Role of the hemopexin domain of matrix metalloproteinases in cell migration

J Cell Physiol. 2008 Dec;217(3):643-51. doi: 10.1002/jcp.21535.


The biological functions of matrix metalloproteinases (MMPs) extend beyond extracellular matrix degradation. Non-proteolytic activities of MMPs are just beginning to be understood. Herein, we evaluated the role of proMMPs in cell migration. Employing a Transwell chamber migration assay, we demonstrated that transfection of COS-1 cells with various proMMP cDNAs resulted in enhancement of cell migration. Latent MMP-2 and MMP-9 enhanced cell migration to a greater extent than latent MMP-1, -3, -11 and -28. To examine if proteolytic activity is required for MMP-enhanced cell migration, three experimental approaches, including fluorogenic substrate degradation assay, transfection of cells with catalytically inactive mutant MMP cDNAs, and addition of hydroxamic acid-derived MMP inhibitors, were employed. We demonstrated that the proteolytic activities of MMPs are not required for MMP-induced cell migration. To explore the mechanism underlying MMP-enhanced cell migration, structure-function relationship of MMP-9 on cell migration was evaluated. By using a domain swapping approach, we demonstrated that the hemopexin domain of proMMP-9 plays an important role in cell migration when examined by a transwell chamber assay and by a phagokinetic migration assay. TIMP-1, which interacts with the hemopexin domain of proMMP-9, inhibited cell migration, whereas TIMP-2 had no effect. Employing small molecular inhibitors, MAPK and PI3K pathways were found to be involved in MMP-9-mediated cell migration. In conclusion, we demonstrated that MMPs utilize a non-proteolytic mechanism to enhance epithelial cell migration. We propose that hemopexin homodimer formation is required for the full cell migratory function of proMMP-9.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Cell Adhesion / drug effects
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Chlorocebus aethiops
  • Enzyme Inhibitors / pharmacology
  • Enzyme Precursors / metabolism
  • Hemopexin / chemistry*
  • Humans
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases / chemistry*
  • Matrix Metalloproteinases / metabolism*
  • Protein Processing, Post-Translational / drug effects
  • Protein Structure, Tertiary
  • Signal Transduction / drug effects
  • Structure-Activity Relationship
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Tissue Inhibitor of Metalloproteinase-2 / metabolism
  • Transfection


  • Enzyme Inhibitors
  • Enzyme Precursors
  • Matrix Metalloproteinase Inhibitors
  • Tissue Inhibitor of Metalloproteinase-1
  • Tissue Inhibitor of Metalloproteinase-2
  • Hemopexin
  • Matrix Metalloproteinases
  • Matrix Metalloproteinase 9