Molecular Cancer | |
Receptor protein tyrosine phosphatase beta/zeta is a functional binding partner for vascular endothelial growth factor | |
Research | |
Vasileios Megalooikonomou1  Angeliki Skoura1  Jose Courty2  Evangelia Pantazaka3  Evangelia Papadimitriou3  Evangelia Poimenidi3  Christina Theodoropoulou3  Marina Koutsioumpa4  Kazuyuki Sugahara5  Shuji Mizumoto6  Nelly Kieffer7  | |
[1] Computer Engineering and Informatics Department, University of Patras, GR 26504, Patras, Greece;Laboratoire CRRET, Universite Paris Est Creteil Val de Marne, Paris, France;Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504, Patras, GR, Greece;Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, 26504, Patras, GR, Greece;Current address: Center for Systems Biomedicine, Division of Digestive Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA;Proteoglycan Signaling and Therapeutics Research Group, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan;Proteoglycan Signaling and Therapeutics Research Group, Faculty of Advanced Life Science, Hokkaido University, Sapporo, Japan;Current address: Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 463-8503, Nagoya, Japan;Sino-French Research Centre for Life Sciences and Genomics, CNRS/LIA124, Rui Jin Hospital, Jiao Tong University Medical School, Shanghai, China; | |
关键词: Chondroitin sulphate; Endothelial cells; Migration; Pleiotrophin; Tyrosine phosphatases; Vascular endothelial growth factor; | |
DOI : 10.1186/s12943-015-0287-3 | |
received in 2014-05-22, accepted in 2015-01-02, 发布年份 2015 | |
来源: Springer | |
【 摘 要 】
BackgroundReceptor 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.MethodsHuman 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.ResultsRPTPβ/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.ConclusionsThese 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.
【 授权许可】
Unknown
© 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.
【 预 览 】
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