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ADAM28 is activated by MMP-7 (matrilysin-1) and cleaves insulin-like growth factor binding protein-3

Satsuki Mochizuki1, Masayuki Shimoda, Takayuki Shiomi

  • 1Department of Pathology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-0016, Japan.

Biochemical and Biophysical Research Communications
|March 12, 2004
PubMed

Insights

Matrix metalloproteinase-7 (MMP-7) activates the precursor form of ADAM28 (proADAM28s). Activated ADAM28 then digests insulin-like growth factor binding protein-3 (IGFBP-3), revealing a novel activation pathway and substrate.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Enzymology

Background:

  • ADAM28, a metalloproteinase family member, exists as membrane-bound (ADAM28m) and secreted (ADAM28s) isoforms.
  • The precursor form, proADAM28, is synthesized by lymphocytes and cancer cells, but its activation and substrates are largely unknown.

Purpose of the Study:

  • To elucidate the activation mechanism of proADAM28s.
  • To identify the substrates of activated ADAM28s.

Main Methods:

  • Investigated proADAM28s processing using active matrix metalloproteinase-7 (MMP-7).
  • Assessed the proteolytic activity of processed ADAM28s on insulin-like growth factor binding protein-3 (IGFBP-3).
  • Evaluated the effect of inhibitors (EDTA, 1,10-phenanthroline, KB-R7785) and tissue inhibitors (TIMP-3, TIMP-4) on ADAM28s activity.

Main Results:

  • MMP-7 processed proADAM28s (65kDa) into active forms (42- and 40-kDa).
  • Activated ADAM28s efficiently digested both free and IGF-bound IGFBP-3.
  • Enzymatic activity was inhibited by metalloproteinase inhibitors and specific TIMPs.

Conclusions:

  • This study provides the first evidence that MMP-7 activates proADAM28s.
  • ADAM28 is demonstrated to be a direct enzyme that digests IGFBP-3.
  • The findings reveal a novel MMP-7-mediated activation pathway for ADAM28 and its role in IGFBP-3 degradation.

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