Multiple proteins are involved in mediating Wnt signaling. The three established Wnt signaling pathways are referred to as the canonical pathway, the planar cell polarity (PCP) pathway, and the Wnt-Ca2+
pathway. Proteins that promote the canonical beta-Catenin-dependent signaling pathway include GSK-3 beta, Casein Kinase 1 (CK1), Dishevelled, beta-Catenin, and co-activators such as Bcl-9 and Pygopus. Negative regulators of this pathway include APC, Axin-1, GSK-3 beta, and CK1. In the absence of Wnt, GSK-3 beta and CK1 in the Axin-1 complex constitutively phosphorylate beta-Catenin, targeting it for ubiquitin-mediated proteasomal degradation. In the presence of Wnt, the Axin protein complex is recruited to the activated Wnt receptor and GSK-3 beta and CK1 phosphorylate LRP-5/6. Translocation of the Axin-1 complex disrupts beta-Catenin phosphorylation and degradation, allowing beta-Catenin to accumulate in the nucleus, where it serves as a transcriptional activator of the TCF/LEF-1 family of DNA binding proteins.
The non-canonical planar cell polarity (PCP) and Wnt-Ca2+ signaling pathways are relatively less well defined. In the Wnt/Ca2+ pathway, Wnt binding to Frizzled receptors results in the activation of heterotrimeric G proteins with subsequent mobilization of phospholipase C and phosphodiesterase. This induces a decrease in cGMP, a transient increase in intracellular Ca2+, and activation of protein kinase C (PKC), calcium calmodulin mediated kinase II (CAMKII), and the phosphatase calcineurin. Together these proteins promote cell migration and inhibit the canonical beta-Catenin-dependent signaling pathway.
In addition, Wnt can act through the PCP pathway to define polarity in select epithelial tissues, particularly along an axis perpendicular to the apical-basal border. Briefly, Wnt binding to Frizzled activates Dishevelled, likely on the C-terminus of the molecule. Dishevelled then recruits the RhoA and Rac GTPases, which ultimately activate Rho Kinases (ROCK) and c-jun NH2-terminal kinase (JNK). ROCK regulates actin cytoskeleton organization, smooth muscle contraction, and cell motility and adhesion, while JNK signaling activates the transcription factor AP-1.