Density enhanced phosphatase-1 down-regulates urokinase receptor surface expression in confluent endothelial cells

Blood. 2011 Apr 14;117(15):4154-61. doi: 10.1182/blood-2010-09-307694. Epub 2011 Feb 8.


VEGF(165), the major angiogenic growth factor, is known to activate various steps in proangiogenic endothelial cell behavior, such as endothelial cell migration and invasion, or endothelial cell survival. Thereby, the urokinase-type plasminogen activator (uPA) system has been shown to play an essential role not only by its proteolytic capacities, but also by induction of intracellular signal transduction. Therefore, expression of its cell surface receptor uPAR is thought to be an essential regulatory mechanism in angiogenesis. We found that uPAR expression on the surface of confluent endothelial cells was down-regulated compared with subconfluent proliferating endothelial cells. Regulation of uPAR expression was most probably affected by extracellular signal-regulated kinase 1/2 (ERK1/2) activation, a downstream signaling event of the VEGF/VEGF-receptor system. Consistently, the receptor-like protein tyrosine phosphatase DEP-1 (density enhanced phosphatase-1/CD148), which is abundantly expressed in confluent endothelial cells, inhibited the VEGF-dependent activation of ERK1/2, leading to down-regulation of uPAR expression. Overexpression of active ERK1 rescued the DEP-1 effect on uPAR. That DEP-1 plays a biologic role in angiogenic endothelial cell behavior was demonstrated in endothelial cell migration, proliferation, and capillary-like tube formation assays in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Capillaries / cytology
  • Capillaries / physiology
  • Cell Division / physiology
  • Cell Movement / physiology
  • Cells, Cultured
  • Down-Regulation / physiology
  • Endothelial Cells / cytology
  • Endothelial Cells / enzymology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Gene Knockdown Techniques
  • Humans
  • In Vitro Techniques
  • MAP Kinase Signaling System / physiology
  • Neovascularization, Physiologic / physiology*
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3 / metabolism
  • Receptors, Urokinase Plasminogen Activator / genetics*
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Receptors, Vascular Endothelial Growth Factor / metabolism
  • Umbilical Veins / cytology
  • Vascular Endothelial Growth Factor A / metabolism


  • Receptors, Urokinase Plasminogen Activator
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Receptors, Vascular Endothelial Growth Factor
  • Extracellular Signal-Regulated MAP Kinases
  • PTPRJ protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 3