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Significance The ciliary membrane-localized transmembrane Hedgehog receptor Patched1 suppresses the ciliary translocation of the transmembrane oncoprotein Smoothened and consequently Hedgehog pathway activation, but the mechanism underlying this process remains largely unknown. Here, we show that the Patched1–ArhGAP36–PKA–Inversin–Smoothened axis determines this process. We uncover that the ciliary translocation of Smoothened depends on its interaction with phosphorylated ciliary Inversin, which is sequentially achieved by the removal of centrosomal ArhGAP36 with ciliary Patched1 and the accumulation of centrosomal PKA during Hedgehog pathway activation. Our findings reveal how the Hedgehog pathway is spontaneously activated in tumor cells carrying loss-of-function mutations of Patched1 or oncogenic mutations of Smoothened.

Patched1–ArhGAP36–PKA–Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation