β-Catenin was initially discovered in the early 1990s as a component of a mammaliancell adhesion complex: a protein responsible for cytoplasmatic anchoring ofcadherins.[11] But very soon, it was realized that the Drosophila proteinarmadillo – implicated in mediating the morphogenic effects ofWingless/Wnt – is homologous to the mammalian β-catenin, not just in structure but also in function.[12] Thus, β-catenin became one of the first examples ofmoonlighting: a protein performing more than one radically different cellular function.
The core of β-catenin consists of several very characteristicrepeats, each approximately 40 amino acids long. Termedarmadillo repeats, all these elements fold together into a single, rigidprotein domain with an elongated shape – called armadillo (ARM) domain. An average armadillo repeat is composed of threealpha helices. 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.[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. This inner surface serves as a ligand-binding site for the various interaction partners of the ARM domains.
The simplified structure of β-catenin.
The segments N-terminal and far C-terminal to the ARM domain do not adopt any structure in solution by themselves. Yet theseintrinsically disordered regions play a crucial role in β-catenin function. The N-terminal disordered region contains a conservedshort linear motif responsible for binding ofTrCP1 (also known as β-TrCP)E3 ubiquitin ligase – but only when it isphosphorylated.Degradation of β-catenin is thus mediated by this N-terminal segment. The C-terminal region, on the other hand, is a strongtransactivator when recruited ontoDNA. This segment is not fully disordered: part of the C-terminal extension forms a stablehelix that packs against the ARM domain, but may also engage separate binding partners.[14] 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 required for Wnt signaling: possibly to recruit various coactivators, such as 14-3-3zeta.[15] Yet its exact partners among the general transcription complexes are still incompletely understood, and they likely involve tissue-specific players.[16] Notably, the C-terminal segment of β-catenin can mimic the effects of the entireWnt pathway if artificially fused to the DNA binding domain ofLEF1 transcription factor.[17]
Plakoglobin (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.[18] 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 theWnt pathway target genes instead of activating them).[19]
Partners competing for the main binding site on the ARM domain of β-catenin. The auxiliary binding site is not shown.
As sketched above, theARM domain of β-catenin acts as a platform to which specificlinear motifs may bind. Located in structurally diverse partners, the β-catenin binding motifs are typicallydisordered on their own, and typically adopt a rigid structure upon ARM domain engagement – as seen forshort linear motifs. However, β-catenin interacting motifs also have a number of peculiar characteristics. First, they might reach or even surpass the length of 30amino acids in length, and contact the ARM domain on an excessively large surface area. Another unusual feature of these motifs is their frequently high degree ofphosphorylation. SuchSer/Thr phosphorylation events greatly enhance the binding of many β-catenin associating motifs to the ARM domain.[20]
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.[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. 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.[22][23]
Similarly, we find the familiarE-cadherin, whose cytoplasmatic tail contacts the ARM domain in the same canonical fashion.[24] Thescaffold protein axin (two closely related paralogs,axin 1 andaxin 2) contains a similar interaction motif on its long, disordered middle segment.[25] Although one molecule of axin only contains a single β-catenin recruitment motif, its partner theadenomatous polyposis coli (APC) protein contains 11 such motifs in tandem arrangement per protomer, thus capable to interact with several β-catenin molecules at once.[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. This competition is the key to understand how theWnt signaling pathway works.
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 coactivatorBCL9 (or the closely relatedBCL9L) – an important protein involved in Wnt signaling.[27] 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.[28] 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.[29] On the other hand, BCL9 and BCL9L must compete with α-catenin to access β-catenin molecules.[30]
The cellular level of β-catenin is mostly controlled by itsubiquitination andproteosomal degradation. TheE3 ubiquitin ligaseTrCP1 (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 bephosphorylated on the twoserines in order to be capable to bind β-TrCP. Phosphorylation of the motif is performed byGlycogen Synthase Kinase 3 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 requires a "priming kinase" for its activities. In the case of β-catenin, the most important priming kinase isCasein Kinase I (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 orthreonine residue in a row. This process will result in dual phosphorylation of the aforementioned β-TrCP recognition motif as well.
ForGSK3 to be a highly effectivekinase on a substrate, pre-phosphorylation is not enough. There is one additional requirement: Similar to themitogen-activated protein kinases (MAPKs), substrates need to associate with this enzyme through high-affinitydocking motifs. β-Catenin contains no such motifs, but a special protein does:axin. What is more, its GSK3 docking motif is directly adjacent to a β-catenin binding motif.[25] This way,axin acts as a truescaffold protein, bringing an enzyme (GSK3) together with its substrate (β-catenin) into close physical proximity.
Simplified structure of the β-catenin destruction complex. Note the high proportion of intrinsically disordered segments in the axin and APC proteins.
But evenaxin does not act alone. Through its N-terminalregulator of G-protein signaling (RGS) domain, it recruits theadenomatous polyposis coli (APC) protein.APC is like a huge "Christmas tree": with a multitude of β-catenin binding motifs (oneAPC molecule alone possesses 11 such motifs[26]), it may collect as many β-catenin molecules as possible.[31]APC can interact with multipleaxin molecules at the same time as it has threeSAMP motifs (Ser-Ala-Met-Pro) to bind theRGS domains found inaxin. 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 thebeta-catenin destruction complex, although it is distinct from theproteosome machinery actually responsible for β-catenin degradation.[32] It only marks β-catenin molecules for subsequent destruction.
