Wnt signaling has a central role in embryonic development, differentiation, cell motility, cell proliferation, and adult tissue homeostasis. Wnt ligands are a large family of secreted glycoproteins that signal through a canonical beta-Catenin-dependent pathway, and at least two well-characterized beta-Catenin-independent pathways, the Wnt/Ca2+ pathway and the planar cell polarity (PCP) pathway. The canonical beta-Catenin-dependent pathway is initiated by association of Dishevelled with the activated Wnt receptor. Dishevelled recruits the Axin protein complex (Axin, APC, CK1, GSK-3), leading to phosphorylation of the LRP-5/6 co-receptor by Glycogen Synthase Kinase-3 (GSK-3) and Casein Kinase 1 (CK1), and inhibiting phosphorylation of beta-Catenin by these kinases. Unphosphorylated beta-Catenin accumulates and subsequently translocates to the nucleus, where it associates with TCF/LEF family transcription factors and co-activators, such as Bcl-9 and Pygopus (Pygo), to induce the expression of Wnt target genes. In the absence of Wnt, cytoplasmic beta-Catenin is phosphorylated by CK1 and GSK-3, which creates a docking site on beta-Catenin for beta-Trcp, an E3 ubiquitin ligase that promotes its ubiquitination and proteasomal degradation.
In addition to the beta-Catenin-dependent signaling pathway, there are at least two beta-Catenin-independent Wnt signaling pathways. The Wnt-Ca2+ pathway activates Calcium/Calmodulin-dependent Protein Kinase type II (CaMKII) and Protein Kinase C (PKC). This occurs via a classical G protein-coupled signaling pathway that includes upstream activation of Phospholipase C (PLC) and its cleavage of PIP2 into DAG and IP3. DAG activates Protein Kinase C (PKC), while IP3 promotes Ca2+ mobilization from intracellular stores. This pathway ultimately induces cell migration and inhibits the beta-Catenin-dependent pathway. The other major Wnt signaling pathway, the PCP pathway, regulates cell motility and tissue polarity. It involves activation of the Rho and Rac GTPases, Rho-Kinase (ROCK), and c-Jun N-terminal kinase (JNK). Like the Wnt/Ca2+ pathway, the PCP pathway also inhibits the beta-Catenin-dependent Wnt signaling pathway. Both the PCP pathway and the canonical beta-Catenin-dependent pathway are enhanced by R-Spondins binding to the leucine-rich repeat-containing, G protein-coupled receptors (Lgr), Lgr4, Lgr5, and Lgr6. R-Spondin/Lgr-enhanced Wnt/beta-Catenin signaling may require ligand-receptor internalization, as has also been suggested for the Wnt/Frizzled/LRP complex.
Wnt ligands have also been shown to signal through a number of different co-receptors, including ROR2 and Ryk, which may or may not require a Frizzled receptor. Wnt-5a/ROR2 signaling activates JNK to regulate convergent extension in Xenopus, inhibits the beta-Catenin-dependent pathway, and may play a role in regulating the PCP pathway. In contrast, Wnt/Ryk signaling activates the beta-Catenin-dependent or PCP pathways and promotes axon guidance through Src activation. Deregulation of Wnt signaling is associated with a number of developmental disorders and human diseases, including bone and renal diseases, type II diabetes, and tumorigenesis. As a result, extracellular and intracellular modulators of Wnt signaling are of great interest.