The Wntome: A genome-wide analysis of kinases and phosphatases that regulate Wnt signaling

Evolutionarily conserved cell signaling pathways regulate diverse and indispensable processes during metazoan development. A precise control of both the state and threshold of signaling is required for normal development to occur. Cells predominantly utilize the kinase- and phosphatase-mediated reversible phosphorylation of proteins to control signaling. The canonical Wnt signaling pathway has homologous roles during the processes of axis polarization and stem cell maintenance in diverse metazoans. Wnt signaling is regulated through reversible phosphorylation both in its silent and active state. We have identified and characterized the function of Drosophila Hipk, a novel kinase component of the pathway. Genetic and biochemical analyses suggest that Hipk stabilizes the pathway effector Armadillo in a process that is dependent on its catalytic activity. Additionally, Hipk acts to promote pathway activity independent of its effect on Armadillo stability. We find that Hipk2 has a functionally conserved role to regulate Wnt signaling in mammalian cells. Hipk and a limited number of other kinases (and phosphatases) have thus far been implicated in the regulation of Wnt signaling. We have performed an in vivo loss-of-function RNAi screen to identify additional enzymes that regulate this pathway through reversible phosphorylation in Drosophila. Our analyses have identified novel pathway components at all levels of the Wnt signaling relay.