The Shh-Gli pathway and potential sites for blocking it with therapeutic agents

Sonic hedgehog (Shh) acts on the membrane receptor complex formed by Patched (Ptc) and Smoothened (Smo) to inhibit the repression of Smo by Ptc. Smo is then thought to send the signal intracellularly through several cytoplasmic transduction steps (not shown), leading to the nuclear action of the Gli proteins, which regulate target genes. Thick blue arrows pointing up or down indicate activating or inactivating mutations, respectively, that might induce the pathway. Inhibitors of the the pathway with potential therapeutic value (red lines) include: agents that block the action of Smo in the receptor complex, such as the plant alkaloid cyclopamine; agents that inhibit specific aspects of the transduction of the signal, including the nuclear import or activation of Gli proteins; and agents that specifically inhibit Gli function.