Disease relevance of beta-catenin

• Mutations in components of the Wnt/beta-catenin pathway are observed to be the earliest initiating event for most colorectal tumors [1].
• Moreover, the specific APC mutations associated in colon cancer indicate the possibility that the tumor selects for certain truncated forms of APC that partially retain its function, namely, inhibition of beta-catenin [1].
• This novel human CKIdelta mutation may alter the physiological role and enhance the transforming ability of CKIdelta through a Wnt/beta-catenin independent mechanism and thereby influence colonic adenoma development [2].
• Disease-associated casein kinase I delta mutation may promote adenomatous polyps formation via a Wnt/beta-catenin independent mechanism [2].

High impact information on beta-catenin

• Recent evidence indicates that beta-catenin is dorsally stabilized by the localized inhibition of the kinase Xgsk-3, utilizing a novel Wnt ligand-independent mechanism [3].
• N-terminal deletion of XTcf-3 (delta N) abrogates the interaction with beta-catenin, as well as the consequent transcription activation [4].
• The phenotype can be rescued by the injection of beta-catenin mRNA and not by the injection of Xwnt-8 mRNA [5].
• Overexpression of cadherins and underexpression of beta-catenin inhibit dorsal mesoderm induction in early Xenopus embryos [5].
• The same phenotype is produced in embryos that have been depleted of maternal beta-catenin protein by an antisense oligodeoxynucleotide complementary to beta-catenin mRNA [5].

Biological context of beta-catenin

• As greater levels and nuclear accumulation of beta-catenin on the future dorsal side of the embryo correlate with the induction of specific dorsal genes, our data suggest that early asymmetries in beta-catenin presage and may specify dorso-ventral differences in gene expression and cell fate [6].
• We show that beta-catenin, a component of Wnt signaling pathway, physically interacts with Sox17 and potentiates its transcriptional activation of target genes [7].
• Furthermore we show that beta-catenin, an intracellular protein implicated in the Wnt signal transduction cascade, mimics the activity of Xwnt3a [8].
• Full-length Xfz7 rescues the morpholino-induced phenotype, as does activated beta-catenin, suggesting that Xfz7 is signaling through the canonical pathway [9].
• The major nuclear transducers of Wnt signals are the Tcf/LEF family of transcription factors, which have binding sites for both the transcriptional co-repressor groucho, and the co-activator beta-catenin [10].

Anatomical context of beta-catenin

• Because the Wnt signaling pathway (via beta-catenin) is active on the entire dorsal side of the early embryo, we have asked why Siamois expression is not seen in the dorsal ectoderm [11].
• Nuclear beta-catenin is present in endoderm cells of the gastrula, and depletion of beta-catenin from embryos results in a repression of Sox17 target genes [7].
• To investigate whether the activation of posterior neural markers requires mesoderm induction, we performed experiments using a chimeric inducible form of beta-catenin [12].
• Neural induction in the absence of mesoderm: beta-catenin-dependent expression of secreted BMP antagonists at the blastula stage in Xenopus [13].
• Unexpectedly, we found that blocking Spemann organizer formation by UV treatment or beta-Catenin depletion caused BMP inhibition to have much more potent effects, abolishing all ventral development and resulting in embryos having radial central nervous system (CNS) structures [14].

Associations of beta-catenin with chemical compounds

• Taken together, these results suggest that activation of beta-catenin signaling by lithium in this system may occur through a distinct activation mechanism that does not require modulation of levels through regulation of proteasomal degradation [15].
• The binding domain of beta-catenin has been mapped to the NH2-terminal 210 amino acids of alphaN-catenin [16].
• The serine/threonine kinase Xgsk-3 and the intracellular protein beta-catenin are necessary for the establishment of the dorsal-ventral axis in Xenopus [17].
• Lithium chloride exposure also causes ectopic nuclear localization of beta-catenin in cells of the epiblast in the area pellucida [18].
• Here, we show that beta-catenin physically and functionally targets the MED12 subunit in Mediator to activate transcription [19].

Physical interactions of beta-catenin

• Regulation of the pathway occurs through a beta-catenin-degrading complex based on Axin and the tumor suppressor APC [20].
• The inhibition activity of XSox17 beta maps to a region C-terminal to the HMG box; this region of XSox17 beta physically interacts with the Armadillo repeats of beta-catenin [21].
• Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin [21].

Regulatory relationships of beta-catenin

• However, it was found that the beta-catenin pathway regulated the expression of both endogenous goosecoid, and a goosecoid promoter construct, in a cell non-autonomous manner [22].
• The Wnt/Wg signal transducer beta-catenin controls fibronectin expression [23].
• Wnt proteins signal through seven-pass transmembrane receptors of the frizzled family to activate beta-catenin-dependent transcription of target genes [24].
• Axin dramatically accelerates while dishevelled inhibits beta-catenin turnover [25].
• Ectopic expression of XSox17 beta ventralizes embryos by inhibiting the Wnt pathway downstream of beta-catenin but upstream of the Wnt-responsive gene Siamois [21].
• Promoter analysis indicates that beta-catenin represses hhex transcription indirectly via the homeodomain repressor Vent2 [26].

Other interactions of beta-catenin

• Addition of exogenous beta-catenin protein induced expression of Siamois, XTwin, Xnr3, and Cerberus mRNAs in a protein synthesis independent manner, whereas a panel of other Spemann organizer-specific genes did not respond to beta-catenin [15].
• The present results suggest an additional function for beta-Catenin, the early activation of expression of secreted BMP antagonists, such as Chordin, in a preorganizer region in the dorsal side of the Xenopus blastula [13].
• This neural induction correlates with the expression of chordin and other BMP inhibitors-such as noggin, follistatin, and Xnr3-at the blastula stage, and requires beta-Catenin signaling [13].
• Based on these observations, we propose that Frodo and Dapper link Dsh and TCF to regulate Wnt target genes in a pathway parallel to that of beta-catenin [27].
• Interestingly, the Wnt-5A class did not block goosecoid expression or axis induction in response to overexpression of cytoplasmic components of the Wnt-1 signaling pathway, beta-catenin or a kinase-dead gsk-3, or to the unrelated secreted factor, BVg1 [28].

Analytical, diagnostic and therapeutic context of beta-catenin

• Activation of the beta-Catenin pathway by mRNA microinjections or by treatment with LiCl leads to differentiation of neurons, as well as neural crest, in ectodermal explants [13].
• Co-immunoprecipitation studies revealed that the receptor Xfz3 exists as a dimer when expressed in Xenopus embryos, and it has been shown to activate the Wnt/beta-catenin pathway as revealed by expression of the target gene siamois [24].
• Whole-mount in situ hybridization indicates that both genes are expressed in the dorsal ectoderm and mesoderm of tailbud- and tadpole-stage embryos and that beta-catenin is expressed in the midbrain [29].
• Phenotypic analysis of mutant mDvl-1 indicates that phosphorylation of these sites stimulates the Dvl-activated beta-catenin-dependent Wnt signaling pathway in both cell culture and in Xenopus development [30].
• Beta-catenin co-expression, heterotopic transplantation of CNC cells into the pharyngeal pouch area or both in combination failed to prevent neural differentiation of the grafts [31].

References