Fig. 1. Models for Wnt signal production and reception. (A) Wnt signal production. Wnt is palmitoylated (red rectangle) by Porcupine (Porc) in the lumen of the endoplasmic reticulum (ER). Upon reaching the Golgi, Wntless (also known as Evenness interrupted and Sprinter, and as MIG-14 in C. elegans; Wls, orange) associates with Wnt in vesicles bound for secretion (arrows), leading to extracellular association of Wnt with lipoprotein particles (Lp). The retromer complex recycles Wls at the plasma membrane back to the Golgi. (B) A two-step model for Wnt signal reception. In the absence of a Wnt signal, the labile ß-catenin molecule is phosphorylated by a complex consisting of Axin, Apc, and the kinases CK1 and GSK3ß, and is then rapidly degraded. Signaling is initiated (left) by association of Wnt with its co-receptors Lrp5/6 and Fz at the plasma membrane, leading to the Dsh-dependent partial inhibition of ß-catenin degradation and its translocation through the nuclear membrane. In the nucleus, ß-catenin activates target gene transcription by associating with Tcf. Signal amplification (right) occurs via GSK3- and CK1-dependent phosphorylation (P) of Lrp5/6, leading to further recruitment of Axin and Dsh oligomers (n) to form the `Wnt signalosome', causing increased accumulation of nuclear ß-catenin and further upregulation of target gene transcription. See text for references.