Posttranslational modification of β-catenin is associated with pathogenic fibroblastic changes in bronchopulmonary dysplasia.

Sucre JM, Vijayaraj P, Aros CJ, Wilkinson D, Paul M, Dunn B, Guttentag SH, Gomperts BN
Am J Physiol Lung Cell Mol Physiol. 2017 312 (2): L186-L195

PMID: 27941077 · PMCID: PMC5336582 · DOI:10.1152/ajplung.00477.2016

Bronchopulmonary dysplasia (BPD) is a common complication of premature birth. The histopathology of BPD is characterized by an arrest of alveolarization with fibroblast activation. The Wnt/β-catenin signaling pathway is important in early lung development. When Wnt signaling is active, phosphorylation of β-catenin by tyrosine kinases at activating sites, specifically at tyrosine 489 (Y489), correlates with nuclear localization of β-catenin. We examined fetal lung tissue, lung tissue from term newborns, and lung tissue from infants who died with BPD; we found nuclear β-catenin phosphorylation at Y489 in epithelial and mesenchymal cells in fetal tissue and BPD tissue, but not in the lungs of term infants. Using a 3D human organoid model, we found increased nuclear localization of β-catenin phosphorylated at Y489 (p-β-catenin) after exposure to alternating hypoxia and hyperoxia compared with organoids cultured in normoxia. Exogenous stimulation of the canonical Wnt pathway in organoids was sufficient to cause nuclear localization of p-β-catenin in normoxia and mimicked the pattern of α-smooth muscle actin (α-SMA) expression seen with fibroblastic activation from oxidative stress. Treatment of organoids with a tyrosine kinase inhibitor prior to cyclic hypoxia-hyperoxia inhibited nuclear localization of p-β-catenin and prevented α-SMA expression by fibroblasts. Posttranslational phosphorylation of β-catenin is a transient feature of normal lung development. Moreover, the persistence of p-β-catenin is a durable marker of fibroblast activation in BPD and may play an important role in BPD disease pathobiology.

Copyright © 2017 the American Physiological Society.

MeSH Terms (18)

Actins beta Catenin Bronchopulmonary Dysplasia Cell Nucleus Dasatinib Fibroblasts Humans Hyperoxia Hypoxia Infant, Newborn Lung Organoids Phosphorylation Protein Kinase Inhibitors Protein Processing, Post-Translational Protein Transport Up-Regulation Wnt Signaling Pathway

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