Chapter category: Reproductive Biology
Hedgehog Signaling in Endodermally Derived Tumors
Chapter authors:
Marina Pasca di Magliano and Matthias Hebrok
A relatively small number of intercellular signaling pathways, including the Hedgehog (Hh), transforming growth factor ? (TGF-beta), fibroblast growth factor (FGF), Wnt, and Notch pathways, interact to regulate embryonic development and organogenesis. In contrast to the other pathways, the mammalian Hedgehog signaling pathway is relatively compact, comprised of only three known ligands, Sonic (Shh), Indian (Ihh), and Desert Hedgehog (Dhh), and two receptors, patched 1 and 2 (Ptch1/2; (Fig. 1).23 In the absence of the ligands, Patched (Ptch) inhibits the activity of a second transmembrane protein, Smoothened (Smo). As a consequence, transcription factors of the Gli family remain inactive in the cytoplasm through interaction with a protein complex that includes Suppressor of fused su(fu).44 Upon ligand stimulation, Ptch mediated inhibition of Smo is alleviated and a cascade of events that is not fully understood results in the activation and translocation of Gli transcription factors into the nucleus where they activate the transcription of target genes. Some of these are components of the Hedgehog pathway itself, including Gli, Ptch and the Hedgehog interacting protein (Hhip). Both Ptch and Hhip are membrane proteins that attenuate the pathway by binding to and blocking diffusion of Hedgehog ligands.8,10,15,16 Therefore, the Hedgehog signaling pathway regulates itself through a negative feedback mechanism that results in increased expression of Ptch and Hhip in Hedgehog responsive cells.
