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. 2014 Mar 4;4(1):13.
doi: 10.1186/2045-3701-4-13.

Regulation of Wnt/β-catenin signaling by posttranslational modifications

Chenxi Gao, Gutian Xiao, Jing Hu  1
Affiliations

Regulation of Wnt/β-catenin signaling by posttranslational modifications

Chenxi Gao et al. Cell Biosci. .

Abstract

The canonical Wnt signaling pathway (or Wnt/β-catenin pathway) plays a pivotal role in embryonic development and adult homeostasis; deregulation of the Wnt pathway contributes to the initiation and progression of human diseases including cancer. Despite its importance in human biology and disease, how regulation of the Wnt/β-catenin pathway is achieved remains largely undefined. Increasing evidence suggests that post-translational modifications (PTMs) of Wnt pathway components are essential for the activation of the Wnt/β-catenin pathway. PTMs create a highly dynamic relay system that responds to Wnt stimulation without requiring de novo protein synthesis and offer a platform for non-Wnt pathway components to be involved in the regulation of Wnt signaling, hence providing alternative opportunities for targeting the Wnt pathway. This review highlights the current status of PTM-mediated regulation of the Wnt/β-catenin pathway with a focus on factors involved in Wnt-mediated stabilization of β-catenin.

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Figures

Figure 1
Figure 1
Schematic diagram of the simplified Wnt/β-catenin pathway. Left panel: in the absence of Wnt ligand, β-catenin is sequentially phosphorylated by CK1 and GSK3 in the cytoplasmic β-catenin destruction complex. Ubiquitin E3 ligase β-TrCP recognizes phosphorylated β-catenin and promotes its ubiquitination and proteasome degradation. Right panel: Wnt/β-catenin signaling is activated by the binding of Wnt ligand to Fz receptor and LRP5/6 coreceptors, resulting in the recruitment of Dvl and destruction complex to the membrane, which inactivates destruction complex, leading to stabilization of β-catenin. Accumulated β-catenin enters nucleus and activates target gene transcription.
Figure 2
Figure 2
Schematic diagram of the simplified phosphorylation-mediated regulation of the core Wnt/β-catenin pathway components. Phosphorylation of LRP6 at T1479 by CK1γ and at S1490 by GSK3 and Grk5/6 promotes Wnt signaling. Dvl phosphorylation mediated by RIPK4 and CK1ϵ is essential for Wnt signaling. Phosphorylation of Axin at S497/S500 by GSK3 is suppressed by Wnt ligand, resulting in reduced association with LRP6 and β-catenin. C-terminal phosphorylation of β-catenin by PKA inhibits its ubiquitination and thus promotes β-catenin signaling activity. TNIK phosphorylates TCF4 to activate its transcriptional activity. NLK and HIPK2 phosphorylate TCF/LEF factors to inhibit their interaction with DNA.
Figure 3
Figure 3
Ubiquitination-mediated regulation of the core Wnt/β-catenin pathway components. Cell-surface transmembrane ubiquitin E3 ligases ZNRF3 and RNF43 target frizzled for lysosome degradation. UBPY deubiquitinates frizzled to recycle it to the plasma membrane. Palmitolylation and monoubiquitylation regulate LRP6 exit from the endoplasmic reticulum (ER). Multiple ubiquitin E3 ligases target Dvl for degradation, thus negatively regulate Wnt signaling. CYLD and USP14 are deubiquitinases responsible for removing K63-linked polyubiquitin chain of Dvl. RNF146 and Smurf2-mediated ubuiqitination targets Axin for degradation, whereas Smurf1-mediated ubuiqitination of Axin regulates its interaction with LRP5/6. USP15 protects APC from degradative ubuiqitnation. HectD1 modifies APC with K63-linked polyubiquitin chain to promote interaction between APC and Axin. Apart from the β-TrCP-mediated degradative ubiquitination of β-catenin, ubiquitination-mediated by ubiquitin-conjugating enzyme Rad6B increases β-catenin stability. Ubiquitin ligase Jade-1, which is primarily localized in the nucleus, may regulate abundance of the nucleus pool of β-catenin.
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