Cancer biology: a new RING to Wnt signaling

Abstract

The β-catenin-dependent Wnt signaling pathway has key roles in embryonic development and adult tissues and is defective in various cancers. Recent studies highlight the function of two transmembrane RING finger ubiquitin ligases in modulating Wnt signaling and reveal roles for mutations in the RING finger proteins in cancer.

Figure 1

Model for Wnt regulation of the free pool of β-catenin. Left: In the absence of an activating Wnt ligand, β-catenin is phosphorylated at multiple serine/threonine residues in its amino-terminal domain by the ‘destruction complex’, consisting of Axin, APC, GSK3β, and casein kinase 1α (CK1α). The amino-terminally phosphorylated β-catenin is recognized by a ubiquitin ligation complex that contains βTrCP, and the ubiquitinated β-catenin is degraded by the proteasome. The ubquitination and degradation of β-catenin allows the destruction complex to bind and phosphorylate additional β-catenin molecules. Right: In the presence of an activating Wnt ligand, which bridges the Fz–LRP5/6 proteins and brings about phosphorylation of cytoplasmic LRP5/6 sequences by CK1a, the destruction complex is recruited to the phosphorylated cytoplasmic domain of LRP5/6. While the destruction complex can still bind and phosphorylate β-catenin, ubiquitination by βTrCP is blocked, allowing newly synthesized β-catenin to accumulate in the cell and activate transcription in the nucleus, via interactions with TCF proteins and various co-factors, including the p300/CBP histone acetyltransferases, BCL9, and Pygopus (Pygo), among others.