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Human membrane type-2 matrix metalloproteinase is defective in cell-associated activation of progelatinase A

H Miyamori1, T Takino, M Seiki

  • 1Department of Molecular Virology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-0934, Japan.

Biochemical and Biophysical Research Communications
|February 16, 2000
PubMed

Insights

Human membrane type-2 matrix metalloproteinase (MT2-MMP) is defective in activating progelatinase A due to specific amino acid residues in its insertion sequence-2 (IS-2). Mouse MT2-MMP rescues this function, highlighting IS-2

Area of Science:

  • Biochemistry and Molecular Biology
  • Enzymology
  • Cell Biology

Background:

  • Matrix metalloproteinases (MMPs) play crucial roles in extracellular matrix remodeling.
  • Membrane type-2 matrix metalloproteinase (MT2-MMP) is involved in the activation of progelatinase A.
  • Species-specific differences in MT2-MMP function are not fully understood.

Purpose of the Study:

  • To investigate the functional differences between mouse and human MT2-MMP in progelatinase A activation.
  • To identify the specific region and residues responsible for the defect in human MT2-MMP.
  • To elucidate the role of insertion sequence-2 (IS-2) in MT2-MMP functionality.

Main Methods:

  • Transfection of mouse and human MT2-MMP genes into COS-1 cells.
  • Expression and analysis of human and mouse MT2-MMP chimeric proteins.
  • Site-directed mutagenesis to substitute specific amino acid residues.

Main Results:

  • Mouse MT2-MMP activated progelatinase A, while human MT2-MMP did not.
  • The defect in human MT2-MMP was localized to amino acid residues 155-271.
  • Substitution of proline-183 and glutamine-185 in human MT2-MMP with mouse residues restored progelatinase A activation.

Conclusions:

  • Human MT2-MMP exhibits a defect in cell-associated progelatinase A activation.
  • The insertion sequence-2 (IS-2) region, particularly residues 183 and 185, is critical for MT2-MMP function.
  • These findings underscore the importance of IS-2 in MT2-MMP's role in extracellular matrix regulation.

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