Urokinase directly activates matrix metalloproteinases-9: a potential role in glioblastoma invasion

Biochem Biophys Res Commun. 2008 May 16;369(4):1215-20. doi: 10.1016/j.bbrc.2008.03.038. Epub 2008 Mar 18.


Previous reports showed that urokinase plasminogen activator (uPA) converts plasminogen to plasmin which then activates matrix metalloproteinases (MMPs). Here, we report that uPA directly cleaved pro-MMP-9 in a time-dependent manner at both C- and N-terminus and generated two gelatinolytic bands. uPA-activated-MMP-9 efficiently degraded fibronectin and blocked by uPA inhibitor B428 and recombinant tissue inhibitor of metalloproteinase-1 (TIMP-1). B428 inhibited basal and PMA-induced active MMP-9 in glioblastomas (GBM) U1242 cell media as well as cell invasion in vitro. A combination of MMP-9 and uPA antibodies more significantly inhibited U1242 cell invasion than uPA or MMP-9 antibody alone. Both uPA and MMP-9 were highly expressed in U1242 cell and GBM patient specimens. Furthermore, two active MMP-9 fragments with identical molecular weights to the uPA-activated MMP-9 products were detected in GBM patient specimens. These results suggest that uPA-mediated direct activation of MMP-9 may promote GBM cell invasion.

Publication types

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

MeSH terms

  • Acute-Phase Proteins / metabolism
  • Brain Neoplasms / enzymology
  • Brain Neoplasms / pathology*
  • Enzyme Activation
  • Fibronectins / chemistry
  • Gelatin / chemistry
  • Glioblastoma / enzymology
  • Glioblastoma / pathology*
  • Humans
  • Lipocalin-2
  • Lipocalins / metabolism
  • Matrix Metalloproteinase 9 / chemistry
  • Matrix Metalloproteinase 9 / metabolism*
  • Neoplasm Invasiveness
  • Proto-Oncogene Proteins / metabolism
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Urokinase-Type Plasminogen Activator / chemistry
  • Urokinase-Type Plasminogen Activator / metabolism*


  • Acute-Phase Proteins
  • Fibronectins
  • LCN2 protein, human
  • Lipocalin-2
  • Lipocalins
  • Proto-Oncogene Proteins
  • Tissue Inhibitor of Metalloproteinase-1
  • Gelatin
  • Urokinase-Type Plasminogen Activator
  • Matrix Metalloproteinase 9