The known Wnt signaling pathways. (a) In the Wnt/β-catenin pathway, Wnt signaling depends on the steady-state levels of the multi-functional protein β-catenin. In the absence of Wnt signal, a multi-protein destruction complex that includes the adenomatous polyposis coli protein (APC) and a member of the Axin family facilitates the phosphorylation of β-catenin by glycogen synthase kinase 3 (GSK3). GSK3 substrates also include APC and Axin; phosphorylation of each of these proteins leads to enhanced binding of β-catenin. Phosphorylated β-catenin is bound by the F-box protein β-TrCP, a component of an E3 ubiquitin ligase complex, and is ubiquitinated; the ubiquitin tag marks β-catenin for destruction by the proteasome. When a cell is exposed to a Wnt, the Wnt interacts with its coreceptors Frizzled and LRP. Activation of Frizzled and LRP leads to the phosphorylation of Dishevelled (Dsh), a cytoplasmic scaffold protein, perhaps through stimulation of casein kinase Iε (CKIε) and/or casein kinase II (CKII). Dsh then functions through its interaction with Axin to antagonize GSK3, preventing the phosphorylation and ubiquitination of β-catenin. In vertebrates, inhibition of GSK3 may involve the activity of GSK3 binding protein (GBP/Frat), which binds to both Dsh and GSK3 and can promote dissociation of GSK3 from the destruction complex. Unphosphorylated β-catenin escapes degradation, accumulates in the cell, and enters the nucleus, where it interacts with members of the TCF/LEF family of HMG-domain transcription factors to stimulate expression of target genes. In addition to the components of the Wnt/β-catenin pathway described here, many additional proteins with potential roles in regulating Wnt/β-catenin signaling have been reported including the phosphatase PP2A and the kinases Akt/protein kinase B, integrin-linked kinase (ILK), and PKC. (b) Signaling through the Wnt/Ca2+ pathway appears to involve activation of the two pertussis-toxin-sensitive G proteins, Gαo and G.αt, in combination with Gβ2 [34,35]. G-protein activation then leads to an increase in intracellular Ca2+ and the subsequent stimulation of Ca2+/calmodulin-dependent kinase II (CamKII) . Activation of the Wnt/Ca2+ pathway also results in stimulation of PKC activity in the form of the translocation of PKC to the plasma membrane . Downstream targets of the Wnt/Ca2+ pathway have not been identified. (c) The Wnt/polarity pathway, which regulates cytoskeletal organization; the Drosophila Wnt/polarity pathway that regulates the polarity of trichomes in the wing is shown as an example. In this case, the nature of the polarity signal is not known.