Catenin beta-1

Source: Wikipedia, the free encyclopedia.
(Redirected from
Beta-catenin
)
CTNNB1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000168036

ENSMUSG00000006932

UniProt

P35222

Q02248

RefSeq (mRNA)

NM_001098209
NM_001098210
NM_001904
NM_001330729

NM_001165902
NM_007614

RefSeq (protein)

NP_001091679
NP_001091680
NP_001317658
NP_001895

NP_001159374
NP_031640

Location (UCSC)Chr 3: 41.19 – 41.26 MbChr 9: 120.76 – 120.79 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Catenin beta-1, also known as β-catenin (beta-catenin), is a protein that in humans is encoded by the CTNNB1 gene.

β-Catenin is a dual function

cardiomyocytes
.

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

genetic mutation of the APC gene is also strongly linked to cancers, and in particular colorectal cancer resulting from familial adenomatous polyposis
(FAP).

Discovery

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.[12] Thus, β-catenin became one of the first examples of moonlighting: a protein performing more than one radically different cellular function.

Structure

Protein structure

The core of β-catenin consists of several very characteristic

alpha 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 these

intrinsically disordered regions play a crucial role in β-catenin function. 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. Degradation of β-catenin is thus mediated by this N-terminal segment. The C-terminal region, on the other hand, is a strong transactivator when recruited onto DNA. 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.[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 entire Wnt pathway if artificially fused to the DNA binding domain of LEF1 transcription factor.[17]

Wnt pathway target genes instead of activating them).[19]

Partners binding to the armadillo domain

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

As sketched above, the

disordered on their own, and typically adopt a rigid structure upon ARM domain engagement – as seen for short linear motifs. However, β-catenin interacting motifs also have a number of peculiar characteristics. First, they might reach or even surpass the length of 30 amino 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 of phosphorylation. Such Ser/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 familiar E-cadherin, whose cytoplasmatic tail contacts the ARM domain in the same canonical fashion.[24] The scaffold protein axin (two closely related paralogs, axin 1 and axin 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 the adenomatous 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 the Wnt 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 coactivator BCL9 (or the closely related BCL9L) – 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]

Function

Regulation of degradation through phosphorylation

The cellular level of β-catenin is mostly controlled by its

ubiquitination and proteosomal degradation. The E3 ubiquitin ligase TrCP1 (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 phosphorylated on the two serines in order to be capable to bind β-TrCP. Phosphorylation of the motif is performed by Glycogen 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 is Casein 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 or threonine
residues in a row. This process will result in dual phosphorylation of the aforementioned β-TrCP recognition motif as well.

The beta-catenin destruction complex

For

mitogen-activated protein kinases (MAPKs), substrates need to associate with this enzyme through high-affinity docking 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 true scaffold 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 even axin does not act alone. Through its N-terminal

proteosome machinery actually responsible for β-catenin degradation.[32]
It only marks β-catenin molecules for subsequent destruction.

Wnt signaling and the regulation of destruction

In resting cells,

TCF2 or TCF3, β-catenin forces them to disengage their previous partners: Groucho proteins. Unlike Groucho, that recruit transcriptional repressors (e.g. histone-lysine methyltransferases), β-catenin will bind transcriptional activators
, switching on target genes.

Role in cell–cell adhesion

The moonlighting of β-catenin.

adherens junctions.[35] These cell–cell adhesion complexes are necessary for the creation and maintenance of epithelial 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 to actin filaments. Adherens junctions require significant protein dynamics in order to link to the actin cytoskeleton,[35]
thereby enabling mechanotransduction.[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 the

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 the actin cytoskeleton.[41] Organization of the cadherin–catenin complex is additionally regulated through phosphorylation and endocytosis of its components.[citation needed
]

Roles in development

β-Catenin has a central role in directing several developmental processes, as it can directly bind

transcription 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.

Early embryonic patterning

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 mesoderm and initiate gastrulation.[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 as BMP and FGF 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]

In

blastopore 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]

Asymmetric cell division

β-catenin has also been implicated in regulation of cell fates through asymmetric cell division in the model organism C. elegans. 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.[50]

Stem cell renewal

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

pluripotency.[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 promote

differentiation, especially towards mesodermal
cell lineages.

Epithelial-to-mesenchymal transition

β-Catenin also acts as a morphogen in later stages of embryonic development. Together with

type I collagen and fibronectin. 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]

Involvement in cardiac physiology

In

GSK 3-beta phosphorylation sites on β-catenin. Knocking out emerin significantly altered β-catenin localization and the overall intercalated disc architecture, which resembled a dilated cardiomyopathy phenotype.[57]

In animal models of

cardiac 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.

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]

Clinical significance

Role in depression

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 Icahn School of Medicine at Mount Sinai and published November 12, 2014, in the journal Nature.[68] Higher β-catenin signaling increases behavioral flexibility, whereas defective β-catenin signaling leads to depression and reduced stress management.[68]

Role in cardiac disease

Altered expression profiles in β-catenin have been associated with

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.[70] Together with BCL9 and PYGO proteins, β-catenin coordinates different aspects of heard development, and mutations in Bcl9 or Pygo in model organisms - such as the mouse and zebrafish - cause phenotypes that are very similar to human congenital heart disorders.[71]

Involvement in cancer

β-Catenin level regulation and cancer.

β-Catenin is a

pilomatrixoma (PTR)[75] and medulloblastoma (MDB)[76]
These observations may or may not implicate a mutation in the β-catenin gene: other Wnt pathway components can also be faulty.

solid pseudopapillary tumor, staining the nuclei in 98% of such cases.[77]
Cytoplasm is also staining in this case.
uterine 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% of gastrointestinal stromal tumors.[79].

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

SMAD4
) 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.

As a therapeutic target

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 by carnosic 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 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.[87]

Role in fetal alcohol syndrome

β-catenin destabilization by ethanol is one of two known pathways whereby alcohol exposure induces

fetal 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]

Interactions

β-Catenin has been shown to

interact
with:

See also

References

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Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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