Protein disulfide isomerase-mediated disulfide bonds regulate the gelatinolytic activity and secretion of matrix metalloproteinase-9

Maola M.G. Khan, Siro Simizu, Takehiro Suzuki, Akiko Masuda, Makoto Kawatani, Makoto Muroi, Naoshi Dohmae, Hiroyuki Osada

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)904-914
Number of pages11
JournalExperimental Cell Research
Volume318
Issue number8
DOIs
Publication statusPublished - 2012 May 1

Keywords

  • Cysteine-switch
  • Disulfide bond
  • Matrix metalloproteinase-9
  • Protein disulfide isomerase

ASJC Scopus subject areas

  • Cell Biology

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