Role of the Tyrosine Phosphatase SHP-2 in Mediating Adrenomedullin Proangiogenic Activity in Solid Tumors.
| Autor: | Sigaud R; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France., Dussault N; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France., Berenguer-Daizé C; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France., Vellutini C; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France., Benyahia Z; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France., Cayol M; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France., Parat F; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France., Mabrouk K; Aix Marseille University, CNRS, Institut de Chimie Radicalaire (ICR), Unité Mixte de Recherche (UMR) 7273 Chimie Radicalaire Organique et Polymères de Spécialité (CROPS), Marseille, France., Vázquez R; Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France.; Center 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, Italy., Riveiro ME; Preclinical Department, Early Drug Development Group (E2DG), Boulogne-Billancourt, France., Metellus P; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France.; Centre Hospitalier Clairval, Département de Neurochirurgie, Marseille, France., Ouafik L; Aix Marseille University, Centre National de la Recherche Scientifique (CNRS), Institut de Neurophysiopathologie( INP), Inst Neurophysiopathol, Marseille, France.; Assistance Publique Hôpitaux de Marseille (APHM), Centre Hospitalo Universitaire (CHU) Nord, Service d'OncoBiologie, Marseille, France. |
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| Jazyk: | angličtina |
| Zdroj: | Frontiers in oncology [Front Oncol] 2021 Oct 08; Vol. 11, pp. 753244. Date of Electronic Publication: 2021 Oct 08 (Print Publication: 2021). |
| DOI: | 10.3389/fonc.2021.753244 |
| Abstrakt: | 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-cadherin Y731 ) 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-cadherin Y731 takes place through activation of the tyrosine phosphatase SHP-2, as judged by the rise of its active fraction phosphorylated at tyrosine 542 (pSHP-2 Y542 ) 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-cadherin Y731 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-2 Y542 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-2 Y542 to finally modulate cell-cell junctions in the angiogenesis process, thereby promoting a stable and functional tumor vasculature. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Sigaud, Dussault, Berenguer-Daizé, Vellutini, Benyahia, Cayol, Parat, Mabrouk, Vázquez, Riveiro, Metellus and Ouafik.) |
| Databáze: | MEDLINE |
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