Catenin beta-1 - Knowledge

3631: 3703:(the other is ethanol-induced folate deficiency). Ethanol leads to β-catenin destabilization via a G-protein-dependent pathway, wherein activated Phospholipase Cβ hydrolyzes phosphatidylinositol-(4,5)-bisphosphate to diacylglycerol and inositol-(1,4,5)-trisphosphate. Soluble inositol-(1,4,5)-trisphosphate triggers calcium to be released from the endoplasmic reticulum. This sudden increase in cytoplasmic calcium activates Ca2+/calmodulin-dependent protein kinase (CaMKII). Activated CaMKII destabilizes β-catenin via a poorly characterized mechanism, but which likely involves β-catenin phosphorylation by CaMKII. The β-catenin transcriptional program (which is required for normal neural crest cell development) is thereby suppressed, resulting in premature neural crest cell apoptosis (cell death). 3675:

smaller "hotspots" of this surface is sufficient. This way, a "stapled" helical peptide derived from the natural β-catenin binding motif found in LEF1 was sufficient for the complete inhibition of β-catenin dependent transcription. Recently, several small-molecule compounds have also been developed to target the same, highly positively charged area of the ARM domain (CGP049090, PKF118-310, PKF115-584 and ZTM000990). In addition, β-catenin levels can also be influenced by targeting upstream components of the Wnt pathway as well as the β-catenin destruction complex. The additional N-terminal binding pocket is also important for Wnt target gene activation (required for BCL9 recruitment). This site of the ARM domain can be pharmacologically targeted by

3604: 3616: 379: 3679:, for example. That "auxiliary" site is another attractive target for drug development. Despite intensive preclinical research, no β-catenin inhibitors are available as therapeutic agents yet. However, its function can be further examined by siRNA knockdown based on an independent validation. Another therapeutic approach for reducing β-catenin nuclear accumulation is via the inhibition of galectin-3. The galectin-3 inhibitor GR-MD-02 is currently undergoing clinical trials in combination with the FDA-approved dose of ipilimumab in patients who have advanced melanoma. The proteins 2701:

adapted what appeared to be a rigid conformation, with the binding motif spanning many beta-catenin repeats. Relatively strong charged interaction "hot spots" were defined (predicted, and later verified, to be conserved for the β-catenin/E-cadherin interaction), as well as hydrophobic regions deemed important in the overall mode of binding and as potential therapeutic small molecule inhibitor targets against certain cancer forms. Furthermore, following studies demonstrated another peculiar characteristic, plasticity in the binding of the TCF N-terminus to beta-catenin.

356: 3580:. It has been estimated that approximately 10% of all tissue samples sequenced from all cancers display mutations in the CTNNB1 gene. Most of these mutations cluster on a tiny area of the N-terminal segment of β-catenin: the β-TrCP binding motif. Loss-of-function mutations of this motif essentially make ubiquitinylation and degradation of β-catenin impossible. It will cause β-catenin to translocate to the nucleus without any external stimulus and continuously drive transcription of its target genes. Increased nuclear β-catenin levels have also been noted in 2658: 2645:(also called γ-catenin) has a strikingly similar architecture to that of β-catenin. 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. However, plakoglobin is a very weak transactivator when bound to DNA – this is probably caused by the divergence of their C-terminal sequences (plakoglobin appears to lack the transactivator motifs, and thus inhibits the 278: 253: 12023: 2829: 12128: 3214:. The rate of stem cells in the colon is for instance ensured by such accumulation of β-catenin, which can be stimulated by the Wnt pathway. High frequency peristaltic mechanical strains of the colon are also involved in the β-catenin dependent maintenance of homeostatic levels of colonic stem cells through processes of mechanotransduction. This feature is pathologically enhanced towards tumorigenic hyperproliferation in healthy cells compressed by pressure due genetically altered hyperproliferative tumorous cells. 12098: 11963: 12113: 3028: 12083: 11948: 2740:) – an important protein involved in Wnt signaling. Although the precise details are much less clear, it appears that the same site is used by alpha-catenin when β-catenin is localized to the adherens junctions. Because this pocket is distinct from the ARM domain's "main" binding site, there is no competition between alpha-catenin and E-cadherin or between TCF1 and BCL9, respectively. On the other hand, BCL9 and BCL9L must compete with α-catenin to access β-catenin molecules. 12038: 2583:. The first repeat of β-catenin (near the N-terminus) is slightly different from the others – as it has an elongated helix with a kink, formed by the fusion of helices 1 and 2. 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. This inner surface serves as a ligand-binding site for the various interaction partners of the ARM domains. 12158: 12173: 12143: 385: 284: 12068: 12053: 3545: 11978: 12008: 11993: 3120:. Early embryos endomesoderm specification also involves the activation of the β-catenin dependent transcripional activity by the first morphogenetic movements of embryogenesis, though mechanotransduction processes. 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. 42: 3269:. Aberrant activation of the Wnt pathway has been implicated in pathological processes such as fibrosis and cancer. In cardiac muscle development, β-catenin performs a biphasic role. 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. 2724:(APC) protein contains 11 such motifs in tandem arrangement per protomer, thus capable to interact with several β-catenin molecules at once. 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. This competition is the key to understand how the 3070:. Cadherins are capable of homophilic interactions through their extracellular cadherin repeat domains, in a Ca2+-dependent manner; this can hold adjacent epithelial cells together. While in the adherens junction, cadherins recruit β-catenin molecules onto their intracellular regions. β-catenin, in turn, associates with another highly 2631:

required for Wnt signaling: possibly to recruit various coactivators, such as 14-3-3zeta. Yet its exact partners among the general transcription complexes are still incompletely understood, and they likely involve tissue-specific players. Notably, the C-terminal segment of β-catenin can mimic the effects of the entire

