LIG_GSK3_LRP6_1

The canonical Wnt signalling pathway plays a key role during embryonic development and is also crucial for stem cell renewal and tissue homeostasis in adults. Misregulations in the Wnt pathway are known to be involved in multiple diseases including cancers. (Dees,2014) In the absence of secreted Wnt ligands, β-catenin is downregulated by the APC/Axin1 destruction complex. The destruction complex is comprised of glycogen synthase kinase 3β (GSK-3β), casein kinase 1 (CK1), the Adenomatous Polyposis Coli (APC) tumour suppressor protein and the scaffolding protein Axin (Dees,2014).

The phosphorylation of β-catenin takes place sequentially by CK1 at Ser45, which is followed by GSK-3 phosphorylation at Thr41, Ser37 and Ser33 (Wu,2009). Among these residues, Ser33 and Ser37 constitute the key recognition sites of the degron (Stamos,2013). In short, the phosphorylation of β-catenin on Ser33 and Ser37 generates a DSGxxS phosphodegron, which enables it to be targeted by the SCF β-TrCP E3 ubiquitin ligase complex. Once β-catenin is ubiquitinylated, it is degraded by the proteosomal machinery (Wu,2009).

Upon activation of the Wnt pathway in the presence of Wnt ligands, a complex of the membrane receptors Frizzled and LDL receptor related protein 6 (LRP6) is formed. This triggers the phosphorylation of the LRP6 intracellular domain at five conserved PPPSP motifs. Phosphorylation of these motifs occurs sequentially by GSK-3 and CK1 (Zeng,2005). The phosphorylation of both S/T residue of the PPPSP motif is a requirement for biological activity, however the first site is sufficient for GSK-3 inhibition by LRP6 (Stamos,2014). One model suggests that the phosphorylation of LRP6 at these motifs enables Axin to bind in a pseudo-substrate manner, thereby recruiting its associated proteins (including GSK-3) to LRP6 leading to the indirect inhibition of β-catenin phosphorylation. (Wu,2009) More recent studies suggest that phosphorylated LRP6 inhibits GSK-3 directly by recruiting it as a pseudo-substrate (Stamos,2014).

The inhibition of β-catenin phosphorylation terminates its degradation and leads to the accumulation of unphosphorylated β-catenin in the cytoplasm. Subsequently it translocates to the nucleus where it regulates transcription factors (TCF) and expression of genes controlling proliferation and cell cycle progression (Wolf,2008).