The transmembrane collagenase MT1-MMP (membrane-type 1 matrix metalloproteinase), also known as MMP-14, has a critical function both in normal development and in cancer progression, and is subject to extensive controls at the post-translational level which affect proteinase activity. As zymogen activation is crucial for MT1-MMP activity, an α1-PI (α1-proteinase inhibitor)-based inhibitor was designed by incorporating the MT1-MMP propeptide cleavage sequence into the α1-PI reactive-site loop (designated α1-PIMT1) and this was compared with wild-type α1-PI (α1-PIWT) and the furin inhibitory mutant α1-PIPDX. α1-PIMT1 formed an SDS-stable complex with furin and inhibited proMT1-MMP activation. A consequence of the loss of MT1-MMP activity was the activation of proMMP-2 and the inhibition of MT1-MMP-mediated collagen invasion. α1-PIMT1 expression also resulted in the intracellular accumulation of a glycosylated species of proMT1-MMP that was retained in the perinuclear region, leading to significantly decreased cell-surface accumulation of proMT1-MMP. These observations suggest that both the subcellular localization and the activity of MT1-MMP are regulated in a coordinated fashion, such that proMT1-MMP is retained intracellularly until activation of its zymogen, then proMT1-MMP traffics to the cell surface in order to cleave extracellular substrates.
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October 2007
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Research Article|
September 25 2007
Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking
Yi I. Wu;
Yi I. Wu
1
*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, U.S.A.
†Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, U.S.A.
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Hidayatullah G. Munshi;
Hidayatullah G. Munshi
†Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, U.S.A.
‡Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, U.S.A.
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Scott J. Snipas;
Scott J. Snipas
§Program in Apoptosis and Cell Death Research, Burnham Institute, La Jolla, CA 92037, U.S.A.
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Guy S. Salvesen;
Guy S. Salvesen
§Program in Apoptosis and Cell Death Research, Burnham Institute, La Jolla, CA 92037, U.S.A.
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Rafael Fridman;
Rafael Fridman
∥Department of Pathology, Wayne State University, Detroit, MI 48202, U.S.A.
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M. Sharon Stack
M. Sharon Stack
2
*Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, U.S.A.
†Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, U.S.A.
¶Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, U.S.A.
2To whom correspondence should be addressed (email stackm@health.missouri.edu).
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Publisher: Portland Press Ltd
Received:
April 23 2007
Revision Received:
July 18 2007
Accepted:
July 25 2007
Accepted Manuscript online:
July 25 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2007 Biochemical Society
2007
Biochem J (2007) 407 (2): 171–177.
Article history
Received:
April 23 2007
Revision Received:
July 18 2007
Accepted:
July 25 2007
Accepted Manuscript online:
July 25 2007
Citation
Yi I. Wu, Hidayatullah G. Munshi, Scott J. Snipas, Guy S. Salvesen, Rafael Fridman, M. Sharon Stack; Activation-coupled membrane-type 1 matrix metalloproteinase membrane trafficking. Biochem J 15 October 2007; 407 (2): 171–177. doi: https://doi.org/10.1042/BJ20070552
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