• Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor

Koutsioumpa, Marina

Poimenidi, Evangelia

Pantazaka, Evangelia

Theodoropoulou, Christina

Skoura, Angeliki

Megalooikonomou, Vasileios

Kieffer, Nelly

Courty, Jose

Mizumoto, Shuji

Sugahara, Kazuyuki

Papadimitriou, Evangelia

  • Other Chondroitin sulphate
  • Other Endothelial cells
  • Other Migration
  • Other Pleiotrophin
  • Other Tyrosine phosphatases
  • Other Vascular endothelial growth factor
  • NDC 460
  • Background: Receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) is a chondroitin sulphate (CS) transmembrane protein tyrosine phosphatase and is a receptor for pleiotrophin (PTN). RPTPβ/ζ interacts with ανβ3 on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, β3 Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated β3 Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF165) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - ανβ3 integrin association and subsequent signaling. In the present work, we studied whether RPTPβ/ζ mediates angiogenic actions of VEGF. Methods: Human umbilical vein endothelial, human glioma U87MG and stably transfected Chinese hamster ovary cells expressing different β3 subunits were used. Protein-protein interactions were studied by a combination of immunoprecipitation/Western blot, immunofluorescence and proximity ligation assays, properly quantified as needed. RPTPβ/ζ expression was down-regulated using small interference RNA technology. Migration assays were performed in 24-well microchemotaxis chambers, using uncoated polycarbonate membranes with 8 μm pores. Results: RPTPβ/ζ mediates VEGF165-induced c-Src-dependent β3 Tyr773 phosphorylation, which is required for VEGFR2-ανβ3 interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPβ/ζ directly interacts with VEGF165, and this interaction is not affected by bevacizumab, while it is interrupted by both CS-E and PTN. Down-regulation of RPTPβ/ζ by siRNA or administration of exogenous CS-E abolishes VEGF165-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF165 to the levels of its own effect. Conclusions: These data identify RPTPβ/ζ as a cell membrane binding partner for VEGF that regulates angiogenic functions of endothelial cells and suggest that it warrants further validation as a potential target for development of additive or alternative anti-VEGF therapies.
PublisherBiomed Central Ltd
Date Issued 2015-02-03
NIItypejournal article
Identifier URI
  • isIdenticalTo PMID 25644401
  • isIdenticalTo DOI
    • ISSN 1476-4598
    • Molecular Cancer
    14, 19