Targeting Canonical Wnt-signaling Through GSK-3β in Arrhythmogenic Cardiomyopathy: Conservative or Progressive?

Figures

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  Fig. 1. Flowchart of study selection methodology

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  Fig. 2. Diagrammatic representation of the cardiac ID. Among others, the multi-protein structure contains adherens junctions and desmosomes (involved in mechanical cell–cell adhesion) as well as gap junctions (involved in electrical propagation). Figure created with powerpoint

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  Fig. 3. Representation of canonical Wnt signaling. LEFT: Upon binding of Wnt ligands to Fzd/LRP5/6 receptors, Dvl recruits GSK3β, APC and axin into the destruction complex. Active GSK3β phosphorylates serine/threonine residues on the N-terminal domain of β-catenin targeting it for ubiquitination and proteasomal degradation. RIGHT: In the absence of Wnt signals, Dvl activity is inhibited by Fzd. Accordingly, the destruction complex is not formed and β-catenin is free to enter the nucleus where it interacts with the TCF/LEF transcription factors to drive expression of target genes including c-Myc and Cyclin D1. Figure created with draw.io

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  Fig. 4. Representation of canonical Wnt/Hippo pathway crosstalk. Upon activation, MST1/2 phosphorylates LATS1/2 and its scaffold protein MOB1. Active LATS1/2 then phosphorylates and inactivates YAP/TAZ preventing it from translocating into the nucleus and binding to the TEAD transcription factors. There is bidirectional modulation and regulation between the pathways, where YAP/TAZ is inhibited by the Axin/APC/GSK-3β destruction complex. Figure created with draw.io

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  Fig. 5. Illustration of major speculatory concerns over GSK-3β inhibitors in ACM