In resting cells,axin 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 areDishevelled andDIXDC1. (The singleDsh protein ofDrosophila corresponds to three paralogous genes,Dvl1,Dvl2 andDvl3 inmammals.)Dsh associates with the cytoplasmic regions ofFrizzled receptors with itsPDZ andDEPdomains. When aWnt molecule binds toFrizzled, 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 foraxin. Axin is then titrated away from its oligomeric assemblies – the β-catenin destruction complex – byDsh.[33] Once bound to the receptor complex,axin will be rendered incompetent for β-catenin binding and GSK3 activity. Importantly, the cytoplasmic segments of the Frizzled-associatedLRP5 andLRP6 proteins contain GSK3 pseudo-substrate sequences (Pro-Pro-Pro-Ser-Pro-x-Ser), appropriately "primed" (pre-phosphorylated) byCKI, as if it were a true substrate of GSK3. These false target sites greatly inhibit GSK3 activity in a competitive manner.[34] This way receptor-boundaxin 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 nucleus. Upon engaging the transcription factorsLEF1,TCF1,TCF2 orTCF3, β-catenin forces them to disengage their previous partners: Groucho proteins. UnlikeGroucho, that recruittranscriptional repressors (e.g.histone-lysine methyltransferases), β-catenin will bindtranscriptional activators, switching on target genes.
Cell–cell adhesion complexes are essential for the formation of complex animal tissues. β-catenin is part of aprotein complex that formadherens junctions.[35] These cell–cell adhesion complexes are necessary for the creation and maintenance ofepithelial cell 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.[36] The E-cadherin – β-catenin – α-catenin complex is weakly associated toactin filaments. Adherens junctions require significantprotein dynamics in order to link to the actin cytoskeleton,[35]thereby enablingmechanotransduction.[37][38]
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 thedesmosomes. 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[clarification needed]. β-catenin, in turn, associates with another highlydynamic protein,α-catenin, which directly binds to the actin filaments.[39] This is possible because α-catenin and cadherins bind at distinct sites to β-catenin.[40] The β-catenin – α-catenin complex can thus physically form a bridge between cadherins and theactin cytoskeleton.[41] Organization of the cadherin–catenin complex is additionally regulated throughphosphorylation andendocytosis of its components.[citation needed]
β-Catenin has a central role in directing several developmental processes, as it can directly bindtranscription factors 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.
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 developmesoderm and initiategastrulation.[42]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.[43][44][45]
During the blastula and gastrula stages,Wnt as well asBMP andFGF 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).[46]
InXenopus 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.Fertilization of the egg causes a rotation of the outer cortical layers, moving clusters of theFrizzled andDsh 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 bindTCF3 in order to activate several genes that induce dorsal cell characteristics.[47] 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. β-Catenin also plays a crucial role in the induction of theblastopore lip, which in turn initiates gastrulation.[48] 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.[49]
β-catenin has also been implicated in regulation of cell fates throughasymmetric cell division in the model organismC. elegans. Similarly to theXenopus oocytes, this is essentially the result of non-equal distribution ofDsh,Frizzled,axin andAPC in the cytoplasm of the mother cell.[50]
One of the most important results of Wnt signaling and the elevated level of β-catenin in certain cell types is the maintenance ofpluripotency.[46] 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.[51] 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.[52]
In other cell types and developmental stages, β-catenin may promotedifferentiation, especially towardsmesodermal cell lineages.
