Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin

J Clin Invest. 1997 Jul 1;100(1):58-67. doi: 10.1172/JCI119521.


The urokinase receptor (uPAR) coordinates plasmin-mediated cell-surface proteolysis and promotes cellular adhesion via a binding site for vitronectin on uPAR. Because vitronectin also binds plasminogen activator inhibitor type 1 (PAI-1), and plasmin cleavage of vitronectin reduces PAI-1 binding, we explored the effects of plasmin and PAI-1 on the interaction between uPAR and vitronectin. PAI-1 blocked cellular binding of and adhesion to vitronectin by over 80% (IC50 approximately 5 nM), promoted detachment of uPAR-bearing cells from vitronectin, and increased cellular migration on vitronectin. Limited cleavage of vitronectin by plasmin also abolished cellular binding and adhesion and induced cellular detachment. A series of peptides surrounding a plasmin cleavage site (arginine 361) near the carboxy-terminal end of vitronectin were synthesized. Two peptides spanning res 364-380 blocked binding of uPAR to vitronectin (IC50 approximately 8-25 microM) identifying this region as an important site of uPAR-vitronectin interaction. These data illuminate a complex regulatory scheme for uPAR-dependent cellular adhesion to vitronectin: Active urokinase promotes adhesion and also subsequent detachment through activation of plasmin or complex formation with PAI-1. Excess PAI-1 may also promote migration by blocking cellular adhesion and/or promoting detachment, possibly accounting in part for the strong correlation between PAI-1 expression and tumor cell metastasis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Adhesion / drug effects
  • Cell Line
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Chromatography, Affinity
  • Fibrinolysin / pharmacology*
  • Fibronectins
  • Humans
  • Kidney
  • Leukemia, Myelomonocytic, Acute
  • Plasminogen Activator Inhibitor 1 / pharmacology*
  • Receptors, Cell Surface / biosynthesis
  • Receptors, Cell Surface / physiology*
  • Receptors, Urokinase Plasminogen Activator
  • Recombinant Proteins / biosynthesis
  • Transfection
  • Tumor Cells, Cultured
  • Vitronectin / isolation & purification
  • Vitronectin / physiology*


  • Fibronectins
  • PLAUR protein, human
  • Plasminogen Activator Inhibitor 1
  • Receptors, Cell Surface
  • Receptors, Urokinase Plasminogen Activator
  • Recombinant Proteins
  • Vitronectin
  • Fibrinolysin