In cardiac muscle, β-catenin localizes to adherens junctions in intercalated disc structures, which are critical for electrical and mechanical coupling between adjacent cardiomyocytes.

β-Catenin was initially discovered in the early 1990s as a component of a mammalian cell adhesion complex: a protein responsible for cytoplasmatic anchoring of cadherins.

[11] But very soon, it was realized that the Drosophila protein armadillo – implicated in mediating the morphogenic effects of Wingless/Wnt – is homologous to the mammalian β-catenin, not just in structure but also in function.

[13] Due to the complex shape of individual repeats, the whole ARM domain is not a straight rod: it possesses a slight curvature, so that an outer (convex) and an inner (concave) surface is formed.

The N-terminal disordered region contains a conserved short linear motif responsible for binding of TrCP1 (also known as β-TrCP) E3 ubiquitin ligase – but only when it is phosphorylated.

This segment is not fully disordered: part of the C-terminal extension forms a stable helix that packs against the ARM domain, but may also engage separate binding partners.

[16] Notably, the C-terminal segment of β-catenin can mimic the effects of the entire Wnt pathway if artificially fused to the DNA binding domain of LEF1 transcription factor.

Not only their ARM domains resemble each other in both architecture and ligand binding capacity, but the N-terminal β-TrCP-binding motif is also conserved in plakoglobin, implying common ancestry and shared regulation with β-catenin.

[21] This structure demonstrated how the otherwise disordered N-terminus of TCF adapted what appeared to be a rigid conformation, with the binding motif spanning many beta-catenin repeats.

[26] Since the surface of the ARM domain can typically accommodate only one peptide motif at any given time, all these proteins compete for the same cellular pool of β-catenin molecules.

The first helices of the ARM domain form an additional, special protein-protein interaction pocket: This can accommodate a helix-forming linear motif found in the coactivator BCL9 (or the closely related BCL9L) – an important protein involved in Wnt signaling.

There is one additional requirement: Similar to the mitogen-activated protein kinases (MAPKs), substrates need to associate with this enzyme through high-affinity docking motifs.

Importantly, the cytoplasmic segments of the Frizzled-associated LRP5 and LRP6 proteins contain GSK3 pseudo-substrate sequences (Pro-Pro-Pro-Ser-Pro-x-Ser), appropriately "primed" (pre-phosphorylated) by CKI, as if it were a true substrate of GSK3.

Wnt signaling and β-catenin dependent gene expression plays a critical role during the formation of different body regions in the early embryo.

This feature being shared by vertebrate and arthropod bilateria, and by cnidaria, it was proposed to have been evolutionary inherited from its possible involvement in the endomesoderm specification of first metazoa.

Fertilization of the egg causes a rotation of the outer cortical layers, moving clusters of the Frizzled and Dsh proteins closer to the equatorial region.

Similarly to the Xenopus oocytes, this is essentially the result of non-equal distribution of Dsh, Frizzled, axin and APC in the cytoplasm of the mother cell.

Initially, the activation of Wnt/β-catenin is essential for committing mesenchymal cells to a cardiac lineage; however, in later stages of development, the downregulation of β-catenin is required.

Studies in a model of adult rat ventricular cardiomyocytes have shown that the appearance and distribution of β-catenin is spatio-temporally regulated during the redifferentiation of these cells in culture.

Specifically, β-catenin is part of a distinct complex with N-cadherin and alpha-catenin, which is abundant at adherens junctions in early stages following cardiomyocyte isolation for the reformation of cell–cell contacts.

Knocking out emerin significantly altered β-catenin localization and the overall intercalated disc architecture, which resembled a dilated cardiomyopathy phenotype.

[58] In a hamster model of cardiomyopathy and heart failure, cell–cell adhesions were irregular and disorganized, and expression levels of adherens junction/intercalated disc and nuclear pools of β-catenin were decreased.

[59] These data suggest that a loss of β-catenin may play a role in the diseased intercalated discs that have been associated with cardiac muscle hypertrophy and heart failure.

In a rat model of myocardial infarction, adenoviral gene transfer of nonphosphorylatable, constitutively-active β-catenin decreased MI size, activated the cell cycle, and reduced the amount of apoptosis in cardiomyocytes and cardiac myofibroblasts.

This finding was coordinate with enhanced expression of pro-survival proteins, survivin and Bcl-2, and vascular endothelial growth factor while promoting the differentiation of cardiac fibroblasts into myofibroblasts.

These changes were coordinate with Akt activation and glycogen synthase kinase 3β inhibition, suggesting once again that the abnormal stabilization of β-catenin may be involved in the development of cardiomyopathy.

Electrocardiogram measurements captured spontaneous lethal ventricular arrhythmias in the double transgenic animals, suggesting that the two catenins—β-catenin and plakoglobin—are critical and indispensable for mechanoelectrical coupling in cardiomyocytes.

[69] In a particular study, patients with end-stage dilated cardiomyopathy showed almost doubled estrogen receptor alpha (ER-alpha) mRNA and protein levels, and the ER-alpha/beta-catenin interaction, present at intercalated discs of control, non-diseased human hearts was lost, suggesting that the loss of this interaction at the intercalated disc may play a role in the progression of heart failure.

The potential of β-catenin to change the previously epithelial phenotype of affected cells into an invasive, mesenchyme-like type contributes greatly to metastasis formation.

[86] The proteins BCL9 and BCL9L have been proposed as therapeutic targets for colorectal cancers which present hyper-activated Wnt signaling, because their deletion does not perturb normal homeostasis but strongly affects metastases behaviour.