β-Catenin also acts as a morphogen in later stages of embryonic development. Together withTGF-β, 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 associatedmesenchymal phenotype. During this process, epithelial cells lose expression of proteins likeE-cadherin,Zonula occludens 1 (ZO1), andcytokeratin. At the same time they turn on the expression ofvimentin,alpha smooth muscle actin (ACTA2), and fibroblast-specific protein 1 (FSP1). They also produce extracellular matrix components, such astype I collagen andfibronectin. Aberrant activation of the Wnt pathway has been implicated in pathological processes such as fibrosis and cancer.[53] 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.[54][55][42]
Incardiac muscle, β-catenin forms a complex withN-cadherin atadherens junctions withinintercalated disc structures, which are responsible for electrical and mechanical coupling of adjacent cardiac cells. Studies in a model of adult ratventricularcardiomyocytes 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 andalpha-catenin, which is abundant at adherens junctions in early stages followingcardiomyocyte isolation for the reformation of cell–cell contacts.[56] It has been shown that β-catenin forms a complex withemerin in cardiomyocytes at adherens junctions within intercalated discs; and this interaction is dependent on the presence ofGSK 3-betaphosphorylation sites on β-catenin. Knocking out emerin significantly altered β-catenin localization and the overall intercalated disc architecture, which resembled adilated cardiomyopathy phenotype.[57]
In animal models ofcardiac disease, functions of β-catenin have been unveiled. In a guinea pig model ofaortic stenosis and left ventricularhypertrophy, β-catenin was shown to change subcellular localization from intercalated discs to thecytosol, despite no change in the overall cellular abundance of β-catenin.vinculin showed a similar profile of change. N-cadherin showed no change, and there was no compensatory upregulation ofplakoglobin at intercalated discs in the absence of β-catenin.[58] In a hamster model ofcardiomyopathy andheart failure, cell–cell adhesions were irregular and disorganized, and expression levels of adherens junction/intercalated disc andnuclear 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 ofmyocardial infarction,adenoviral gene transfer of nonphosphorylatable, constitutively-active β-catenin decreased MI size, activated thecell cycle, and reduced the amount ofapoptosis in cardiomyocytes and cardiacmyofibroblasts. This finding was coordinate with enhanced expression of pro-survival proteins,survivin andBcl-2, andvascular endothelial growth factor while promoting the differentiation of cardiacfibroblasts into myofibroblasts. These findings suggest that β-catenin can promote the regeneration and healing process following myocardial infarction.[60] In a spontaneously-hypertensiveheart failure rat model, investigators detected a shuttling of β-catenin from the intercalated disc/sarcolemma to thenucleus, 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 betweenglycogen synthase kinase-3β 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 ofcardiac hypertrophy.[61]
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.[62][63][64] A recent study using a conditional knockout mouse that either lacked β-catenin altogether or 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 ventricularmyocardium; however, mice harboring a stabilized form of β-catenin developeddilated cardiomyopathy, suggesting that the temporal regulation of β-catenin by protein degradation mechanisms is critical for normal functioning of β-catenin in cardiac cells.[65] In a mouse model harboring knockout of a desmosomal protein, plakoglobin, implicated inarrhythmogenic right ventricular cardiomyopathy, 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 andglycogen synthase kinase 3β inhibition, suggesting once again that the abnormal stabilization of β-catenin may be involved in the development of cardiomyopathy.[66] Further studies employing a double knockout of plakoglobin and β-catenin showed that the double knockout developed cardiomyopathy,fibrosis andarrhythmias resulting insudden cardiac death. Intercalated disc architecture was severely impaired andconnexin 43-residentgap junctions were markedly reduced.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.[67]
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 theIcahn School of Medicine at Mount Sinai and published November 12, 2014, in the journalNature.[68] Higher β-catenin signaling increases behavioral flexibility, whereas defective β-catenin signaling leads to depression and reduced stress management.[68]
Altered expression profiles in β-catenin have been associated withdilated cardiomyopathy in humans. β-Catenin upregulation of expression has generally been observed in patients with dilated cardiomyopathy.[69] In a particular study, patients with end-stage dilated cardiomyopathy showed almost doubledestrogen receptor alpha (ER-alpha)mRNA andprotein 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.[70] Together withBCL9 and PYGO proteins, β-catenin coordinates different aspects of heard development, and mutations inBcl9 orPygo in model organisms - such as the mouse and zebrafish - cause phenotypes that are very similar to humancongenital heart disorders.[71]
β-Catenin is aproto-oncogene. Mutations of this gene are commonly found in a variety of cancers: inprimary hepatocellular carcinoma,colorectal cancer,ovarian carcinoma,breast cancer,lung cancer andglioblastoma. It has been estimated that approximately 10% of all tissue samples sequenced from all cancers display mutations in the CTNNB1 gene.[72] 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 inbasal cell carcinoma (BCC),[73]head and neck squamous cell carcinoma (HNSCC),prostate cancer (CaP),[74]pilomatrixoma (PTR)[75] andmedulloblastoma (MDB)[76] These observations may or may not implicate a mutation in the β-catenin gene: other Wnt pathway components can also be faulty.
β-catenin immunohistochemistry insolid pseudopapillary tumor, staining the nuclei in 98% of such cases.[77] Cytoplasm is also staining in this case.Immunohistochemistry for β-catenin inuterine leiomyoma, 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.[78]Likewise, negative nuclear staining is seen in approximately 95% ofgastrointestinal stromal tumors.[79].
Similar mutations are also frequently seen in the β-catenin recruiting motifs ofAPC. Hereditary loss-of-function mutations of APC cause a condition known asfamilial adenomatous polyposis. Affected individuals develop hundreds ofpolyps in their large intestine. Most of these polyps are benign in nature, but they have the potential to transform into deadlycancer as time progresses. Somatic mutations of APC in colorectal cancer are also not uncommon.[80] β-Catenin and APC are among the key genes (together with others, likeK-Ras andSMAD4) 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.
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 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.[81] 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 bycarnosic acid, for example.[82] That "auxiliary" site is another attractive target for drug development.[83] 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.[84] Another therapeutic approach for reducing β-catenin nuclear accumulation is via the inhibition of galectin-3.[85] 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.[86] The proteinsBCL9 andBCL9L 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 affectsmetastases behaviour.[87]
β-catenin destabilization by ethanol is one of two known pathways whereby alcohol exposure inducesfetal alcohol syndrome (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).[88]
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