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layers and barriers. As a component of the complex, β-catenin can regulate cell growth and adhesion between cells. It may also be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. The E-cadherin – β-catenin – α-catenin

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The structure of β-catenin in complex with the catenin binding domain of the transcriptional transactivation partner TCF provided the initial structural roadmap of how many binding partners of β-catenin may form interactions. This structure demonstrated how the otherwise disordered N-terminus of TCF

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Due to its involvement in cancer development, inhibition of β-catenin continues to receive significant attention. But the targeting of the binding site on its armadillo domain is not the simplest task, due to its extensive and relatively flat surface. However, for an efficient inhibition, binding to

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Bonvini P, An WG, Rosolen A, Nguyen P, Trepel J, Garcia de Herreros A, et al. (February 2001). "Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription".

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Regarding the mechanistic role of β-catenin in cardiac hypertrophy, transgenic mouse studies have shown somewhat conflicting results regarding whether upregulation of β-catenin is beneficial or detrimental. A recent study using a conditional knockout mouse that either lacked β-catenin altogether or

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that packs against the ARM domain, but may also engage separate binding partners. This small structural element (HelixC) caps the C-terminal end of the ARM domain, shielding its hydrophobic residues. HelixC is not necessary for β-catenin to function in cell–cell adhesion. On the other hand, it is

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in order to activate several genes that induce dorsal cell characteristics. This signaling results in a region of cells known as the grey crescent, which is a classical organizer of embryonic development. If this region is surgically removed from the embryo, gastrulation does not occur at all.

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Hertig CM, Butz S, Koch S, Eppenberger-Eberhardt M, Kemler R, Eppenberger HM (January 1996). "N-cadherin in adult rat cardiomyocytes in culture. II. Spatio-temporal appearance of proteins involved in cell-cell contact and communication. Formation of two distinct N-cadherin/catenin complexes".

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will abolish mediating the phosphorylation of β-catenin. Since β-catenin is no longer marked for destruction, but continues to be produced, its concentration will increase. Once β-catenin levels rise high enough to saturate all binding sites in the cytoplasm, it will also translocate into the

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alpha and beta (GSK3α and GSK3β). GSK3s are constitutively active enzymes implicated in several important regulatory processes. There is one requirement, though: substrates of GSK3 need to be pre-phosphorylated four amino acids downstream (C-terminally) of the actual target site. Thus it also

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expressed a non-degradable form of β-catenin in cardiomyocytes reconciled a potential reason for these discrepancies. There appears to be strict control over the subcellular localization of β-catenin in cardiac muscle. Mice lacking β-catenin had no overt phenotype in the left ventricular

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molecules oligomerize with each other through their C-terminal DIX domains, which have two binding interfaces. Thus they can build linear oligomers or even polymers inside the cytoplasm of cells. DIX domains are unique: the only other proteins known to have a DIX domain are

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Wang B, Kishihara K, Zhang D, Hara H, Nomoto K (February 1997). "Molecular cloning and characterization of a novel human receptor protein tyrosine phosphatase gene, hPTP-J: down-regulation of gene expression by PMA and calcium ionophore in Jurkat T lymphoma cells".

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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. Together with

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However, this "main" binding site on the ARM domain β-catenin is by no means the only one. 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

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inhibition, suggesting once again that the abnormal stabilization of β-catenin may be involved in the development of cardiomyopathy. Further studies employing a double knockout of plakoglobin and β-catenin showed that the double knockout developed cardiomyopathy,

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Oyama T, Kanai Y, Ochiai A, Akimoto S, Oda T, Yanagihara K, et al. (December 1994). "A truncated beta-catenin disrupts the interaction between E-cadherin and alpha-catenin: a cause of loss of intercellular adhesiveness in human cancer cell lines".

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Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, et al. (November 2005). "beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee".

3439:, suggesting that the temporal regulation of β-catenin by protein degradation mechanisms is critical for normal functioning of β-catenin in cardiac cells. In a mouse model harboring knockout of a desmosomal protein, plakoglobin, implicated in 3472:

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.

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lip, which in turn initiates gastrulation. Inhibition of GSK-3 translation by injection of antisense mRNA may cause a second blastopore and a superfluous body axis to form. A similar effect can result from the overexpression of β-catenin.

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Tickenbrock L, Kössmeier K, Rehmann H, Herrmann C, Müller O (March 2003). "Differences between the interaction of beta-catenin with non-phosphorylated and single-mimicked phosphorylated 20-amino acid residue repeats of the APC protein".

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and be regulated by a diffusible extracellular substance: Wnt. It acts upon early embryos to induce entire body regions, as well as individual cells in later stages of development. It also regulates physiological regeneration processes.

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Mulholland DJ, Read JT, Rennie PS, Cox ME, Nelson CC (August 2003). "Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis".

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proteins closer to the equatorial region. β-catenin will be enriched locally under the influence of Wnt signaling pathway in the cells that inherit this portion of the cytoplasm. It will eventually translocate to the nucleus to bind

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Wnt signaling and β-catenin dependent gene expression plays a critical role during the formation of different body regions in the early embryo. Experimentally modified embryos that do not express this protein will fail to develop

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pathways will induce the antero-posterior axis formation, regulate the precise placement of the primitive streak (gastrulation and mesoderm formation) as well as the process of neurulation (central nervous system development).

