cancer (Foundation of Public Interest, Belgium)
- Plan National Cancer (Service Public Federal, Belgium)
- European Community [201279]
- Grosserer Alfred Nielsen og Hustrus Foundation
- Copenhagen University Hospital
- University of Copenhagen, Faculty of Science
- Lundbeck Foundation [R67-2010-6200, R118-2012-11578] Funding Source: researchfish
- Novo Nordisk Fonden [NNF12OC0002353] Funding Source: researchfish
The group of matrix metalloproteases (MMPs) is responsible for multiple processes of extracellular matrix remodeling in the healthy body but also for matrix and tissue destruction during cancer invasion and metastasis. The understanding of the contributions from each individual MMP, both in healthy and pathological events, has been complicated by the lack of specific inhibitors and the fact that some of the potent MMPs are multifunctional enzymes. These factors have also hampered the setup of therapeutic strategies targetingMMPactivity. A tempting target is the membrane-associated MT1-MMP, which has well-documented importance in matrix degradation but which takes part in more than one pathway in this regard. In this report, we describe the selective targeting of a single function of this enzyme by means of a specific monoclonal antibody against MT1-MMP, raised in an MT1-MMP knock-out mouse. The antibody blocks the enzyme ability to activate proMMP-2 without interfering with the collagenolytic function or the general proteolytic activity of MT1-MMP. Using this antibody, we have shown that the MT1-MMP-catalyzed activation of proMMP-2 is involved in the outgrowth of cultured lymphatic endothelial cells in a collagen matrix in vitro, as well as in lymphatic vessel sprouting assayed ex vivo. This is the first example of the complete inactivation of a single function of a multifunctional MMP and the use of this strategy to pursue its role.
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