Pleiotrophin Regulates Lung Epithelial Cell Proliferation and Differentiation during Fetal Lung Development via β-Catenin and Dlk1

• Published in: The Journal of biological chemistry 2009-10, Vol.284 (41), p.28021-28032
• Main Authors: Weng, Tingting, Gao, Li, Bhaskaran, Manoj, Guo, Yujie, Gou, Deming, Narayanaperumal, Jeyaparthasarathy, Chintagari, Narendranath Reddy, Zhang, Kexiong, Liu, Lin
• Format: Article
• Language: English
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Carrier Proteins - pharmacology; Cell Differentiation - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Cytokines - pharmacology; Epithelial Cells - cytology; Epithelial Cells - drug effects; Epithelial Cells - physiology; Female; Fetus - anatomy & histology; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Lung - anatomy & histology; Lung - embryology; Membrane Proteins - genetics; Membrane Proteins - metabolism; Molecular Basis of Cell and Developmental Biology; Morphogenesis - drug effects; Pregnancy; Promoter Regions, Genetic; Rats; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - metabolism; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction - physiology; TCF Transcription Factors - metabolism; Tissue Culture Techniques
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M109.052530

The role of pleiotrophin in fetal lung development was investigated. We found that pleiotrophin and its receptor, protein-tyrosine phosphatase receptor β/ζ, were highly expressed in mesenchymal and epithelial cells of the fetal lungs, respectively. Using isolated fetal alveolar epithelial type II cells, we demonstrated that pleiotrophin promoted fetal type II cell proliferation and arrested type II cell trans-differentiation into alveolar epithelial type I cells. Pleiotrophin also increased wound healing of injured type II cell monolayer. Knockdown of pleiotrophin influenced lung branching morphogenesis in a fetal lung organ culture model. Pleiotrophin increased the tyrosine phosphorylation of β-catenin, promoted β-catenin translocation into the nucleus, and activated T cell factor/lymphoid enhancer factor transcription factors. Dlk1, a membrane ligand that initiates the Notch signaling pathway, was identified as a downstream target of the pleiotrophin/β-catenin pathway by endogenous dlk1 expression, promoter assay, and chromatin immunoprecipitation. These results provide evidence that pleiotrophin regulates fetal type II cell proliferation and differentiation via integration of multiple signaling pathways including pleiotrophin, β-catenin, and Notch pathways.