Journal
EXPERIMENTAL CELL RESEARCH
Volume 318, Issue 8, Pages 904-914Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2012.02.021
Keywords
Matrix metalloproteinase-9; Protein disulfide isomerase; Disulfide bond; Cysteine-switch
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT)
- Grants-in-Aid for Scientific Research [20113008] Funding Source: KAKEN
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Matrix metalloproteinase-9 (MMP-9) is one of the major MMPs that can degrade extracellular matrix. Besides normal physiological functions, MMP-9 is involved in metastasis and tumor angiogenesis. Although several inhibitors of MMP-9 have been identified, in vivo regulators of MMP-9 activation are unknown. In the present study we intended to investigate novel therapeutic target protein(s) that regulate MMP-9 activation and/or secretion. We have identified protein disulfide isomerase as a novel upstream regulator of MMP-9. Mass spectrometric analysis of post-translational modification in MMP-9 confirmed six disulfide bonds in the catalytic domain and one disulfide bond in the hemopexin domain of MMP-9. Establishment of cells that overexpressed wild-type and mutant forms of MMP-9 revealed that 'cysteine-switch' and disulfide bonds within the catalytic domain are necessary for the secretion and intracellular trafficking of MMP-9. However, the disulfide bond of the hemopexin domain and other cysteines have no significant role in secretion. These insights into the secretion of MMP-9 constitute the basis for the development of potential drugs against metastasis. (C) 2012 Elsevier Inc. All rights reserved.
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