Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator

Hedgehog (Hh) signaling controls development and tissue homeostasis through the Cubitus interruptus (Ci)/glioma-associated oncogene homolog (Gli) transcription factors, and abnormal Gli activity causes congenital diseases and cancers. Here we show that Ci/Gli phosphorylation by Casein kinase 1 positively regulates Hh pathway activity, providing insights into the regulation of Ci/Gli activity. By showing that phosphorylation protects the Ci/Gli activator from premature degradation, our study not only sheds lights on how the production and degradation of Ci/Gli activator are delicately balanced to achieve optimal pathway activity but also provides the first evidence (to our knowledge) that protein degradation by the Cullin 3 family of E3 ubiquitin ligases is negatively regulated by phosphorylation.