Fine-tuning of nuclear-catenin by Chibby and 14-3-3

Abstract

Chibby (Cby) is an evolutionarily conserved antagonist of beta-catenin, a central player of the canonical Wnt signaling pathway, which acts as a transcriptional coactivator. Cby physically interacts with the C-terminal activation domain of beta-catenin and blocks its transcriptional activation potential through competition with DNA-binding Tcf/Lef transcription factors. Our recent study revealed a second mechanism for Cby-mediated beta-catenin inhibition in which Cby cooperates with 14-3-3 adaptor proteins to facilitate nuclear export of beta-catenin, following phosphorylation of Cby by Akt kinase. Therefore, our findings unravel a novel molecular mechanism regulating the dynamic nucleo-cytoplasmic trafficking of beta-catenin and provide new insights into the cross-talk between the Wnt and Akt signaling pathways. Here, we review recent literature concerning Cby function and discuss our current understanding of the relationship between Wnt and Akt signaling.

Figure 1

Simplified overview of the canonical Wnt/β-catenin signaling pathway. (left panel) In the absence of a Wnt signal, β-catenin is sequestered in the destruction complex containing the scaffold proteins APC and Axin, and sequentially phosphorylated by the kinases CK1 and GSK3. This results in degradation of β-catenin via the uiquitin-proteasome pathway. In the nucleus, Tcf/Lef target genes are repressed through recruitment of transcriptional co-repressors including Groucho. (right panel) Upon Wnt signaling, Frz-Dsh complex formation and the sequential phosphorylation of LRP5/6 by GSK3 and CK1 promote translocation of Axin to the plasma membrane, leading to inactivation of the destruction complex. Stabilized β-catenin then enters the nucleus and forms a complex with Tcf/Lef factors to stimulate expression of Wnt target genes by recruiting various co-activators such as CBP. β-Catenin is also a key component of cell-cell adhesion, linking cadherins to the actin cytoskeleton.

Figure 2

Inhibition of β-catenin signaling by Cby and other nuclear export pathways. In the nucleus, Cby interacts with β-catenin and competes with Tcf/Lef transcription factors, thereby blocking expression of target genes. In addition, phosphorylation of Cby and β-catenin by Akt facilitates 14-3-3 binding, resulting in nuclear export of β-catenin to the cytoplasm. APC, Axin and RanBP3 have been shown to promote nuclear export of β-catenin. See text for details.