Figure 1. A simplified view of the Hedgehog (HH) signalling pathway. In cells that do not receive the HH signal (a), Patched (PTC) acts by repressing Smoothened (SMO), and the proteins Fused (FU), Suppressor of Fused (SU(FU)), Costal2 (COS2) and Cubitus interruptus (CI) (GLI in vertebrates) form a complex associated to microtubules. CI is proteolytically cleaved in a process involving phosphorylation by protein kinase A (PKA) and the activity of SLIMB, rendering a form of CI that keeps HH-dependent targets repressed. In cells that do receive the HH signal (b), interaction of HH with PTC relieves the repressive effect on SMO, which leads to the dissociation of the protein complex from microtubules and inhibition of CI processing. This results in the full-length form of CI acting as an activator of HH-dependent targets, interacting with Cre-Binding Protein (CBP) and other nuclear proteins. It is still not known whether activation of SMO antagonizes PKA activity and SLIMB. In cells that produce the HH signal (c), activity of the protein Dispatched is required for releasing the lipid-modified active form of the HH protein, so that it can signal to adjacent cells. Lipid-modified HH proteins are found associated to lipid rafts, where interaction with glycosaminoglycans (GAGs) may also assist in the diffusion and/or interaction of HH with its receptor.