Distinct Roles of Wnt/β-Catenin Signaling in the Pathogenesis of Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis

Figure 1

Illustration of Wnt signaling cascades. Based on the dependence of β-catenin, Wnt signaling can be classified as β-catenin-dependent Wnt signaling pathway (canonical Wnt signaling pathway) and β-catenin-independent Wnt signaling pathway (noncanonical Wnt signaling pathway). In canonical Wnt signaling pathway, in the absence of Wnt ligand(s), cytoplasmic β-catenin is targeted for phosphorylation by a multiprotein complex comprised of Axin, adenomatous polyposis coli (APC), glycogen synthase kinase 3β (GSK3β), and casein kinase 1α (CK1α). The phosphorylated form of β-catenin is recognized by an E3 ubiquitin ligase (β-TrCP) and then targeted for proteosomal degradation, resulting in low cytosolic levels (left panel); in the presence of Wnt ligand(s), Wnt ligand binds to a FZD and LRP coreceptors, which triggers a signaling cascade by activating Dvl. The activated Dvl inhibits GSK3β, which destroys the stability of the multiprotein complex and accordingly leads to the intracellular accumulation of cytosolic β-catenin. The stable and active β-catenin then translocates into the nucleus, in which it acts as a transcriptional coactivator with TCF/LEF to activate Wnt-responsive target genes (left panel). In a noncanonical Wnt signaling pathway, Wnt ligand (such as the Wnt5a, a typical noncanonical Wnt) binds to its receptor (FZD) and coreceptor (Ror1/2) and triggers noncanonical signaling cascades, which include the Wnt/calcium (Ca²⁺) and Wnt/planar cell polarity (PCP) pathways. In the Wnt/Ca²⁺ pathway (left panel), Wnt protein binds to FZD and Ror2 receptor and leads to activated G proteins, resulting in enhanced intracellular calcium level or decreased cGMP; the calcium/calmodulin-dependent protein kinase II (CaMKII) or protein kinase C (PKC) was then activated. In the Wnt/PCP pathway (right panel), the Wnt ligand binds to a FZD receptor on the cell surface, followed by activating Rho/Rac small GTPase and Jun N-terminal kinase (JNK) to assist with cytoskeletal organization and gene expression (right panel).