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

Tingting Weng,Li Gao,Manoj Bhaskaran,Yujie Guo,Deming Gou,Jeyaparthasarathy Narayanaperumal,Narendranath Reddy Chintagari,Kexiong Zhang,Lin Liu

doi:10.1074/jbc.m109.052530

Abstract

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. Knockdown 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 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/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.

Highlights

Grant R01 HL-052146, R01 HL-071628, and R01 HL-083188
Fibroblast growth factor 10 in turn binds to its receptor, which is located on the surface of epithelial cells
PTN and RPTP ␤/␨ Expression in the Developing Lung—We have previously shown that PTN mRNA and protein are highly expressed in the late stage of fetal lung development by analyzing fetal lungs at different gestational days as well as the lungs of newborn and adult rats using DNA microarray analysis, realtime PCR, and Western blots [19]

Summary

Introduction

Grant R01 HL-052146, R01 HL-071628, and R01 HL-083188 The regulation of fetal lung development includes coordinated regulation of molecular pathways as well as reciprocal interactions among mesenchymal cells, epithelial cells, and the extracellular matrix [2]. Fibroblast growth factor 10 in turn binds to its receptor, which is located on the surface of epithelial cells. The interaction between Shh and Ptc has been shown to be required for lung bud formation [5] Other growth factors such as platelet-derived growth factor, transforming growth factor-␤, epidermal growth factor, and vascular endothelial growth factor play active roles in mesenchyme-epithelium interactions [2]. In U373-MG glioblastoma cells, the binding of PTN with RPTP ␤/␨ results in the dimerization and inactivation of the receptor, leading to an increase in tyrosine phosphorylation of ␤-catenin [16]. PTN may act via the receptor-tyrosine kinase, anaplastic lymphoma kinase receptor [17]

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