Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor.
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 (VEGFâ‚₆₅) 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.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.RPTPβ/ζ mediates VEGFâ‚₆₅-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 VEGFâ‚₆₅-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGFâ‚₆₅ to the levels of its own effect.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.
Mesh Terms:
Animals, CHO Cells, Cell Line, Cell Movement, Cricetulus, Down-Regulation, Glioma, Human Umbilical Vein Endothelial Cells, Humans, Integrins, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Binding, Protein Interaction Maps, RNA, Small Interfering, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Vascular Endothelial Growth Factor A
Animals, CHO Cells, Cell Line, Cell Movement, Cricetulus, Down-Regulation, Glioma, Human Umbilical Vein Endothelial Cells, Humans, Integrins, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Binding, Protein Interaction Maps, RNA, Small Interfering, Receptor-Like Protein Tyrosine Phosphatases, Class 5, Vascular Endothelial Growth Factor A
Mol. Cancer
Date: Feb. 03, 2015
PubMed ID: 25644401
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