Hedgehog-regulated atypical PKC promotes phosphorylation and activation of Smoothened and Cubitus interruptus in Drosophila

Hedgehog (Hh) signaling by Smoothened (Smo) is mediated by phosphorylation and cell surface/cilium accumulation, but how the localization of Smo is controlled remains poorly understood. We show that the atypical PKC (aPKC)-partition defective 6 (Par6) complex promotes Hh signaling by phosphorylating Smo and regulating Smo basolateral accumulation in addition to phosphorylating the transcription factor cubitus interruptus (Ci). Our results demonstrate direct involvement of aPKC in Hh signaling beyond its role in cell polarity and suggest that basolateral accumulation of Smo is critical for its activity. Abnormal activation of Smo results in several types of cancers, and Smo can easily acquire drug resistance through mutations. A better understanding of the mechanisms of Smo regulation is critical to developing more effective therapeutic treatments for cancers caused by Smo dysregulation.