NDLI: Binding of Active (57 kDa) Membrane Type 1-Matrix Metalloproteinase (MT1-MMP) to Tissue Inhibitor of Metalloproteinase (TIMP)-2 Regulates MT1-MMP Processing and Pro-MMP-2 Activation

Content Provider	Journal of Biological Chemistry (JBC)
Author	Hernandez-Barrantes, Sonia Toth, Marta Bernardo, M. Margarida Yurkova, Maria Gervasi, David C. Raz, Yuval Sang, QingXiang Amy Fridman, Rafael
Abstract	Previous studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP) (MMP-14) initiates pro-MMP-2 activation in a process that is tightly regulated by the level of tissue inhibitor of metalloproteinase (TIMP)-2. However, given the difficulty in modulating TIMP-2 levels, the direct effect of TIMP-2 on MT1-MMP processing and on pro-MMP-2 activation in a cellular system could not be established. Here, recombinant vaccinia viruses encoding full-length MT1-MMP or TIMP-2 were used to express MT1-MMP alone or in combination with various levels of TIMP-2 in mammalian cells. We show that TIMP-2 regulates the amount of active MT1-MMP (57 kDa) on the cell surface whereas in the absence of TIMP-2 MT1-MMP undergoes autocatalysis to a 44-kDa form, which displays a N terminus starting at Gly285 and hence lacks the entire catalytic domain. Neither pro-MT1-MMP (N terminus Ser24) nor the 44-kDa form bound TIMP-2. In contrast, active MT1-MMP (N terminus Tyr112) formed a complex with TIMP-2 suggesting that regulation of MT1-MMP processing is mediated by a complex of TIMP-2 with the active enzyme. Consistently, TIMP-2 enhanced the activation of pro-MMP-2 by MT1-MMP. Thus, under controlled conditions, TIMP-2 may act as a positive regulator of MT1-MMP activity by promoting the availability of active MT1-MMP on the cell surface and consequently, may support pericellular proteolysis.
Related Links	http://www.jbc.org/content/275/16/12080.abstract
Ending Page	12089
Starting Page	12080
Page Count	10
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	16
Volume Number	275
DOI	10.1074/jbc.275.16.12080
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2000-04-21
Access Restriction	Open
Subject Keyword	Extracellular matrix (ECM) Matrix metalloproteinase (MMP) Tissue inhibitor of metalloproteinase (TIMP) Polyacrylamide gel electrophoresis (PAGE) Phosphate-buffered saline (PBS) Monoclonal antibody (mAb) Polyclonal antibody (pAb) Plaque-forming units (pfu) Fetal bovine serum (FBS) Enhanced chemiluminescence (ECL) Plasma membrane (PM) Membrane-type (MT) ENZYME CATALYSIS AND REGULATION
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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