| First Author | Weng J | Year | 2019 |
| Journal | J Mol Cell Cardiol | Volume | 127 |
| Pages | 174-184 | PubMed ID | 30592964 |
| Mgi Jnum | J:269930 | Mgi Id | MGI:6273048 |
| Doi | 10.1016/j.yjmcc.2018.12.012 | Citation | Weng J, et al. (2018) beta-Catenin phosphorylation at Y654 and Y142 is crucial for high mobility group box-1 protein-induced pulmonary vascular hyperpermeability. J Mol Cell Cardiol 127:174-184 |
| abstractText | OBJECTIVE: Endothelial hyperpermeability is a hallmark of acute lung injury in response to sepsis. The imbalance between adherence junction (AJ) mediated cell-cell adherence forces and stress fiber driven contractile forces contributes to increased endothelial permeability. Here, we spotlight the effects of beta-catenin Y654 andY142 phosphorylation on HMGB1-mediated endothelial barrier leakage. APPROACH AND RESULTS: Our results showed that phospho-deficiencies at both beta-catenin Y654and Y142ameliorated pulmonary vascular dysfunction in male C57 mice receiving a cecal ligation and puncture operation. In vitro analysis indicated that high mobility group box-1 protein (HMGB1) triggered beta-catenin Y654 and Y142 phosphorylation, causing beta-catenin translocation and adherence junction (AJ) disruptions as well as cytoskeleton rearrangement. In addition,beta-catenin Y654 dephosphorylation attenuated HMGB1-mediated dissociation of VE-cadherin/beta-catenin and, hence, partially prevented endothelial hyperpermeability. beta-catenin Y142 dephosphorylation abolished HMGB1-induced uncoupling of beta-catenin and alpha-catenin, suppressed cytoskeletal reassembly and, hence, alleviated endothelial hyperpermeability. Further investigation demonstrated that RAGE and Src were required forbeta-catenin Y654 phosphorylation in response to HMGB1, while FAK was responsible for HMGB1-triggered beta-catenin Y142 phosphorylation. CONCLUSIONS: In sum, this study revealed the role of beta-catenin Y654 and Y142 phosphorylation in HMGB1-mediated endothelial hyperpermeability through dysregulation between adherence and contractile forces. This result advances understanding of the mechanisms underlying pulmonary vascular hyperpermeability in sepsis. |
