Given the importance of Shh signaling in cancer, and the role of cilia in Shh signaling, it is important to dissect the fundamental role of ciliary signaling in the pathogenesis of Shh-dependent tumors.
We have discovered a critical missing piece in the basal repression machinery of Shh signaling. The cAMP-activated protein kinase A (PKA) is pivotal in the processing of Gli2/3 into the GliRs; however, the pathways that mediate this activation of PKA remain unknown. We have identified a novel ciliary GPCR, Gpr161, which prevents Gli3R formation by cAMP signaling. Utilizing a variety of biochemical, cell biological and reverse genetic approaches, we will better define the role of this new repression mechanism in Shh-mediated signaling and oncogenesis.
Characterization of this novel pathway also provides us with a fundamentally new strategy for therapeutic intervention in Shh-dependent tumors, and for bypassing tumor resistance to available drugs.