Hedgehog signal path

Hedgehog proteins are signaling proteins that play an important role in cell growth and differentiation during animal embryogenesis. The Hedgehog signaling pathway appeared very early in evolutionary history. Malfunction of this pathway leads to massive malformations during embryonic development and can cause carcinomas in adults. In mammals, 3 Hedgehog proteins are currently known (sonic hedgehog, indian hedgehog and desert hedgehog).

The Hedgehog signaling pathway is based on proteolysis. It becomes active when the Hedgehog protein binds to the receptor Patched (see PTCH 1 gene below). This removes the (physiological) inhibition of the receptor(SMO = Smoothened) by PTCH1.

When Hedgehog is active and transmits a signal, the protein Ci can no longer be degraded, diffuses into the cell nucleus and regulates gene expression there. The Hedgehog signaling pathway has been shown to play a critical role in the pathogenesis of basal cell carcinoma. Most sporadic basal cell carcinomas show mutations in this signalling pathway. In addition, mutations of the p-53 tumor suppressor gene are also found. For the autosomal dominant Gorlin-Goltz syndrome a mutation in the PTCH1 gene could be detected.

Inhibitors of the Hedgehog signalling pathway (GDC-0449/Fa. Gentech; see also Itraconazole) represent a new drug approach in the therapy of advanced basal cell carcinoma. GDC-0449 is a small molecule that binds to SMO and thus inhibits signal transduction (see below Basal cell carcinoma).

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4. Zugasti O et al (2005) The function and expansion of the Patched- and Hedgehog-related homologs in C. elegans. Genome Research 15: 1402-1410