Matrix metalloproteinase-14 is a mechanically regulated activator of secreted MMPs and invasion |
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Authors: | Amanda Haage Dong Hyun Nam Xin Ge Ian C Schneider |
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Institution: | 1. Department of Chemical and Biological Engineering, Iowa State University, 2114 Sweeney Hall, Ames, IA 50011-2230, United States;2. Department of Genetics, Development and Cell Biology, Iowa State University, 1210 Molecular Biology Building, Ames, IA 50011-3260, United States;3. Molecular, Cellular and Developmental Biology Interdepartmental Graduate Program, Iowa State University, 2018 Molecular Biology Building, Ames, IA 50011-3260, United States;4. Department of Chemical and Environmental Engineering, University of California, Riverside, Riverside, CA 92512, United States |
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Abstract: | Matrix metalloproteinases (MMPs) are extracellular matrix (ECM) degrading enzymes and have complex and specific regulation networks. This includes activation interactions, where one MMP family member activates another. ECM degradation and MMP activation can be initiated by several different stimuli including changes in ECM mechanical properties or intracellular contractility. These mechanical stimuli are known enhancers of metastatic potential. MMP-14 facilitates local ECM degradation and is well known as a major mediator of cell migration, angiogenesis and invasion. Recently, function blocking antibodies have been developed to specifically block MMP-14, providing a useful tool for research as well as therapeutic applications. Here we utilize a selective MMP-14 function blocking antibody to delineate the role of MMP-14 as an activator of other MMPs in response to changes in cellular contractility and ECM stiffness. Inhibition using function blocking antibodies reveals that MMP-14 activates soluble MMPs like MMP-2 and -9 under various mechanical stimuli in the pancreatic cancer cell line, Panc-1. In addition, inhibition of MMP-14 abates Panc-1 cell extension into 3D gels to levels seen with non-specific pan-MMP inhibitors at higher concentrations. This strengthens the case for MMP function blocking antibodies as more potent and specific MMP inhibition therapeutics. |
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Keywords: | MMP matrix metalloproteinase ECM extracellular matrix CAT catalytic domain MT-MMP membrane-tethered MMP S-MMP soluble MMP |
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