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

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Title: Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
Authors: Koutsioumpa, Marina Browse this author
Poimenidi, Evangelia Browse this author
Pantazaka, Evangelia Browse this author
Theodoropoulou, Christina Browse this author
Skoura, Angeliki Browse this author
Megalooikonomou, Vasileios Browse this author
Kieffer, Nelly Browse this author
Courty, Jose Browse this author
Mizumoto, Shuji Browse this author
Sugahara, Kazuyuki Browse this author →KAKEN DB
Papadimitriou, Evangelia Browse this author
Keywords: Chondroitin sulphate
Endothelial cells
Tyrosine phosphatases
Vascular endothelial growth factor
Issue Date: 3-Feb-2015
Publisher: Biomed Central Ltd
Journal Title: Molecular Cancer
Volume: 14
Start Page: 19
Publisher DOI: 10.1186/s12943-015-0287-3
PMID: 25644401
Abstract: 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.
Type: article
Appears in Collections:生命科学院・先端生命科学研究院 (Graduate School of Life Science / Faculty of Advanced Life Science) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 菅原 一幸

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