Module 2: Figure Hedgehog signalling pathway

Activation of gene transcription by the Hedgehog signalling pathway.

Under resting conditions, the patched (PTC) receptor for Hedgehog (Hh) inhibits the activity of the seven-membrane-spanning receptor smoothened (SMO). In this inhibited state, SMO is not able to act on the complex of cytoplasmic factors that collectively regulate the transcription factor GLI1. When Hh is present, it binds to PTC, and this removes the inhibitory effect of the latter on SMO, which is now capable of activating transcription by releasing GLI from its associated cytoplasmic factors. GLI1 then translocates into the nucleus, where it activates a variety of genes that fall into three main groups. One group consists of components of the signalling pathway, such as GLI1 and missing in metastasis (MIM), which set up a positive-feedback loop. The second group consists of genes coding for PTC and Hh-interacting protein (HIP), which thus set up a negative-feedback loop. The HIP protein acts on the outside to bind Hh and thus reduce its activity. The last group of genes code for proteins not involved in Hedgehog signalling, but some do function in other signalling pathways such as Wnt (Module 2: Figure Wnt canonical pathway) and the bone morphogenetic proteins (BMPs) (Module 2: Figure Smad signalling).