Wnt signalling: What The X@# is WTX?

In this issue of The EMBO Journal, Tanneberger et al demonstrate that Amer1/WTX, a tumour suppressor protein previously known for promoting b-catenin degradation and thus antagonizing Wnt signalling, is also required for LRP6 receptor phosphorylation and therefore activation of Wnt signalling. Amer1/WTX is recruited by PtdIns(4,5)P2 to the plasma membrane, and in turn recruits the Axin–GSK3 complex and CK1c to phosphorylate LRP6. While dichotomic players like Amer1/WTX are common in Wnt signalling, these new findings add more intrigues to this enigmatic protein and pathway. Wnt/b-catenin signalling controls embryogenesis and homeostasis, and has a central role in many diseases including cancer and osteoporosis (MacDonald et al, 2009). In the absence of an extracellular Wnt ligand, cytoplasmic b-catenin is phosphorylated and targeted for degradation via a complex assembled by the scaffolding protein Axin, the tumour suppressor APC (adenomatous polyposis coli), and kinases GSK3 and CKIa. Binding of a Wnt ligand to a frizzled (Fz) serpentine receptor and its coreceptor, low density lipoprotein receptor-related protein 6 (LRP6, or its relative LRP5), inhibits b-catenin phosphorylation and degradation, leading to increased b-catenin and its association with LEF/TCF DNAbinding factors for transcription of Wnt target genes (MacDonald et al, 2009). Wnt-induced phosphorylation of LRP6 represents a key step in receptor activation. Most critical are phosphorylation events at multiple PPPSPxS motifs, which provide docking sites for Axin and are sequentially carried out by GSK3 and CKI (Tamai et al, 2004, Zeng et al, 2005). Other phosphorylation events include those that are performed by CKI (likely CKIg) at a S/T-rich cluster (Davidson et al, 2005). This complex pattern of LRP6 phosphorylation is subjected to regulation by many components including Fz, Dishevelled (Dvl), and also Axin (Bilic et al, 2007; Zeng et al, 2008) (Figure 1). LRP6 phosphorylation also requires phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2), whose production is induced by Wnt through Dvl binding and activation of phosphatidylinositol 4-kinase type II a (PI4KIIa) and phosphatidylinositol-4-phosphate 5-kinase type I (PIP5KI) (Pan et al, 2008). The mechanism by which PtdIns(4,5)P2 promotes LRP6 phosphorylation has remained unclear and Tanneberger et al (2011) now demonstrate that Amer1/WTX (APC membrane recruitment 1/Wilms tumour gene on the X chromosome) is recruited by PtdIns(4,5)P2 to the plasma membrane to promote LRP6 phosphorylation by Axin–GSK3 and CK1g. Amer1 was initially identified as an APC-binding protein, which regulates APC cellular localization (Grohmann et al, 2007). Amer1 is identical to WTX, which is mutated in some cases of Wilms tumour, a paediatric kidney cancer (Rivera