Posttranscriptional regulation of smoothened is part of a self-correcting mechanism in the hedgehog signaling system

Hedgehog signaling, mediated through its Patched-Smoothened receptor comple x, is essential for pattern formation in animal development. Activating mut ations within Smoothened have been associated with basal cell carcinoma, su ggesting that smoothened is a protooncogene. Thus, regulation of Smoothened levels might be critical for normal development. We show that Smoothened p rotein levels in Drosophila embryos are regulated posttranscriptionally by a mechanism dependent on Hedgehog signaling but not on its nuclear effector Cubitus interruptus. Hedgehog signaling upregulates Smoothened levels, whi ch are otherwise downregulated by Patched. Demonstrating properties of a se lf-correcting system, the Hedgehog signaling pathway adjusts the concentrat ions of Smoothened and Patched to each other and to that of the Hedgehog si gnal, which ensures that activation of Hedgehog target genes by Smoothened signaling becomes strictly dependent on Hedgehog.