Wnt/β-catenin pathway in arrhythmogenic cardiomyopathy

Figures

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  Figure 1. Schematic representation of β-catenin–mediated canonical Wnt pathway (Left) In the absence of Wnt ligands, the Wnt signaling is suppressed. Cytosolic β-catenin is phosphorylated by a destruction complex composed of Axin, APC, GSK3β and CK1 and then ubiquitinated and targeted to proteasomal degradation. Into the nucleus, the transcription of Wnt target genes is repressed by Groucho binding to Tcf/Lef. (Right) Wnt activation. The binding of Wnt ligands to their receptors Fzd/LRP5/6/Dvl, determines the disruption of the β-catenin destruction complex, thus inducing the stabilization of the protein, which can translocate into the nucleus, function as a cofactor for Tcf/Lef and activate Wnt target genes (APC, adenomatous polyposis coli; β-cat, β-catenin; CK1, casein kinase cell factor/lymphoid enhancer-binding factor).

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  Figure 2. Models of AC pathogenesis AC gene mutations involve area composita and desmosome proteins (asterisks) and lead to abnormalities in intercalated disc (ID) consisting of cell adhesion defects, gap junction and ion channel remodelling. (A) Mutations in ID proteins can result also in the perturbation of the Wnt/β-catenin signaling. (B) Wnt/β-catenin signaling is suppressed in concomitance with the activation of Hippo pathway [93]. The impaired localization of phosphorylated protein kinase C-α to the perturbed IDs is associated with activation of neurofibromin 2 (NF2) and results in cascade phosphorylation leading to increased phospho-Yes-associated protein (pYAP) and its retention in the cytoplasm. pYAP interacts with β-catenin (β-cat), which is not able to translocate into the nucleus and, as a consequence, the expression of the effectors of both Hippo and canonical Wnt pathways (TEAD and Tcf/Lef, respectively) is suppressed and adipogenesis is enhanced (B1). Other experimental data reveal that loss of plakoglobin leads to the activation of AKT and the subsequent inhibition of glycogen synthase kinase 3β (GSK3β) resulting in the stabilization of β-cat and its translocation in the…