Pleiotrophin regulates lung epithelial cell proliferation and differentiation during fetal lung development via ß-catenin and Dlk1.
Weng T, Gao L, Bhaskaran M, Guo Y, Gou D, Narayanaperumal J, Chintagari NR, Zhang K, Liu L.
JBC Papers in Press published on August 6, 2009 as 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 beta/zeta, 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. Knock-down of pleiotrophin influenced lung branching morphogenesis in a fetal lung organ culture model. Pleiotrophin increased the tyrosine phosphorylation of beta-catenin, promoted beta-catenin translocation into the nucleus and activated TCF/LEF transcription factors. Dlk1, a membrane ligand that initiates the Notch signaling pathway, was identified as a down-stream target of the pleiotrophin/beta-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, beta-catenin and Notch pathways.
