Sonic Hedgehog Signaling Inhibitors

Mammalian Hedgehog proteins include Sonic Hedgehog (Shh), Indian Hedgehog (Ihh), and Desert Hedgehog (Dhh). Shh is expressed mainly in the epithelia in the tooth, hair, whisker, gut, bladder, urethra, vas deferens, and lung, Dhh is found in Schwann and Sertoli cell precursors and Ihh is expressed in gut and cartilage. Hedgehog proteins undergo autocatalysis to generate a ~20 kDa N-terminal domain and a ~25 kDa C-terminal domain. This autoprocessing causes the covalent attachment of cholesterol onto the carboxy-terminus of the N-terminal domain. The N-terminal domain retains all signaling capabilities while the C-terminal domain is responsible for the intramolecular precursor processing. The cholesterol moiety is believed to be responsible for directing Hedgehog traffic in the secretory cell.

Shh, a secreted morphogen, has been implicated in several embryonic developmental processes. It displays inductive, proliferative, neurotrophic, and neuroprotective properties. Shh often works in concert with the Wnt signaling protein in setting embryonic patterns. The Wnt pathway uses Β-catenin to transduce its signals to the nucleus; however, the Shh pathway utilizes a 155 amino acid protein, Cubitus interruptus (Ci155) in Drosophila or Gli in mammals. In the absence of a Shh signal, Ci is targeted for proteolysis, which generates a truncated 75-amino acid residues form (Ci75) that acts as a transcriptional repressor. In vertebrates three Gli proteins (Gli1, Gli2, and Gli3) have been reported. Despite several homologous regions, including a DNAbinding domain with five C2-H2 zinc fingers and a C-terminal transcription activation domain, these proteins have distinct activities and are not considered to be functionally equivalent.

Shh signaling is known to occur through a receptor complex associating two membrane proteins, Patched (Ptc) and Smoothened (Smo). Ptc is a twelve-pass membrane protein that acts as a receptor and binds Hedgehog ligand; Smo is a seven-pass membrane protein that acts as a signal transducer. In the absence of a ligand, Ptc interacts with Smo and inhibits its activity. Shh binding to Ptc removes the inhibitory effect and allows Gli to enter the nucleus and act as a transcriptional activator. Shh signaling is required throughout embryonic development and is involved in the determination of cell fate and embryonic patterning during early vertebrate development. During the late stage of development, Shh is involved in the proper formation of a variety of tissues and organs. Shh also functions with other signaling molecules such as the fibroblast growth factors and bone morphogenetic protein to mediate developmental processes. Mutations in any of the components of the Shh pathway can lead to congenital defects and diseases, including cancer. Hence, the Shh pathway has become a potential target for drug development for the treatment of cancers and degenerative diseases.

References:
Lum, L., and Beachy, P.A. 2004. Science 304, 1755.
Wetmore, C. 2003. Curr. Opin. Genet. Dev. 13, 34.
Pola, R., et al. 2001. Nat. Med. 7, 706.
Chuong, C.M., et al. 2000. Cell. Mol. Life Sci.57, 1692.
McMahon, A.P. 2000. Cell 100, 185.
Pepinsky, R.B., et al. 1998. J. Biol. Chem. 273, 14037.
Porter, J.A., et al. 1996. Science 274, 255.