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Wnt Intracellular Signaling

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.