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Published on: August 7, 2014

Clusterin, an abundant serum factor, is a possible negative regulator of MT6-MMP/MMP-25 produced by neutrophils

Akira Matsuda1, Yoshifumi Itoh, Naohiko Koshikawa

  • 1Division of Cancer Cell Research, Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

The Journal of Biological Chemistry
|July 16, 2003
PubMed

Insights

Clusterin inhibits the activity of membrane-type 6 matrix metalloproteinase (MT6-MMP), a protein found in neutrophils and brain tumors. This interaction suggests clusterin may act as a natural regulator of MT6-MMP in the body.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzymology

Background:

  • Membrane-type 6 matrix metalloproteinase (MT6-MMP/MMP-25) is a recently identified member of the matrix metalloproteinase (MMP) family.
  • MT6-MMP is expressed in neutrophils and certain brain tumors, and its proteolytic activity is known to degrade extracellular matrix components.
  • The C-terminal hemopexin-like domain of MT6-MMP may modulate its activity through interactions with other proteins.

Purpose of the Study:

  • To investigate the function of the hemopexin-like domain of MT6-MMP.
  • To explore potential protein interactions and regulatory mechanisms of MT6-MMP activity.

Main Methods:

  • Purification of a recombinant soluble form of MT6-MMP containing the hemopexin-like domain using a Madin-Darby canine kidney cell line.
  • Identification of co-purified proteins using N-terminal amino acid sequencing.
  • Assay of MT6-MMP enzymatic activity in the presence and absence of co-purified proteins and purified clusterin.
  • Comparison of clusterin's effect on MT6-MMP, MMP-2, and soluble MT1-MMP activities.

Main Results:

  • Soluble MT6-MMP was purified, along with associated proteins identified as clusterin.
  • MT6-MMP formed stable complexes with clusterin, which were also detected in human neutrophils.
  • The enzymatic activity of MT6-MMP was inhibited when complexed with clusterin.
  • Purified clusterin demonstrated inhibitory effects specifically on soluble MT6-MMP, but not on MMP-2 or soluble MT1-MMP.

Conclusions:

  • Clusterin forms stable complexes with MT6-MMP, potentially regulating its proteolytic activity.
  • The interaction between MT6-MMP and clusterin suggests a novel inhibitory mechanism.
  • Clusterin may function as an endogenous negative regulator of MT6-MMP activity in vivo, given its abundance in bodily fluids.

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