Roles of Serine/Threonine Phosphatases in Low-Dose Endothelial Monocyte-Activating Polypeptide-II-Induced Opening of Blood–Tumor Barrier
Autor: | Ping Wang, Yixue Xue, Jun Ma, Zhen Li, Yilong Yao, Yunhui Liu, Libo Liu, Jing Liu, Xiaobai Liu |
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Rok vydání: | 2015 |
Předmět: |
RHOA
macromolecular substances Occludin Capillary Permeability Dephosphorylation Cellular and Molecular Neuroscience chemistry.chemical_compound Cell Line Tumor Protein Phosphatase 1 Animals Guanine Nucleotide Exchange Factors Protein Phosphatase 2 Rats Wistar Rho-associated protein kinase Cells Cultured Protein Kinase C Protein kinase C rho-Associated Kinases biology Protein phosphatase 1 Glioma General Medicine Molecular biology Rats Cell biology chemistry biology.protein Phosphorylation Endothelium Vascular Tautomycin rhoA GTP-Binding Protein |
Zdroj: | Journal of Molecular Neuroscience. 57:11-20 |
ISSN: | 1559-1166 0895-8696 |
Popis: | Previous studies have demonstrated that low-dose endothelial monocyte-activating polypeptide-II (EMAP-II) induces blood-tumor barrier (BTB) opening via RhoA/Rho kinase/PKC-α/β signaling pathway. In a recent study, we revealed that low-dose EMAP-II induced significant increases in expression levels of serine/threonine (Ser/Thr) phosphatase (PP)1 and 2A in rat brain microvascular endothelial cells (RBMECs) of BTB model. In addition, PKC-ζ/PP2A signaling pathway is involved in EMAP-II-induced BTB hyperpermeability. The present study further investigated the exact roles of PPs in this process. In an in vitro BTB model, low-dose EMAP-II (0.05 nM) induced a significant increase in PP1 activity in RBMECs. There was an interaction between PKC-α/β and PP1 in RBMECs. Inhibition of PKC-α/β activity with GÖ6976 completely blocked EMAP-II-induced activation of PP1. Conversely, inhibition of PP1 activity with tautomycin had no effect on EMAP-II-induced PKC-α/β activation. Like GÖ6976, tautomycin significantly prevented EMAP-II-induced BTB hyperpermeability and MLC phosphorylation in RBMECs. Also, in this study, EMAP-II induced a marked redistribution of occludin and a significant dephosphorylation of occludin on Ser/Thr residues in RBMECs. Similar with GÖ6976 pretreatment, tautomycin pretreatment dramatically diminished EMAP-II-induced redistribution of occludin. Furthermore, pretreatment with tautomycin significantly inhibited EMAP-II-induced dephosphorylation of occludin on Ser residues. However, pretreatment with okadaic acid (an inhibitor of PP2A) significantly prevented changes in Ser-phosphorylated occludin induced by EMAP-II treatment. Collectively, this study demonstrates that low-dose EMAP-II increases BTB permeability via a RhoA/Rho kinase/PKC-α/β/PP1 signaling pathway and that PP1/PP2A-mediated Ser/Thr dephosphorylation of occludin plays an important role in EMAP-II-induced BTB hyperpermeability. |
Databáze: | OpenAIRE |
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