Wnts are secreted glycoproteins that bind to frizzled seven-transmembrane-span receptors. The proteoglycan dally acts as a co-receptor for Wnts. Various secreted factors, such as WIF-1, cerberus (cer) and FrzB, bind to Wnts and block the interaction with frizzled proteins. Dickkopf (Dkk) antagonises Wnt action in an unknown fashion. In Drosophila, secretion of the Wnt homologue, Wingless, depends on the protein Porcupine (PORC).
Intracellularly, Wnt signalling leads to stabilisation of cytosolic ß-catenin. In the absence of Wnts, ß-catenin is phosphorylated by glycogen synthase kinase 3ß (GSK3ß), which triggers ubiquitination of ß-catenin by ßTrCP and degradation in proteasomes. Phosphorylation of ß-catenin occurs in a multiprotein complex assembled by the scaffolding protein axin or conductin. In the presence of Wnts, dishevelled (dsh) blocks ß-catenin degradation, possibly by recruiting the GSK3ß inhibitor GBP to the complex. In certain tumors, mutation of axin, ß-catenin or the tumor suppressor APC also lead to stabilisation of ß-catenin. ß-catenin degradation is modulated by the casein kinase CK1 and by the protein phosphatases PP2A and PP2C.
Stabilised ß-catenin enters the cell nucleus and associates with TCF transcription factors, which leads to the transcription of Wnt-target genes. Smad4, Tsh, XSox17 and the histone acetyl transferase CBP modulate target gene expression. When ß-catenin is absent, certain TCFs repress transcription by interacting with the co-repressors groucho and CtBP. Phosphorylation of TCFs by a MAP-kinase pathway involving TAK1 and NLK negatively regulates Wnt signalling. ß-catenin also binds to cadherin cell adhesion molecules and provides a link to the actin cytoskeleton.
Data for the Wnt pathway have been obtained from a variety of systems and organisms. Related genes and alternative names follow: Wnt/Wingless; GBP/frat1; axin/conductin; GSK3ß/Zeste-white3/Shaggy; ßTrCP/Slimb/FWD1; TCF/LEF; CBP/p300.