School of Biosciences

Wnt ligands such as Wnt1, Wnt3a, and Wnt8 couple the seven-transmembrane domain receptor Frizzled (Fzd) and the single-membrane-spanning low-density receptor-related protein 5/6 (LRP5/6) at the cell surface. This induces phosphorylation of LRP5/6 and inhibition of the β-catenin destruction complex (which includes axin, GSK3, Dvl, CK1, and the tumor suppressor adenomatous polyposis coli). Thus, β-catenin is stabilized and can translocate to the nucleus, where it activates target genes through binding to TCF/LEF transcription factors.

I am interested in how Wnt induces the phosphorylation of LRP6 (which is thought to be via the enzymes GSK3 and CK1). The intracellular domain of LRP6 contains repeats of a PPP(S/T)P sequence. Phosphorylation of at least one of these repeats is known to be necessary for Axin binding. Phosphorylation of other S or T residues nearby are also thought to be critical, leading to clustering of different proteins (including LRP6, Dvl and Axin) in what has been defined as the LRP6 signalosome.

I am purifying a small region of the intracellular domain of LRP6 with a phosphorylated PPPSP repeat.  This will enable me to study the biochemistry of GSK3 and Axin binding to the receptor and for a structural analysis of the bound forms. In the longer term, this information should be useful to the design of inhibitors of Wnt signalling at the stage of receptor complex formation.