WNT Signaling in Lung Disease

Abstract

The WNT family of signaling proteins is essential to organ development in general and lung morphogenesis in particular. Originally identified as a developmentally active signaling pathway, the WNT pathway has recently been linked to the pathogenesis of important lung diseases, in particular lung cancer and pulmonary fibrosis. This review summarizes our current understanding about WNT signaling in lung development and disease, and is structured into three chapters. The first chapter presents an introduction to WNT signaling, outlining WNT proteins, their receptors and signaling intermediates, as well as the regulation of this complex pathway. The second chapter focuses on the role of WNT signaling in the normal embryonic and adult lung, and highlights recent findings of altered WNT signaling in lung diseases, such as lung cancer, pulmonary fibrosis, or pulmonary arterial hypertension. In the last chapter, we will discuss novel data and ideas about the biological effects of WNT signaling on the cellular level, highlighting pleiotropic effects induced by WNT ligands on distinct cell types, and how these cellular effects may be relevant to the pathogenesis of the aforementioned diseases.

Ghrelin ameliorates hypoxia-induced pulmonary hypertension via phospho-GSK3β/β-catenin signaling in neonatal rats

“…The activity of GSK3b is inhibited by phosphorylation of serine 9. Subsequently, b-catenin is neither phosphorylated nor degraded and accumulates in the cytoplasm where it is translocated into the nucleus and acts as a cotranscriptional activator of Lef1/T-cell factor regulating downstream target genes such as Pparg, Tnc, and Myc (Van Scoyk et al 2008, Konigshoff & Eickelberg 2010. Wnt signaling has recently been suggested to regulate smooth muscle cell precursor proliferation and development in embryonic lung development and adult lung disease.…”

The lens as a model for fibrotic disease

“…The Wnt signalling pathway has also been implicated in fibrotic disorders and is reported to play a key role in TGFb-induced transdifferentiation [95][96][97][98]. The canonical Wnt signalling pathway regulates b-catenin activity.…”

“…Wnt ligand binding to receptors (Frizzled) and co-receptor low-density lipoprotein receptor-related protein (LRP) leads to the phosphorylation of LRP6, by glycogen synthase kinase-3b (GSK-3b) and casein kinase g, in its cytoplasmic region. This leads to the recruitment of cytosolic proteins, dishevelled and axin [96]. As a result of the association of GSK-3b with Frizzled receptors and LRP, b-catenin phosphorylation is reduced.…”

Regulation and role of notch signaling in epithelial progenitor cell differentiation and proliferation in the normal and the fibrotic lung

“…Another pathway which plays a major role in lung development and adult tissue homeostasis is the Wnt/β-catenin network (127). Epithelial cell-specific expression of constitutively active β-catenin leads to epithelial cell dysplasia and ectopic differentiation of alveolar epithelial type II cells in the conducting airways during embryonic development.…”