3078:, which directly binds to the actin filaments. This is possible because α-catenin and cadherins bind at distinct sites to β-catenin. The β-catenin – α-catenin complex can thus physically form a bridge between cadherins and the 3363:

pools of β-catenin were decreased. 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

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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

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Navarro P, Lozano E, Cano A (August 1993). "Expression of E- or P-cadherin is not sufficient to modify the morphology and the tumorigenic behavior of murine spindle carcinoma cells. Possible involvement of plakoglobin".

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Davies G, Jiang WG, Mason MD (April 2001). "The interaction between beta-catenin, GSK3beta and APC after motogen induced cell-cell dissociation, and their involvement in signal transduction pathways in prostate cancer".

3666:) involved in colorectal cancer development. 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. 2876:. In addition, axin also has the potential to oligomerize through its C-terminal DIX domain. The result is a huge, multimeric protein assembly dedicated to β-catenin phosphorylation. This complex is usually called the 392: 291: 3507:

in humans. β-Catenin upregulation of expression has generally been observed in patients with dilated cardiomyopathy. In a particular study, patients with end-stage dilated cardiomyopathy showed almost doubled

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Whether or not a given individual's brain can deal effectively with stress, and thus their susceptibility to depression, depends on the β-catenin in each person's brain, according to a study conducted at the

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Kraus C, Liehr T, Hülsken J, Behrens J, Birchmeier W, Grzeschik KH, Ballhausen WG (September 1994). "Localization of the human beta-catenin gene (CTNNB1) to 3p21: a region implicated in tumor development".

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Peifer M, Rauskolb C, Williams M, Riggleman B, Wieschaus E (April 1991). "The segment polarity gene armadillo interacts with the wingless signaling pathway in both embryonic and adult pattern formation".

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Kesavapany S, Lau KF, McLoughlin DM, Brownlees J, Ackerley S, Leigh PN, et al. (January 2001). "p35/cdk5 binds and phosphorylates beta-catenin and regulates beta-catenin/presenilin-1 interaction".

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Lewalle JM, Bajou K, Desreux J, Mareel M, Dejana E, Noël A, Foidart JM (December 1997). "Alteration of interendothelial adherens junctions following tumor cell-endothelial cell interaction in vitro".

3626:, which is negative as there is only staining of cytoplasm but not of cell nuclei. This is a consistent finding, which helps in distinguishing such tumors from β-catenin positive spindle cell tumors. 9340:

Takahashi K, Suzuki K, Tsukatani Y (July 1997). "Induction of tyrosine phosphorylation and association of beta-catenin with EGF receptor upon tryptic digestion of quiescent cells at confluence".

2768:(also known as β-TrCP) can recognize β-catenin as its substrate through a short linear motif on the disordered N-terminus. However, this motif (Asp-Ser-Gly-Ile-His-Ser) of β-catenin needs to be 12022: 11143:

Yan HX, He YQ, Dong H, Zhang P, Zeng JZ, Cao HF, et al. (December 2002). "Physical and functional interaction between receptor-like protein tyrosine phosphatase PCP-2 and beta-catenin".

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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

3419:, evidenced by a reduction of β-catenin expression in the membrane protein fraction and an increase in the nuclear fraction. Additionally, they found a weakening in the association between 3237:, an important role of β-catenin is to induce a morphogenic change in epithelial cells. It induces them to abandon their tight adhesion and assume a more mobile and loosely associated 10794:"Dax-1 (dosage-sensitive sex reversal-adrenal hypoplasia congenita critical region on the X chromosome, gene 1) gene transcription is regulated by wnt4 in the female developing gonad" 12127: 6207:

Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, et al. (October 2007). "Identification of stem cells in small intestine and colon by marker gene Lgr5".

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Sinn HW, Balsamo J, Lilien J, Lin JJ (September 2002). "Localization of the novel Xin protein to the adherens junction complex in cardiac and skeletal muscle during development".

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Besco JA, Hooft van Huijsduijnen R, Frostholm A, Rotter A (October 2006). "Intracellular substrates of brain-enriched receptor protein tyrosine phosphatase rho (RPTPrho/PTPRT)".

7509: 2720:) contains a similar interaction motif on its long, disordered middle segment. Although one molecule of axin only contains a single β-catenin recruitment motif, its partner the 3423:

and β-catenin, which may indicate altered protein stability. Overall, results suggest that an enhanced nuclear localization of β-catenin may be important in the progression of

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Behrens J, von Kries JP, Kühl M, Bruhn L, Wedlich D, Grosschedl R, Birchmeier W (August 1996). "Functional interaction of beta-catenin with the transcription factor LEF-1".

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Zheng Q, Chen P, Xu Z, Li F, Yi XP (October 2013). "Expression and redistribution of β-catenin in the cardiac myocytes of left ventricle of spontaneously hypertensive rat".

10378:"Association of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathways" 9721:

Klingelhöfer J, Troyanovsky RB, Laur OY, Troyanovsky S (August 2000). "Amino-terminal domain of classic cadherins determines the specificity of the adhesive interactions".

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Sadot E, Simcha I, Iwai K, Ciechanover A, Geiger B, Ben-Ze'ev A (April 2000). "Differential interaction of plakoglobin and β-catenin with the ubiquitin-proteasome system".

3443:, the stabilization of β-catenin was also enhanced, presumably to compensate for the loss of its plakoglobin homolog. These changes were coordinate with Akt activation and 11264:"Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway" 8125:

Ryo A, Nakamura M, Wulf G, Liou YC, Lu KP (September 2001). "Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC".

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An important component of the adherens junctions are the cadherin proteins. Cadherins form the cell–cell junctional structures known as adherens junctions as well as the

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oocytes, β-catenin is initially equally localized to all regions of the egg, but it is targeted for ubiquitination and degradation by the β-catenin destruction complex.

