Wnt signaling: complexity at the surface

Wnts are secreted proteins that are essential for a wide array of developmental and physiological processes. They signal across the plasma membrane by interacting with serpentine receptors of the Frizzled (Fz) family and members of the low-density-lipoprotein-related protein (LRP) family. Activation of Fz-LRP promotes the stability and nuclear localization of beta-catenin by compromising the ability of a multiprotein complex containing axin, adenomatosis polyposis coli (APC) and glycogen synthase kinase 3 (GSK3) to target it for degradation and block its nuclear import. The Fz-LRP receptor complex probably accomplishes this by generating multiple signals in the cytoplasm. These involve activation of Dishevelled (Dsh), possibly through trimeric G proteins and LRP-mediated axin binding and/or degradation. However, individual Wnts and Fzs can activate both P-catenin-dependent and independent pathways, and Fz co-receptors such as LRP probably provide some of this specificity. Additional, conflicting data concern the role of the atypical receptor tyrosine kinase Ryk, which might mediate Wnt signaling independently of Fz and/or function as a Fz co-receptor in some cells.