HH signaling pathway in the primary cilium. In the absence of SHH, PTC1 is located at PC, indirectly inhibiting accumulation of SMO by transporting putative sterol ligand outside with a ‘tunnel’ structure. Meanwhile, PKA is up-regulated by GPR161, located at the base of PC, through increasing cAMP level. GLI2 and GLI3 are then phosphorylated by PKA, CK1, GSK3b, and sequestered by SUFU. Phosphorylated GLI2 and GLI3 are easy to get cleaved and repress the GLI-dependent transcription of target genes. In the presence of SHH ligand, the inhibit of SMO declined by the interaction between SHH and PTC1. SMO forms a complex with EVC and EVC2, and transports into PC structure. Level of cAMP is then down-regulated, preventing GLI2 and GLI3 from being phosphorylated. Full-length GLI2 and GLI3 actives GLI1 to translocate to the nucleus and induces the expression of HH target genes.