2785:(CKI). Once a serine-threonine rich substrate has been "primed", GSK3 can "walk" across it from C-terminal to N-terminal direction, phosphorylating every 4th serine or 10189:

Kanai Y, Ochiai A, Shibata T, Oyama T, Ushijima S, Akimoto S, Hirohashi S (March 1995). "c-erbB-2 gene product directly associates with beta-catenin and plakoglobin".

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Geng L, Burrow CR, Li HP, Wilson PD (December 2000). "Modification of the composition of polycystin-1 multiprotein complexes by calcium and tyrosine phosphorylation".

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He Y, Yan H, Dong H, Zhang P, Tang L, Qiu X, et al. (April 2005). "Structural basis of interaction between protein tyrosine phosphatase PCP-2 and beta-catenin".

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Davies G, Jiang WG, Mason MD (April 2001). "HGF/SF modifies the interaction between its receptor c-Met, and the E-cadherin/catenin complex in prostate cancer cells".

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Schroeder JA, Adriance MC, Thompson MC, Camenisch TD, Gendler SJ (March 2003). "MUC1 alters beta-catenin-dependent tumor formation and promotes cellular invasion".

10745:"T-cell factor 4N (TCF-4N), a novel isoform of mouse TCF-4, synergizes with beta-catenin to coactivate C/EBPalpha and steroidogenic factor 1 transcription factors" 9970:"ErbB-beta-catenin complexes are associated with human infiltrating ductal breast and murine mammary tumor virus (MMTV)-Wnt-1 and MMTV-c-Neu transgenic carcinomas" 9895:

Aberle H, Butz S, Stappert J, Weissig H, Kemler R, Hoschuetzky H (December 1994). "Assembly of the cadherin-catenin complex in vitro with recombinant proteins".

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Takemaru K, Yamaguchi S, Lee YS, Zhang Y, Carthew RW, Moon RT (April 2003). "Chibby, a nuclear beta-catenin-associated antagonist of the Wnt/Wingless pathway".

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into myofibroblasts. These findings suggest that β-catenin can promote the regeneration and healing process following myocardial infarction. In a spontaneously-

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Kucerová D, Sloncová E, Tuhácková Z, Vojtechová M, Sovová V (December 2001). "Expression and interaction of different catenins in colorectal carcinoma cells".

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as time progresses. Somatic mutations of APC in colorectal cancer are also not uncommon. β-Catenin and APC are among the key genes (together with others, like

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Shasby DM, Ries DR, Shasby SS, Winter MC (June 2002). "Histamine stimulates phosphorylation of adherens junction proteins and alters their link to vimentin".

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Wendeler MW, Praus M, Jung R, Hecking M, Metzig C, Gessner R (April 2004). "Ksp-cadherin is a functional cell-cell adhesion molecule related to LI-cadherin".

12097: 7802:"Endogenous and exogenous galectin-3 promote the adhesion of tumor cells with low expression of MUC1 to HUVECs through upregulation of N-cadherin and CD44" 6066:"Establishment of the dorso-ventral axis in Xenopus embryos is presaged by early asymmetries in β-catenin that are modulated by the Wnt signaling pathway" 7918:"Calcium-mediated repression of β-catenin and its transcriptional signaling mediates neural crest cell death in an avian model of fetal alcohol syndrome" 3495:. Higher β-catenin signaling increases behavioral flexibility, whereas defective β-catenin signaling leads to depression and reduced stress management. 2083: 14746: 3320:

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

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in length, and contact the ARM domain on an excessively large surface area. Another unusual feature of these motifs is their frequently high degree of

2064: 214: 11962: 2958:, it induces a poorly known cascade of events, that result in the exposure of dishevelled's DIX domain and the creation of a perfect binding site for 2832:

Simplified structure of the β-catenin destruction complex. Note the high proportion of intrinsically disordered segments in the axin and APC proteins.

4602:"The C-terminal transactivation domain of beta-catenin is necessary and sufficient for signaling by the LEF-1/beta-catenin complex in Xenopus laevis" 4185:

Noordermeer J, Klingensmith J, Perrimon N, Nusse R (January 1994). "dishevelled and armadillo act in the wingless signalling pathway in Drosophila".

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Haegel H, Larue L, Ohsugi M, Fedorov L, Herrenknecht K, Kemler R (November 1995). "Lack of beta-catenin affects mouse development at gastrulation".

9792: 7494: 7430: 2982:, as if it were a true substrate of GSK3. These false target sites greatly inhibit GSK3 activity in a competitive manner. This way receptor-bound 10483:

In ... zebrafish, reporter transgenes containing the TOPFLASH promoter are expressed in certain Wnt-responsive cell types (...Dorsky et al. 2002).

10278:"A functional screen in human cells identifies UBF2 as an RNA polymerase II transcription factor that enhances the beta-catenin signaling pathway" 6536:

Wang X, Gerdes AM (February 1999). "Chronic pressure overload cardiac hypertrophy and failure in guinea pigs: III. Intercalated disc remodeling".

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Murayama M, Tanaka S, Palacino J, Murayama O, Honda T, Sun X, et al. (August 1998). "Direct association of presenilin-1 with beta-catenin".

