The phosphatase Pgam5 antagonizes Wnt/β-Catenin signaling in embryonic anterior-posterior axis patterning

The scaffold protein Dishevelled is a central intracellular component of Wnt signaling pathways. Various kinases have been described that regulate and modulate Wnt signaling through phosphorylation of Dishevelled. However, besides general protein phosphatases 1 and 2 (PP1 and PP2), no specific protein phosphatases have been identified. Here, we report on the identification and functional characterization of the protein phosphatase Pgam5 in vitro and in vivo in Xenopus. Pgam5 is a novel antagonist of Wnt/beta-Catenin signaling in human cells and Xenopus embryogenesis. In early development, Pgam5 is essential for head formation, and for establishing and maintaining the Wnt/beta-Catenin signaling gradient that patterns the anterior-posterior body axis. Inhibition of Wnt/beta-Catenin signaling and developmental function depend on Pgam5 phosphatase activity. We show that Pgam5 interacts with Dishevelled2 and that Dishevelled2 is a substrate of Pgam5. Pgam5 mediates a marked decrease in Dishevelled2 phosphorylation in the cytoplasm and in the nucleus, as well as decreased interaction between Dishevelled2, Tcf1 and beta-Catenin, indicating that Pgam5 regulates Dishevelled function upstream and downstream of beta-Catenin stabilization.