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

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 α(ν)β(3) on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Ty...

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Autores principales: Koutsioumpa, Marina, Poimenidi, Evangelia, Pantazaka, Evangelia, Theodoropoulou, Christina, Skoura, Angeliki, Megalooikonomou, Vasileios, Kieffer, Nelly, Courty, Jose, Mizumoto, Shuji, Sugahara, Kazuyuki, Papadimitriou, Evangelia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323219/
https://www.ncbi.nlm.nih.gov/pubmed/25644401
http://dx.doi.org/10.1186/s12943-015-0287-3
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author Koutsioumpa, Marina
Poimenidi, Evangelia
Pantazaka, Evangelia
Theodoropoulou, Christina
Skoura, Angeliki
Megalooikonomou, Vasileios
Kieffer, Nelly
Courty, Jose
Mizumoto, Shuji
Sugahara, Kazuyuki
Papadimitriou, Evangelia
author_facet Koutsioumpa, Marina
Poimenidi, Evangelia
Pantazaka, Evangelia
Theodoropoulou, Christina
Skoura, Angeliki
Megalooikonomou, Vasileios
Kieffer, Nelly
Courty, Jose
Mizumoto, Shuji
Sugahara, Kazuyuki
Papadimitriou, Evangelia
author_sort Koutsioumpa, Marina
collection PubMed
description 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 α(ν)β(3) on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, β(3) Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated β(3) Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF(165)) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - α(ν)β(3) 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 β(3) 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 VEGF(165)-induced c-Src-dependent β(3) Tyr773 phosphorylation, which is required for VEGFR2-α(ν)β(3) interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPβ/ζ directly interacts with VEGF(165), 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 VEGF(165)-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF(165) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-015-0287-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-43232192015-02-11 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 Mol Cancer Research 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 α(ν)β(3) on the cell surface and upon binding of PTN leads to c-Src dephosphorylation at Tyr530, β(3) Tyr773 phosphorylation, cell surface nucleolin (NCL) localization and stimulation of cell migration. c-Src-mediated β(3) Tyr773 phosphorylation is also observed after vascular endothelial growth factor 165 (VEGF(165)) stimulation of endothelial cells and is essential for VEGF receptor type 2 (VEGFR2) - α(ν)β(3) 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 β(3) 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 VEGF(165)-induced c-Src-dependent β(3) Tyr773 phosphorylation, which is required for VEGFR2-α(ν)β(3) interaction and the downstream activation of phosphatidylinositol 3-kinase (PI3K) and cell surface NCL localization. RPTPβ/ζ directly interacts with VEGF(165), 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 VEGF(165)-induced endothelial cell migration, while PTN inhibits the migratory effect of VEGF(165) 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12943-015-0287-3) contains supplementary material, which is available to authorized users. BioMed Central 2015-02-03 /pmc/articles/PMC4323219/ /pubmed/25644401 http://dx.doi.org/10.1186/s12943-015-0287-3 Text en © Koutsioumpa et al.; licensee BioMed Central. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Koutsioumpa, Marina
Poimenidi, Evangelia
Pantazaka, Evangelia
Theodoropoulou, Christina
Skoura, Angeliki
Megalooikonomou, Vasileios
Kieffer, Nelly
Courty, Jose
Mizumoto, Shuji
Sugahara, Kazuyuki
Papadimitriou, Evangelia
Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
title Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
title_full Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
title_fullStr Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
title_full_unstemmed Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
title_short Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
title_sort receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323219/
https://www.ncbi.nlm.nih.gov/pubmed/25644401
http://dx.doi.org/10.1186/s12943-015-0287-3
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