11223:"Abrogation of the presenilin 1/beta-catenin interaction and preservation of the heterodimeric presenilin 1 complex following caspase activation" 3440: 2681:. However, β-catenin interacting motifs also have a number of peculiar characteristics. First, they might reach or even surpass the length of 30 8636:"Liganded androgen receptor interaction with beta-catenin: nuclear co-localization and modulation of transcriptional activity in neuronal cells" 7510:"Immunohistochemistry for beta-catenin in the differential diagnosis of spindle cell lesions: analysis of a series and review of the literature" 9142:"p120 Catenin-associated Fer and Fyn tyrosine kinases regulate beta-catenin Tyr-142 phosphorylation and beta-catenin-alpha-catenin Interaction" 7248:

Saldanha G, Ghura V, Potter L, Fletcher A (July 2004). "Nuclear beta-catenin in basal cell carcinoma correlates with increased proliferation".

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Graham TA, Ferkey DM, Mao F, Kimelman D, Xu W (December 2001). "Tcf4 can specifically recognize beta-catenin using alternative conformations".

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Oneyama C, Nakano H, Sharma SV (March 2002). "UCS15A, a novel small molecule, SH3 domain-mediated protein-protein interaction blocking drug".

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McCrea PD, Turck CW, Gumbiner B (November 1991). "A homolog of the armadillo protein in Drosophila (plakoglobin) associated with E-cadherin".

15604: 15010: 14739: 11863: 4046: 9507:"Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-beta-catenin complexes from the cytoskeleton by oxidative stress" 4028: 2550:– is homologous to the mammalian β-catenin, not just in structure but also in function. Thus, β-catenin became one of the first examples of 7336:"beta-Catenin is expressed aberrantly in tumors expressing shadow cells. Pilomatricoma, craniopharyngioma, and calcifying odontogenic cyst" 6739:"The beta-catenin/T-cell factor/lymphocyte enhancer factor signaling pathway is required for normal and stress-induced cardiac hypertrophy" 5259:

Liu J, Xing Y, Hinds TR, Zheng J, Xu W (June 2006). "The third 20 amino acid repeat is the tightest binding site of APC for beta-catenin".

6481:"Identification of an emerin-beta-catenin complex in the heart important for intercalated disc architecture and beta-catenin localisation" 8466:"Recruitment of beta-catenin by wild-type or mutant androgen receptors correlates with ligand-stimulated growth of prostate cancer cells" 8278:"Molecular mechanisms of beta-catenin recognition by adenomatous polyposis coli revealed by the structure of an APC-beta-catenin complex" 5339:"Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating β-catenin" 15240: 14022: 12037: 11895: 11874: 8882:

Jiang MC, Liao CF, Tai CC (June 2002). "CAS/CSE 1 stimulates E-cadhrin-dependent cell polarity in HT-29 human colon epithelial cells".

6573:"Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters" 4292: 2970:

will be rendered incompetent for β-catenin binding and GSK3 activity. Importantly, the cytoplasmic segments of the Frizzled-associated

2322: 15084: 15079: 14042: 11868: 8327:"Axin, an inhibitor of the Wnt signalling pathway, interacts with beta-catenin, GSK-3beta and APC and reduces the beta-catenin level" 3925: 3600:(MDB) These observations may or may not implicate a mutation in the β-catenin gene: other Wnt pathway components can also be faulty. 2315: 11858: 9386:

Dobrosotskaya IY, James GL (April 2000). "MAGI-1 interacts with beta-catenin and is associated with cell-cell adhesion structures".

6897:"Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling" 6614:"Beta-catenin overexpression reduces myocardial infarct size through differential effects on cardiomyocytes and cardiac fibroblasts" 3293:

structures, which are responsible for electrical and mechanical coupling of adjacent cardiac cells. Studies in a model of adult rat

13974: 13959: 13954: 13949: 13944: 13934: 13855: 13564: 13544: 13514: 13509: 12157: 3936: 3210:

One of the most important results of Wnt signaling and the elevated level of β-catenin in certain cell types is the maintenance of

12172: 12142: 10622:"The c-Src tyrosine kinase regulates signaling of the human DF3/MUC1 carcinoma-associated antigen with GSK3 beta and beta-catenin" 14184: 14179: 14174: 14169: 13924: 13914: 13904: 13899: 13870: 13574: 13569: 12616: 12504: 12494: 12469: 12449: 12353: 12333: 5475: 5440:

Brembeck FH, Rosário M, Birchmeier W (February 2006). "Balancing cell adhesion and Wnt signaling, the key role of beta-catenin".

3954: 3488: 12067: 12052: 10704:"The epidermal growth factor receptor regulates interaction of the human DF3/MUC1 carcinoma antigen with c-Src and beta-catenin" 6946:"Loss of cadherin-binding proteins β-catenin and plakoglobin in the heart leads to gap junction remodeling and arrhythmogenesis" 15431: 12576: 9856:"A mutation in alpha-catenin disrupts adhesion in clone A cells without perturbing its actin and beta-catenin binding activity" 5914:"Mechano-biochemical marine stimulation of inversion, gastrulation, and endomesoderm specification in multicellular Eukaryota" 11927: 7647:"An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid" 6260:"Ret kinase-mediated mechanical induction of colon stem cells by tumor growth pressure stimulates cancer progression in vivo" 6183: 3630: 2978:

proteins contain GSK3 pseudo-substrate sequences (Pro-Pro-Pro-Ser-Pro-x-Ser), appropriately "primed" (pre-phosphorylated) by

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The segments N-terminal and far C-terminal to the ARM domain do not adopt any structure in solution by themselves. Yet these

11977: 11880: 10437:"Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling" 5605:"Activated nanoscale actin-binding domain motion in the catenin-cadherin complex revealed by neutron spin echo spectroscopy" 5294:

Kimelman D, Xu W (December 2006). "beta-catenin destruction complex: insights and questions from a structural perspective".

4926:"The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin" 4011: 2789:

residues in a row. This process will result in dual phosphorylation of the aforementioned β-TrCP recognition motif as well.

