Figure 2 The Wnt pathway in the “off and on” states. Off: signalling is kept in an off state either in the absence of Wnt or when Wnt factors are prevented to bind to the membrane‐bound receptors Frizzled (Frz) and coreceptors low‐density lipoprotein receptor‐related protein (LRP). This is achieved either by the extracellular Wnt‐titrating inhibitors SFRPs (secreted Frz‐related peptides), WIF‐1 (Wnt inhibitory factor‐1) and Cerberus‐1(CER1), or by specific members of the Dickkopf (Dkk) family that stimulate the Kremen‐dependent endocytosis of LRP. In the cytoplasm, β‐catenin is tagged by phosphorylation (P) in the destruction complex containing the core components adenomatous polyposis coli (APC), axin/conductin and the kinases casein kinase 1 (CK1) and glycogen synthase kinase 3β (GSK3β). β‐Transducin repeat‐containing protein (βTrCP) targets phosphorylated β‐catenin to the proteasome where it is degraded. In the nucleus, the Wnt target genes are kept silent by the repressor Groucho interacting with DNA‐bound T cell factor (TCF). APC is thought to actively export β‐catenin. The inhibitors, inhibitor of β‐catenin (ICAT) and Chibby, can also repress β‐catenin activity in the nucleus. The occupancy of Frz and LRP by Wnt triggers the phosphorylation of the cytoplasmic tail of LRP by CK1 and GSK3β and the dishevelled (Dsh)‐dependent recruitment of axin on to phosphorylated LRP. In the nucleus, transcription of Wnt target genes is initiated by the displacement of Groucho, the interaction of β‐catenin with TCF and the recruitment of B cell lymphoma 9 (Bcl9), Pygopus, the mixed‐lineage leukaemia (MLL) methyltransferases, APC, C‐terminal‐binding protein (CtBP) and βTrCP.