[4] It has been observed that when α-catenin is not in a molecular complex with β-catenin, it dimerizes and functions to regulate actin filament assembly,[5] possibly by competing with Arp2/3 protein.

Its direct relationship with cytoskeletal components was not reported until almost a decade later.4 From 1994-1996, the characterization of interaction domains between α-catenin, beta-catenin, and plakoglobin were defined.

In parallel, from the early 1990s to about 2010, α-catenin dysregulation was widely implicated in various cancers ranging from breast, esophageal, Laryngeal, Prostate, Thyroid, Lung, Pancreatic, bladder, and more.5 In lieu of this research, the data suggests that α-catenin plays a more profound role than just stabilizing adhesion-junctions and promoting cell-cell adhesion.

Simply put, in the cadherin-catenin complex, cadherin molecules are linked through beta-catenin to α-Catenin, which then binds to filamentous actin (F-actin).

9 Le et al. quantified the stability of the mechanotransduction properties of the α‐catenin/β‐catenin complex and showed that it can be stable for hundreds of seconds, at physiological force ranges.10 Additionally, they showed that phosphorylation of the complex severely reduces this time by up to 10-fold.10 Despite this canonical structure, there is also evidence of α-catenin being found in the cytosol dimerized with itself or bound with Beta-catenin.

αE-catenin primarily found in epithelium and the canonical catenin of the three, αN-catenin found in neural tissues, and αT-catenin found primarily in the heart.13 As a homodimer, α-catenin, binds directly to F-actin.14 Wood et al. show that a chemical induction of homodimerization α-catenin reproduces in vitro its recruitment to the cell periphery.15 They expand further on this notion by showing that this recruitment promotes protrusion of filopodia and accumulates actin at the edges.15 This interaction is largely mediated by phosphatidylinositol 3-kinase and overall promotes cell adhesion and orientation.15 Other studies show that α-catenin can interact with many different actin-binding proteins (α-actinin, ZO-1, afadin) to remodel cytoskeletal structure.

16-18 Along the same vein, a study found that in vascular endothelial cells, the fusion of VE-cadherin to α-catenin enhances its interaction with F-actin and this leads to a stronger endothelial barrier blocking inflammatory processes.19 Duong et al. expanded on these findings by reporting that the α1-helix of the actin-binding domain (ABD), exposed in this chimeric fusion protein, is responsible for stabilizing the adherence junctions and creating a stronger bond with actin.20 More importantly the discovered that this epitope is exposed in normal α-catenin when there is thrombin activity hence the constitutive reinforced binding to actin can be found in nonchimeric α-catenin and may play a role in other cell types.20 In 2001, Vasioukhen et al. targeted the ablation of α-catenin in mouse embryonic skin and reported that although cell adhesion was present, the epithelium exhibited a phenotypic mass of hyperproliferative epithelia that was reminiscent of squamous cell carcinoma.

22 Some of the mechanisms by which RhoGEF on endosomes interact with α-catenin to establish cell polarity and migration have been elucidate via biosensors and depletion assays.23 Vassilev et al. have described the regulation of cell migration by a pathway found on endosomes that is driven in part by α-catenin.

21, 22 In the central nervous system, the ablation of αE-catenin resulted in brain hyperplasia and discovery of an upregulation in sonic hedgehog (shh) signaling.

25 It was found that αE-catenin also played a role in the Hippo pathway as a tumor suppressor by inhibiting the nuclear translocation of YAP1.26 This group found that by deleting αE-catenin in the stem cell niche of the skin, there was an accumulation os SOX 9+ progenitors that hyper proliferate resulting in early onset of squamous cell carcinoma.

This entire process was attributed to YAP signaling and the Hippo Pathway.26 Recent research by Pavel et al. describe α-catenin’s involvement in a feedback look mechanism of autophagy negatively regulating the levels of α-catenin, LC3-interacting proteins inhibiting the YAP/TAZ oncogenes, resulting in upregulating of autophagy.

27They further report that this feedback loop maybe tissue context specific as it negatively regulates epithelial cell proliferation in the skin while positively affects those in the liver.

30 In parallel, choi et al., found a different mechanism by which α-catenin binds beta-catenin to TCF/LEF family DNA-binding proteins and recruits APC into a histone complex to regulate transcription of Wnt target genes.

33 Dictyostelium discoideum, a slime mold, has been shown to have both beta-catenin and α-catenin homologues named Aardvark and Ddα-catenin respectively.34 Additionally, they display similar interactions of binding with each other as has been observed in eukaryotes.

Vestweber D, Kemler R. Rabbit antiserum against a purified surface glycoprotein decompacts mouse preimplantation embryos and reacts with specific adult tissues.

Ishiyama N, Tanaka N, Abe K, Yang YJ, Abbas YM, Umitsu M, et al. An autoinhibited structure of alpha-catenin and its implications for vinculin recruitment to adherens junctions.

Watabe-Uchida M, Uchida N, Imamura Y, Nagafuchi A, Fujimoto K, Uemura T, et al. alpha-Catenin-vinculin interaction functions to organize the apical junctional complex in epithelial cells.

Wood MN, Ishiyama N, Singaram I, Chung CM, Flozak AS, Yemelyanov A, et al. alpha-Catenin homodimers are recruited to phosphoinositide-activated membranes to promote adhesion.

Kobielak A, Pasolli HA, Fuchs E. Mammalian formin-1 participates in adherens junctions and polymerization of linear actin cables.

Itoh M, Nagafuchi A, Moroi S, Tsukita S. Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to alpha catenin and actin filaments.

Duong CN, Bruckner R, Schmitt M, Nottebaum AF, Braun LJ, Meyer Zu Brickwedde M, et al. Force-induced changes of alpha-catenin conformation stabilize vascular junctions independently of vinculin.

Vasioukhin V, Bauer C, Degenstein L, Wise B, Fuchs E. Hyperproliferation and defects in epithelial polarity upon conditional ablation of alpha-catenin in skin.

Vassilev V, Platek A, Hiver S, Enomoto H, Takeichi M. Catenins Steer Cell Migration via Stabilization of Front-Rear Polarity.

Lien WH, Klezovitch O, Fernandez TE, Delrow J, Vasioukhin V. alphaE-catenin controls cerebral cortical size by regulating the hedgehog signaling pathway.

Silvis MR, Kreger BT, Lien WH, Klezovitch O, Rudakova GM, Camargo FD, et al. alpha-catenin is a tumor suppressor that controls cell accumulation by regulating the localization and activity of the transcriptional coactivator Yap1.

Pavel M, Park SJ, Frake RA, Son SM, Manni MM, Bento CF, et al. alpha-Catenin levels determine direction of YAP/TAZ response to autophagy perturbation.

Jimenez-Caliani AJ, Pillich R, Yang W, Diaferia GR, Meda P, Crisa L, et al. alphaE-Catenin Is a Positive Regulator of Pancreatic Islet Cell Lineage Differentiation.

Daugherty RL, Serebryannyy L, Yemelyanov A, Flozak AS, Yu HJ, Kosak ST, et al. alpha-Catenin is an inhibitor of transcription.

alpha-Catenin interacts with APC to regulate beta-catenin proteolysis and transcriptional repression of Wnt target genes.

Orsulic S, Peifer M. An in vivo structure-function study of armadillo, the beta-catenin homologue, reveals both separate and overlapping regions of the protein required for cell adhesion and for wingless signaling.