The Wnt signalling pathway

doi:10.1242/jcs.00089 Recent advances in the field require an update of our Wnt pathway scheme (Hülsken and Behrens, 2000). Intracellular signaling of the Wnt pathway diversifies into at least three branches: (1) the b-catenin pathway (canonical Wnt pathway, blue), which activates target genes in the nucleus; (2) the planar cell polarity pathway, which involves jun N-terminal kinase (JNK) and cytoskeletal rearrangements (orange); and (3) the Wnt/Ca2+ pathway (green). Wnts are secreted glycoproteins that bind to frizzled seven-transmembrane-span receptors, which may be coupled to heterotrimeric G proteins. LRP5/6 (arrow in Drosophila), which are members of the low-density lipoprotein receptor-related protein family, act as essential co-receptors of Wnt ligands for canonical b-catenin-dependent signal transduction. Various secreted factors, such as cerberus (Cer) and FrzB, bind to Wnts and block the interaction with frizzled proteins. Dickkopf (Dkk) antagonises Wnt action by blocking access to the LRP co-receptor and induction of LRP endocytosis in cooperation with kremen. Intracellularly, Wnt signalling leads to stabilisation of cytosolic b-catenin. In the absence of Wnts, b-catenin is phosphorylated by casein kinase Ia (CKIa) and/or CKIe at Ser45; this in turn enables glycogen synthase kinase 3b (GSK3b) to phosphorylate serine/ threonine residues 41, 37 and 33. Phosphorylation of these last two residues triggers ubiquitylation of b-catenin by b TrCP and degradation in proteasomes. Phosphorylation of b-catenin occurs in a multiprotein complex containing the scaffold protein axin, which can form a homodimer or a heterodimer with the related protein conductin/axin2, the tumor suppressor gene product APC and diversin, which links CK1e to the complex. b-Catenin