15584: 12841: 7753:"Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments" 4365:

Kemler R (September 1993). "From cadherins to catenins: cytoplasmic protein interactions and regulation of cell adhesion".

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Peifer M, Berg S, Reynolds AB (March 1994). "A repeating amino acid motif shared by proteins with diverse cellular roles".

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in their large intestine. Most of these polyps are benign in nature, but they have the potential to transform into deadly

14533: 12206: 10448: 10142:"DIX domains of Dvl and axin are necessary for protein interactions and their ability to regulate beta-catenin stability" 3990: 2674: 2595: 6258:

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3359:, cell–cell adhesions were irregular and disorganized, and expression levels of adherens junction/intercalated disc and 3313:

in cardiomyocytes at adherens junctions within intercalated discs; and this interaction is dependent on the presence of

2884:

machinery actually responsible for β-catenin degradation. It only marks β-catenin molecules for subsequent destruction.

4743:

Xu W, Kimelman D (October 2007). "Mechanistic insights from structural studies of β-catenin and its binding partners".

3832: 3397: 2988: 2636: 9930:

Reuver SM, Garner CC (April 1998). "E-cadherin mediated cell adhesion recruits SAP97 into the cortical cytoskeleton".

7410: 5550:"The major β-catenin/E-cadherin junctional binding site is a primary molecular mechano-transductor of differentiation 5081:"Wnt/wingless signaling requires BCL9/legless-mediated recruitment of pygopus to the nuclear beta-catenin-TCF complex" 10927:"The protein tyrosine phosphatase Pez is a major phosphatase of adherens junctions and dephosphorylates beta-catenin" 9090:"EBP50, a beta-catenin-associating protein, enhances Wnt signaling and is over-expressed in hepatocellular carcinoma" 3820: 2869: 2841: 2806: 2661:

Partners competing for the main binding site on the ARM domain of β-catenin. The auxiliary binding site is not shown.

378: 14936: 12031:: The Structure of a beta-Catenin Binding Repeat from Adenomatous Polyposis Coli (APC) in Complex with beta-Catenin 3786: 3603: 11804:

De Ferrari GV, Moon RT (December 2006). "The ups and downs of Wnt signaling in prevalent neurological disorders".

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Su LK, Vogelstein B, Kinzler KW (December 1993). "Association of the APC tumor suppressor protein with catenins".

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of β-catenin is thus mediated by this N-terminal segment. The C-terminal region, on the other hand, is a strong

2491:. Alterations in the localization and expression levels of β-catenin have been associated with various forms of 14798: 14526: 13629: 13472: 12199: 10976:"Cellular redistribution of protein tyrosine phosphatases LAR and PTPsigma by inducible proteolytic processing" 9003:"Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin" 7053:

Perriard JC, Hirschy A, Ehler E (January 2003). "Dilated cardiomyopathy: a disease of the intercalated disc?".

4878:

Poy F, Lepourcelet M, Shivdasani RA, Eck MJ (December 2001). "Structure of a human Tcf4-beta-catenin complex".

3647: 3635: 3347:

showed a similar profile of change. N-cadherin showed no change, and there was no compensatory upregulation of

2781:

requires a "priming kinase" for its activities. In the case of β-catenin, the most important priming kinase is

2523: 2128: 10229:"Interaction between Smad7 and beta-catenin: importance for transforming growth factor beta-induced apoptosis" 5491:"An ensemble of flexible conformations underlies mechanotransduction by the cadherin-catenin adhesion complex" 3261:(ACTA2), and fibroblast-specific protein 1 (FSP1). They also produce extracellular matrix components, such as 14508: 14062: 11992: 8507:"Antiandrogen effects of mifepristone on coactivator and corepressor interactions with the androgen receptor" 11864:"The role of β-catenin in signal transduction, cell fate determination and trans-differentiation" at nih.gov 2109: 15589: 9682:"N-cadherin-catenin complexes form prior to cleavage of the proregion and transport to the plasma membrane" 6845:

Hirschy A, Croquelois A, Perriard E, Schoenauer R, Agarkova I, Hoerstrup SP, et al. (September 2010).

3309:

isolation for the reformation of cell–cell contacts. It has been shown that β-catenin forms a complex with

2697:

phosphorylation events greatly enhance the binding of many β-catenin associating motifs to the ARM domain.

1599:

canonical Wnt signaling pathway involved in positive regulation of cardiac outflow tract cell proliferation

277: 252: 194: 17: 12136:: THE CRYSTAL STRUCTURE OF BETA-CATENIN ARMADILLO REPEAT COMPLEXED WITH A PHOSPHORYLATED APC 20MER REPEAT. 8926:"The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton" 6115:"Induction of a secondary embryonic axis in zebrafish occurs following the overexpression of beta-catenin" 5548:

Röper JC, Mitrossilis D, Stirnemann G, Waharte F, Brito I, Fernandez-Sanchez ME, et al. (July 2018).

