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Claudin promotes activation of pro-matrix metalloproteinase-2 mediated by membrane-type matrix metalloproteinases

H Miyamori1, T Takino, Y Kobayashi

  • 1Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-0934,

The Journal of Biological Chemistry
|May 31, 2001
PubMed

Insights

Claudins, such as claudin-5, promote the activation of pro-matrix metalloproteinase-2 (pro-MMP-2) by membrane-type matrix metalloproteinases (MT-MMPs). This claudin-mediated activation is independent of TIMP-2 and enhances pro-MMP-2 processing on the cell surface.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Matrix metalloproteinases (MMPs), particularly membrane-type MMPs (MT-MMPs), play crucial roles in extracellular matrix remodeling.
  • The activation of pro-matrix metalloproteinase-2 (pro-MMP-2) is a key step regulated by MT-MMPs, often involving tissue inhibitor of metalloproteinase-2 (TIMP-2).
  • Endothelial tight junctions, composed of claudins, are critical for vascular barrier integrity and cell signaling.

Purpose of the Study:

  • To identify novel regulators of membrane-type matrix metalloproteinase-1 (MT1-MMP)-mediated pro-MMP-2 processing.
  • To investigate the role of claudins in the activation of pro-MMP-2 by MT-MMPs.
  • To elucidate the mechanism by which claudins influence MT-MMP activity and substrate processing.

Main Methods:

  • Expression cloning in 293T cells to screen for genes regulating MT1-MMP activity.
  • Analysis of pro-MMP-2 processing using wild-type and mutant forms of MT1-MMP, pro-MMP-2, and claudins.
  • Immunoprecipitation assays to demonstrate direct interactions between claudins, MT1-MMP, and MMP-2.
  • Co-localization studies using microscopy to assess the cellular distribution of MT1-MMP and claudins.

Main Results:

  • Claudin-5 was identified as a potent promoter of pro-MMP-2 activation by MT1-MMP, independent of TIMP-2.
  • Claudins (claudin-1, -2, -3, and -5) stimulated pro-MMP-2 activation mediated by various MT-MMPs and MT1-MMP mutants.
  • Claudins facilitate the recruitment of MT-MMPs and pro-MMP-2 to the cell surface, enhancing pro-MMP-2 activation.
  • Direct interaction between claudin-1, MT1-MMP, and MMP-2 was confirmed, and MT1-MMP co-localized with claudin-1.

Conclusions:

  • Claudins are novel positive regulators of MT-MMP-mediated pro-MMP-2 activation.
  • Claudins enhance pro-MMP-2 activation by concentrating MT-MMPs and pro-MMP-2 at the cell surface.
  • This mechanism highlights a new role for claudins in regulating extracellular matrix dynamics beyond their function in tight junctions.

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