The Hedgehog signal transduction pathway. The Patched protein in the cell membrane is an inhibitor of the Smoothened protein. (A) In the absence of Hedgehog binding to Patched, the Ci protein is tethered to the microtubules (by the Cos2 and Fused proteins). This allows the PKA and Slimb proteins to cleave Ci into a transcriptional repressor that blocks the transcription of particular genes. (B) When Hedgehog binds to Patched, its conformation changes, releasing the inhibition of the Smoothened protein. Smoothened releases Ci from the microtubules (probably by adding more phosphates to the Cos2 and Fused proteins) and inactivates the cleavage proteins PKA and Slimb. The Ci protein enters the nucleus, binds a CBP protein and acts as a transcriptional activator of particular genes. (After Johnson and Scott 1998.)