2579:

with an elongated shape – called armadillo (ARM) domain. An average armadillo repeat is composed of three

15050: 12769: 10009:

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regions play a crucial role in β-catenin function. The N-terminal disordered region contains a conserved

391: 290: 15064: 14972: 14888: 14859: 14715: 14240: 10663:"Protein kinase C delta regulates function of the DF3/MUC1 carcinoma antigen in beta-catenin signaling" 9140:

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3643: 3532:

in model organisms - such as the mouse and zebrafish - cause phenotypes that are very similar to human

3128: 2845: 2805:

on a substrate, pre-phosphorylation is not enough. There is one additional requirement: Similar to the

2721: 2504: 1604:

canonical Wnt signaling pathway involved in positive regulation of epithelial to mesenchymal transition

384: 283: 11464:"The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation" 9191:"Promyogenic members of the Ig and cadherin families associate to positively regulate differentiation" 5212:"Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions" 15460: 15298: 15098: 11920: 11619: 10050:

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3012: 2962:. Axin is then titrated away from its oligomeric assemblies – the β-catenin destruction complex – by 6017:"Beta-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos" 5030:"Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer?" 2817:. What is more, its GSK3 docking motif is directly adjacent to a β-catenin binding motif. This way, 181: 14917: 14803: 14473: 11852: 10497:"Interaction of the DF3/MUC1 breast carcinoma-associated antigen and beta-catenin in cell adhesion" 7645:

de la Roche M, Rutherford TJ, Gupta D, Veprintsev DB, Saxty B, Freund SM, Bienz M (February 2012).

7412: 6401:"Formation of multiple hearts in mice following deletion of beta-catenin in the embryonic endoderm" 3699:β-catenin destabilization by ethanol is one of two known pathways whereby alcohol exposure induces 3557: 3246: 3175: 3132: 3098:β-Catenin has a central role in directing several developmental processes, as it can directly bind 2856:

molecule alone possesses 11 such motifs ), it may collect as many β-catenin molecules as possible.

2825:, bringing an enzyme (GSK3) together with its substrate (β-catenin) into close physical proximity. 2468: 2294: 2269: 2265: 2261: 2231: 2210: 2202: 2198: 202: 3524:

and PYGO proteins, β-catenin coordinates different aspects of heard development, and mutations in

15143: 14821: 14669: 11859:"A diverse set of proteins modulate the canonical Wnt/β-catenin signaling pathway." at cancer.gov 8229:"DAP-1, a novel protein that interacts with the guanylate kinase-like domains of hDLG and PSD-95" 7140:

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3615: 3533: 3083: 2769: 2686: 2611: 2572: 1364:

negative regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis

7867:

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7751:

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7150:

genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling"

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Shibamoto S, Hayakawa M, Takeuchi K, Hori T, Miyazawa K, Kitamura N, et al. (March 1995).

5857:"Evolutionary conservation of early mesoderm specification by mechanotransduction in Bilateria" 3854: 3700: 3504: 3436: 3321: 3035: 3016: 2673:

may bind. Located in structurally diverse partners, the β-catenin binding motifs are typically

2646: 2568: 2496: 2404: 11025:"Association of human protein-tyrosine phosphatase kappa with members of the armadillo family" 8170:"Association and regulation of casein kinase 2 activity by adenomatous polyposis coli protein" 6996:

Dias C, Feng J, Sun H, Shao NY, Mazei-Robison MS, Damez-Werno D, et al. (December 2014).

6571:

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5912:

Nguyen NM, Merle T, Broders-Bondon F, Brunet AC, Battistella A, Land EB, et al. (2022).

3365: 3099: 2951: 2725: 2677:

on their own, and typically adopt a rigid structure upon ARM domain engagement – as seen for

2632: 2433: 10227:

Edlund S, Lee SY, Grimsby S, Zhang S, Aspenström P, Heldin CH, Landström M (February 2005).

10011:"Heart-specific localization of emerin: new insights into Emery-Dreifuss muscular dystrophy" 5489:

Bush M, Alhanshali BM, Qian S, Stanley CB, Heller WT, Matsui T, et al. (October 2019).

3038:

complexes are essential for the formation of complex animal tissues. β-catenin is part of a

2522:

gene is also strongly linked to cancers, and in particular colorectal cancer resulting from

222: 15445: 14518: 13161: 11913: 11869:"Researchers Offer First Direct Proof of How Arthritis Destroys Cartilage" at rochester.edu 11416: 10452: 10389: 10334: 9202: 8684: 8181: 7974: 7854:

for "Galectin Inhibitor (GR-MD-02) and Ipilimumab in Patients With Metastatic Melanoma" at

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positive regulation of epithelial cell proliferation involved in prostate gland development

266: 8325:

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5823: 5728: 5620: 5506: 5354: 4335: 4198: 3339:, β-catenin was shown to change subcellular localization from intercalated discs to the 2626:. This segment is not fully disordered: part of the C-terminal extension forms a stable 1899:

canonical Wnt signaling pathway involved in midbrain dopaminergic neuron differentiation

15599: 14958: 14731: 12921: 12551: 11829: 11675: 11542: 11380: 11355: 11336: 11288: 11279: 11263: 11203: 11089: 11000: 10975: 10907: 10859: 10834: 10602: 10474: 10358: 10076: 10051: 9639:

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structures, which are critical for electrical and mechanical coupling between adjacent

2408: 226: 11787: 11762: 11697:

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rat model, investigators detected a shuttling of β-catenin from the intercalated disc/

2708:, whose cytoplasmatic tail contacts the ARM domain in the same canonical fashion. The 2467:

Mutations and overexpression of β-catenin are associated with many cancers, including

