Wnt signaling and stem cell control

Wnt proteins comprise one family of secreted signaling molecules that is conserved in a wide range of species, from the cnidarianHydra to humans. Members of the Wnt family are classified based on sequence homology with the first-identified Wnt proteins: mouse Wnt-1 and Drosoph-ila wingless. Signaling by Wnt ligands is used in a variety of contexts, having key roles in both embryonic develop-ment and adult homeostasis (for review, see Logan and Nusse 2004). Misregulation of Wnt signaling has been implicated in developmental abnormalities and cancer. Most Wnt signaling events are transduced by what is referred to as the canonicalWnt pathway (Fig. 2). In this set-ting, Wnt ligands are secreted and bind to their cognate receptor complex on the surface of receiving cells. The re-ceptor complex consists of Frizzled, a 7-transmembrane domain receptor, and a low-density lipoprotein (LDL) receptor-related protein (LRP) coreceptor (Bhanot et al. 1996; Wehrli et al. 2000). The signal is relayed through the intracellular protein Dishevelled (Dsh/Dvl), which, in the presence of Wnt ligand binding, promotes inhibition of a destruction complex consisting of Axin, APC (adenoma-tous polyposis coli), and GSK3 (glycogen synthase kinase 3) (for review, see Cadigan and Liu 2006). In the absence of a Wnt signal, the destruction complex phosphorylates β-catenin, targeting it for degradation by the proteasome. Inhibition of the destruction complex leads to an accumula-tion of cytoplasmic β-catenin and the subsequent transloca-tion of β-catenin into the nucleus. In the nucleus, β-catenin interacts with T-cell factor/lymphoid enhancer facto