Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors
VE-cadherin is an essential adhesion molecule in endothelial adherens junctions, and the integrity of these complexes is thought to be regulated by VE-cadherin tyrosine phosphorylation. We have previously shown that adrenomedullin (AM) blockade correlates with elevated levels of phosphorylated VE-ca...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-10-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.753244/full |
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| author | Romain Sigaud Nadège Dussault Caroline Berenguer-Daizé Christine Vellutini Zohra Benyahia Mylène Cayol Fabrice Parat Kamel Mabrouk Ramiro Vázquez Ramiro Vázquez Maria E. Riveiro Philippe Metellus Philippe Metellus L’Houcine Ouafik L’Houcine Ouafik |
| author_facet | Romain Sigaud Nadège Dussault Caroline Berenguer-Daizé Christine Vellutini Zohra Benyahia Mylène Cayol Fabrice Parat Kamel Mabrouk Ramiro Vázquez Ramiro Vázquez Maria E. Riveiro Philippe Metellus Philippe Metellus L’Houcine Ouafik L’Houcine Ouafik |
| author_sort | Romain Sigaud |
| collection | DOAJ |
| description | VE-cadherin is an essential adhesion molecule in endothelial adherens junctions, and the integrity of these complexes is thought to be regulated by VE-cadherin tyrosine phosphorylation. We have previously shown that adrenomedullin (AM) blockade correlates with elevated levels of phosphorylated VE-cadherin (pVE-cadherinY731) in endothelial cells, associated with impaired barrier function and a persistent increase in vascular endothelial cell permeability. However, the mechanism underlying this effect is unknown. In this article, we demonstrate that the AM-mediated dephosphorylation of pVE-cadherinY731 takes place through activation of the tyrosine phosphatase SHP-2, as judged by the rise of its active fraction phosphorylated at tyrosine 542 (pSHP-2Y542) in HUVECs and glioblastoma-derived-endothelial cells. Both pre-incubation of HUVECs with SHP-2 inhibitors NSC-87877 and SHP099 and SHP-2 silencing hindered AM-induced dephosphorylation of pVE-cadherinY731 in a dose dependent-manner, showing the role of SHP-2 in the regulation of endothelial cell contacts. Furthermore, SHP-2 inhibition impaired AM-induced HUVECs differentiation into cord-like structures in vitro and impeded AM-induced neovascularization in in vivo Matrigel plugs bioassays. Subcutaneously transplanted U87-glioma tumor xenograft mice treated with AM-receptors-blocking antibodies showed a decrease in pSHP-2Y542 associated with VE-cadherin in nascent tumor vasculature when compared to control IgG-treated xenografts.Our findings show that AM acts on VE-cadherin dynamics through pSHP-2Y542 to finally modulate cell-cell junctions in the angiogenesis process, thereby promoting a stable and functional tumor vasculature. |
| first_indexed | 2024-12-21T06:23:06Z |
| format | Article |
| id | doaj.art-213926a4514e458da5ff6110a8a97da0 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T06:23:06Z |
| publishDate | 2021-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-213926a4514e458da5ff6110a8a97da02022-12-21T19:13:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-10-011110.3389/fonc.2021.753244753244Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid TumorsRomain Sigaud0Nadège Dussault1Caroline Berenguer-Daizé2Christine Vellutini3Zohra Benyahia4Mylène Cayol5Fabrice Parat6Kamel Mabrouk7Ramiro Vázquez8Ramiro Vázquez9Maria E. Riveiro10Philippe Metellus11Philippe Metellus12L’Houcine Ouafik13L’Houcine Ouafik14Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAix Marseille University, CNRS, Institut de Chimie Radicalaire (ICR), Unité Mixte de Recherche (UMR) 7273 Chimie Radicalaire Organique et Polymères de Spécialité (CROPS), Marseille, FrancePreclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, FranceCenter for Genomic Science of Istituto Italiano di Tecnologia, Center for Genomic Science, European School of Molecular Medicine (IIT@SEMM), Fondazione Istituto Italiano di Tecnologia (IIT), Milan, ItalyPreclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceCentre Hospitalier Clairval, Département de Neurochirurgie, Marseille, FranceAix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, FranceAssistance Publique Hôpitaux de Marseille (APHM), Centre Hospitalo Universitaire (CHU) Nord, Service d’OncoBiologie, Marseille, FranceVE-cadherin is an essential adhesion molecule in endothelial adherens junctions, and the integrity of these complexes is thought to be regulated by VE-cadherin tyrosine phosphorylation. We have previously shown that adrenomedullin (AM) blockade correlates with elevated levels of phosphorylated VE-cadherin (pVE-cadherinY731) in endothelial cells, associated with impaired barrier function and a persistent increase in vascular endothelial cell permeability. However, the mechanism underlying this effect is unknown. In this article, we demonstrate that the AM-mediated dephosphorylation of pVE-cadherinY731 takes place through activation of the tyrosine phosphatase SHP-2, as judged by the rise of its active fraction phosphorylated at tyrosine 542 (pSHP-2Y542) in HUVECs and glioblastoma-derived-endothelial cells. Both pre-incubation of HUVECs with SHP-2 inhibitors NSC-87877 and SHP099 and SHP-2 silencing hindered AM-induced dephosphorylation of pVE-cadherinY731 in a dose dependent-manner, showing the role of SHP-2 in the regulation of endothelial cell contacts. Furthermore, SHP-2 inhibition impaired AM-induced HUVECs differentiation into cord-like structures in vitro and impeded AM-induced neovascularization in in vivo Matrigel plugs bioassays. Subcutaneously transplanted U87-glioma tumor xenograft mice treated with AM-receptors-blocking antibodies showed a decrease in pSHP-2Y542 associated with VE-cadherin in nascent tumor vasculature when compared to control IgG-treated xenografts.Our findings show that AM acts on VE-cadherin dynamics through pSHP-2Y542 to finally modulate cell-cell junctions in the angiogenesis process, thereby promoting a stable and functional tumor vasculature.https://www.frontiersin.org/articles/10.3389/fonc.2021.753244/fulladrenomedullinSHP-2endothelial cellcell-cell adhesionsangiogenesisglioblastoma-associated endothelial cells |
| spellingShingle | Romain Sigaud Nadège Dussault Caroline Berenguer-Daizé Christine Vellutini Zohra Benyahia Mylène Cayol Fabrice Parat Kamel Mabrouk Ramiro Vázquez Ramiro Vázquez Maria E. Riveiro Philippe Metellus Philippe Metellus L’Houcine Ouafik L’Houcine Ouafik Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors Frontiers in Oncology adrenomedullin SHP-2 endothelial cell cell-cell adhesions angiogenesis glioblastoma-associated endothelial cells |
| title | Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors |
| title_full | Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors |
| title_fullStr | Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors |
| title_full_unstemmed | Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors |
| title_short | Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors |
| title_sort | role of the tyrosine phosphatase shp 2 in mediating adrenomedullin proangiogenic activity in solid tumors |
| topic | adrenomedullin SHP-2 endothelial cell cell-cell adhesions angiogenesis glioblastoma-associated endothelial cells |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.753244/full |
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