Somatic mutations of CTNNB1, both gain-of-function and loss-of-function, are observed in many cancers. CTNNB1 encodes β-catenin, a protein that plays separable roles in cell adhesion and as a core component in the canonical Wnt signaling pathway. In Drosophila, there is a single orthologous gene, arm, for which an extensive collection of genetic reagents has been generated, including loss-of-function mutations, RNAi-targeting constructs, alleles caused by insertional mutagenesis, and overexpression constructs. Dmel\arm is also related to a second human gene, JUP.
A UAS construct of the human Hsap\CTNNB1 gene has been introduced into flies, but has not been characterized.
A fly model has been used in conjunction with studies of pH-sensitive regulation of CTNNB1 stability; it has been determined that a conserved histidine (H36) is critical for these interactions. Somatic missense mutations of this amino acid have been found in human cancers, including the specific missense mutation H36R. The analogous mutation in the fly arm gene has been assessed by targeted expression in the developing eye. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): H42R in the fly arm (corresponds to H36R in the human CTNNB1 gene).
Expression in the developing eye of a construct carrying wild-type arm does not result in visible defects in the adult eye. In contrast, expression of the H42R variant results in variable but severe patterning defects; in ~8% of animals tumor-like protrusions of eye tissue are observed; elevated Wnt signaling throughout the eye disc is detected. In this eye-expression assay a known gain-of-function mutation of arm results in similar patterning defects, but not in the most severe defects or in tumor-like protrusions. Thus, it is postulated that the H42R variant (H36R in the human gene) may have neomorphic effects.
For more information on the canonical Wnt signaling pathway in Drosophila, see related pathway reports (FBgg0000889 and FBgg0000890).
[updated Sep. 2020 by FlyBase; FBrf0222196]
Genetic or epigenetic events leading to hypo- or hyper-activation of the Wnt-β-catenin signaling cascade been associated with human diseases such as cancer (Steinhart and Angers, 2018; pubmed:29884654).
Somatic mutations of CTNNB1 are observed in many cancers; H36R (and more frequently H36P) mutations have been detected in multiple cancer types, most commonly in cancers of the liver. [COSMIC, CTNNB1; 2020.09.13]
Both gain-of-function and loss-of-function somatic mutations of CTNNB1 have been detected in human cancers (Katoh, 2018; pubmed:29786110).
The protein encoded by CTNNB1 is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The CTNNB1 protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. [Gene Cards, CTNNB1; 2020.09.13]
The protein encoded by CTNNB1 is a key downstream component of the canonical Wnt signaling pathway. In the presence of Wnt ligand, CTNNB1 is not ubiquitinated and accumulates in the nucleus, where it acts as a coactivator for transcription factors of the TCF/LEF family, leading to activate Wnt responsive genes. [Gene Cards, CTNNB1; 2020.09.13]
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human CTNNB1, moderate-scoring ortholog of human JUP (1 Drosophila to 2 human). Dmel\arm shares 63-67% identity and 76-77% similarity with the human genes.
