Wnt/beta-catenin signaling: new (and old) players and new insights

Abstract

Wnt/beta-catenin signaling has central roles in embryogenesis and human diseases including cancer. A central scheme of the Wnt pathway is to stabilize the transcription coactivator beta-catenin by preventing its phosphorylation-dependent degradation. Significant progress has been made toward the understanding of this crucial regulatory pathway, including the protein complex that promotes beta-catenin phosphorylation-degradation, and the mechanism by which the extracellular Wnt ligand engages cell surface receptors to inhibit beta-catenin phosphorylation-degradation. Here we review some recent discoveries in these two areas, and highlight some crucial questions that remain to be resolved.

Figure 1

The β-catenin degradation complex. This complex is assembled by Axin, and containsβ-catenin, APC, GSK3 and CK1. PP1 and WTX may also associate with the Axin complex. β-catenin phosphorylation by CK1 and GSK3 results in β-catenin recognition by β-Trcp, thereby triggering its degradation (1). Note that CK1 and GSK3 also phosphorylate Axin and APC, and in general these phosphorylation events result in tighter association of Axin and APC with β-catenin. PP1 dephosphorylation of Axin (at sites phosphorylated by CK1) reduces/releases GSK3-binding to Axin, which should not only result in less β-catenin phosphorylation by GSK3, but also less Axin phosphorylation by GSK3, thereby releasing β-catenin from Axin as well (2). APC has a role in Axin degradation (3) in addition to β-catenin degradation (1), thus plays dual functions in the Wnt pathway.

Figure 2

Activation of the Wnt receptor complex. (A) The initiation-amplification model. In the Wnt-induced Fz-LRP6 complex Fz recruits Dvl, which in turn recruits the Axin-GSK3 complex to initiate LRP6 phosphorylation on PPPSPxS motifs (initiation). Phosphorylated PPPSPxS motifs recruit more Axin-GSK3 complex to promote further PPPSPxS phosphorylation (amplification). Dvl-or Axin-associated CK1 (α, δ, or ε) and membrane-associated CK1γ may phosphorylate LRP6 and are omitted from the model for clarity. MACF1 associates with the cytosolic Axin complex and may have a role in promotion of Axin recruitment to the receptor complex. (B) Receptor aggregation model. Dvl polymerization promotes both the clustering of the Fz-LRP6 complex and the recruitment of the Axin complex, resulting in LRP6 phosphorylation.