Balancing cell adhesion and Wnt signaling, the key role of β-catenin
Introduction
In the past two decades, researchers have identified crucial molecular components that control patterning and organogenesis in the embryo and which, when de-regulated, modulate tumorigenesis [1, 2, 3, 4]. These molecules are members of a few signaling pathways that interact in a controlled fashion and regulate proliferation, differentiation and cell–cell interactions. Research in several laboratories has provided evidence that the Wnt–β-catenin pathway is of particular importance in these cellular processes [2, 5, 6, 7]. β-catenin is the central and essential component in the Wnt signaling cascade. Initially characterized in Drosophila as the product of the segment polarity gene Armadillo [8], β-catenin and its relative plakoglobin (γ-catenin) were subsequently shown to be components of adhesion junctions. Here, β-catenin links cadherins at the plasma membrane to α-catenin (Figure 1) [9, 10, 11, 12, 13]. Recent studies demonstrated that the E-cadherin–β-catenin–α-catenin complex at the adherens junctions forms a dynamic, rather than a stable, link to the cytoskeleton [14••, 15••]. In the Wnt signaling pathway, by contrast, β-catenin functions as a transcriptional activator in conjunction with LEF/TCF (lymphoid enhancer factor/T-cell factor) DNA binding proteins [16, 17, 18, 19].
In this review, we address the mechanisms by which the dual functions of β-catenin are regulated. In particular, we discuss the role of the novel BCL9 (B-cell lymphoma 9) proto-oncogene family in regulating the function of β-catenin in cell adhesion and in Wnt signaling.
Section snippets
The role of β-catenin in tumorigenesis
The need to balance the adhesive and transcriptional functions of β-catenin is clear from the analysis of human malignancies. Tumor genetics revealed that mutations in members of the Wnt–β-catenin pathway occur in approximately 90% of colorectal cancers as well as in other cancer types, such as hepatocellular carcinomas or gastric cancers (Figure 2) [4, 20, 21, 22, 23, 24]. Mutations that activate the Wnt–β-catenin pathway promote stabilization of β-catenin and induce its nuclear accumulation [
Regulation of β-catenin signaling by the Wnt pathway
The signaling function of β-catenin is regulated principally through alteration of its stability. Wnt signaling induces the stabilization of the ‘free’ cytoplasmic pool of β-catenin [5, 23, 24]. In the absence of Wnt signaling, β-catenin is rapidly degraded by a destruction complex consisting of APC, axin (conductin homolog), glycogen synthase kinase 3-beta (GSK3β) and casein kinase (CKI) (Figure 1) [52, 53, 54, 55]. CKI and GSK3β induce amino-terminal serine–threonine phosphorylation of
Regulation of β-catenin function by tyrosine phosphorylation
β-catenin function can also be regulated through tyrosine phosphorylation. This regulatory mechanism modulates the binding ability of β-catenin and enables the controlled formation of specific protein–protein interactions [41, 43, 46]. Of particular importance are two tyrosine residues in β-catenin: tyrosine 142 in the first armadillo repeat; and tyrosine 654 in the last armadillo repeat. It was shown that phosphorylation of these two key tyrosine residues leads to the disassembly of the
Tyrosine-phosphorylated β-catenin binds the nuclear co-factor BCL9-2
The role of tyrosine phosphorylation of β-catenin in cellular signaling has been enigmatic. Tyrosine phosphorylation of β-catenin has been shown to lead not only to loss of adhesion but also to increased transcription [49, 50, 51, 78••]. The molecular mechanism of this switch, however, remained largely unclear until recent research revealed that phosphorylation of tyrosine 142 in β-catenin is crucial for this switch. Importantly, phosphorylation of tyrosine 142 disrupts binding to α-catenin but
Central role of BCL9 family members in Wnt–β-catenin signaling
The recent discovery that the BCL9–Legless family members act as essential co-activators in Wnt signaling has provided a new mechanism for the regulation of β-catenin transcriptional activity (Figure 3a) [78••, 80]. The human oncogene product BCL9 is the ortholog of the Drosophila segment polarity gene product Legless. In 2002, the group led by Konrad Basler [80] identified the Legless gene product as being required for wingless signaling in the fly. Legless interacts with Armadillo–β-catenin
Essential role of BCL9-2 in switching between adhesive and transcriptional functions of β-catenin
It was shown that BCL9-2 plays an important role in the switch between the adhesive and the transcriptional functions of β-catenin. This switch is modulated by phosphorylation of β-catenin tyrosine 142, which induces binding to BCL9-2 and precludes the interaction with α-catenin (Figure 1) [78••]. BCL9-2 and α-catenin share an overlapping binding site on β-catenin, which includes the first armadillo repeat where tyrosine 142 is located [71, 78••]. Introduction of a negative charge on residue
The role of the BCL9 proto-oncogene family in human tumors
BCL9 and BCL9-2 expression might enhance Wnt–β-catenin signaling during tumor formation. Overexpression of BCL9-2 targets β-catenin to the nucleus and interferes with the adhesive functions of the E-cadherin–catenin complex, and might promote invasion and metastasis [78••, 86••]. The Akiyama group [93•] demonstrated that BCL9-2 is required for enhanced β-catenin transcription in colorectal tumor cells, indicating that this co-factor is crucial for aberrant Wnt signaling. These investigators
A transcriptionally active state of β-catenin
A second mechanism to regulate the transcription function of β-catenin was recently described by Gottardi and Gumbiner [103••]. These investigators have demonstrated the existence of two different molecular forms of β-catenin that act in adhesion and transcription, respectively [103••]. In this model, the formation of β-catenin–α-catenin complexes is essential to regulate β-catenin function. Using affinity precipitation experiments, it was shown that the adhesive form consists of
Conclusion
The control of the dual functions of β-catenin in cellular adhesion and in transcriptional regulation is crucial for maintaining normal cellular function. De-regulation of this system, which promotes the transcriptional function of β-catenin at the cost of its function in adhesion, lies at the heart of the development and progression of many human malignancies. The switch between these two functions is controlled by several factors, including protein stability and conformation, the presence of
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank the granting agency The Dr Mildred Scheel Stiftung für Krebsforschung for supporting our research.
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