1998: 1993: 1988: 1983: 1978: 1973: 1968: 1963: 1958: 1953: 1948: 1943: 1938: 1933: 1928: 1923: 1918: 1913: 1908: 1903: 1898: 1893: 1888: 1883: 1878: 1873: 1868: 1863: 1858: 1853: 1848: 1843: 1838: 1833: 1828: 1823: 1818: 1813: 1808: 1803: 1798: 1793: 1788: 1783: 1778: 1773: 1768: 1763: 1758: 1753: 1748: 1743: 1738: 1733: 1728: 1723: 1718: 1713: 1708: 1703: 1698: 1693: 1688: 1683: 1678: 1673: 1668: 1663: 1658: 1653: 1648: 1643: 1638: 1633: 1628: 1623: 1618: 1613: 1608: 1603: 1598: 1593: 1588: 1583: 1578: 1573: 1568: 1563: 1558: 1553: 1548: 1543: 1538: 1533: 1528: 1523: 1518: 1513: 1508: 1503: 1498: 1493: 1488: 1483: 1478: 1473: 1468: 1463: 1458: 1453: 1448: 1443: 1438: 1433: 1428: 1423: 1418: 1413: 1408: 1403: 1398: 1393: 1388: 1383: 1378: 1373: 1368: 1363: 1358: 1353: 1348: 1343: 1338: 1333: 1328: 1323: 1318: 1313: 1308: 1303: 1298: 1293: 1288: 1283: 1278: 1273: 1268: 1263: 1258: 1253: 1248: 1243: 1238: 1233: 1228: 1223: 1218: 1213: 1208: 1203: 1198: 1193: 1188: 1183: 1178: 1173: 1168: 1163: 1158: 1153: 1148: 1143: 1138: 1133: 1128: 1123: 1118: 1113: 1108: 1103: 1098: 1093: 1088: 1083: 1078: 1073: 1068: 1063: 1058: 1053: 1048: 1032: 1027: 1022: 1017: 1012: 1007: 1002: 997: 992: 987: 982: 977: 972: 967: 962: 957: 952: 947: 942: 937: 932: 927: 922: 917: 912: 907: 902: 897: 892: 887: 882: 877: 872: 867: 862: 857: 852: 847: 842: 837: 832: 827: 822: 817: 812: 807: 802: 797: 781: 776: 771: 766: 761: 756: 751: 746: 741: 736: 731: 726: 721: 716: 711: 706: 701: 691: 686: 681: 676: 671: 15594: 14319: 12683: 11821: 11792: 11749: 11714: 11667: 11632: 11587: 11534: 11529: 11512: 11493: 11444: 11439: 11404: 11385: 11328: 11293: 11244: 11195: 11160: 11125: 11081: 11046: 11005: 10956: 10899: 10864: 10815: 10774: 10760: 10725: 10684: 10643: 10594: 10559: 10518: 10466: 10417: 10412: 10377: 10350: 10307: 10293: 10258: 10206: 10171: 10122: 10099:

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Pawlowski JE, Ertel JR, Allen MP, Xu M, Butler C, Wilson EM, Wierman ME (June 2002).

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in order to be capable to bind β-TrCP. Phosphorylation of the motif is performed by

2534:β-Catenin was initially discovered in the early 1990s as a component of a mammalian 1739:

canonical Wnt signaling pathway involved in negative regulation of apoptotic process

15395: 15172: 15158: 14697: 14267: 13391: 12746: 12741: 11813: 11782: 11774: 11739: 11706: 11659: 11624: 11577: 11569: 11524: 11483: 11475: 11434: 11424: 11375: 11367: 11320: 11283: 11275: 11234: 11187: 11152: 11117: 11077: 11073: 11036: 10995: 10987: 10946: 10938: 10891: 10854: 10846: 10805: 10764: 10756: 10715: 10674: 10633: 10586: 10549: 10508: 10456: 10407: 10397: 10362: 10342: 10297: 10289: 10248: 10240: 10198: 10161: 10153: 10112: 10071: 10063: 10022: 9981: 9939: 9904: 9867: 9826: 9766: 9730: 9693: 9652: 9611: 9570: 9526: 9518: 9477: 9469: 9430: 9395: 9349: 9309: 9301: 9257: 9220: 9210: 9161: 9153: 9101: 9059: 9022: 9014: 8937: 8891: 8854: 8846: 8805: 8735: 8712: 8692: 8647: 8620: 8600: 8559: 8518: 8477: 8436: 8395: 8387: 8338: 8297: 8289: 8262: 8240: 8227:

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is like a huge "Christmas tree": with a multitude of β-catenin binding motifs (one

2828: 2822: 2762: 2709: 2607: 2515: 471: 402: 346: 301: 10882:

Behrens J (October 2008). "One hit, two outcomes for VHL-mediated tumorigenesis".

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4959: 3553: 3241:

phenotype. During this process, epithelial cells lose expression of proteins like

3147:

of the egg causes a rotation of the outer cortical layers, moving clusters of the

206: 15558: 14409: 13023: 12873: 12756: 7719: 7702:

Takada K, Zhu D, Bird GH, Sukhdeo K, Zhao JJ, Mani M, et al. (August 2012).

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Kypta RM, Waxman J (August 2012). "Wnt/β-catenin signalling in prostate cancer".

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Similar mutations are also frequently seen in the β-catenin recruiting motifs of

3597: 3589: 3388:. This finding was coordinate with enhanced expression of pro-survival proteins, 3373: 3332: 3317: 3262: 3082:. Organization of the cadherin–catenin complex is additionally regulated through 3039: 2979: 2782: 2619: 446: 230: 9063: 7884: 7613: 5130:"Structure of the dimerization and beta-catenin-binding region of alpha-catenin" 4051:

National Center for Biotechnology Information, U.S. National Library of Medicine

4033:

National Center for Biotechnology Information, U.S. National Library of Medicine

15361: 14372: 12932: 12763: 12272: 12191: 12106:: Crystal structure of beta-catenin/ICAT helical domain/unphosphorylated APC R3 11628: 11479: 11462:

Barker N, Hurlstone A, Musisi H, Miles A, Bienz M, Clevers H (September 2001).

11409: