Posttranscriptional regulation of smoothened is part of a self-correcting mechanism in the Hedgehog signaling system.
Hedgehog signaling, mediated through its Patched-Smoothened receptor complex, is essential for pattern formation in animal development. Activating mutations within Smoothened have been associated with basal cell carcinoma, suggesting that smoothened is a protooncogene. Thus, regulation of Smoothened levels might be critical for normal development. We show that Smoothened protein 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, which are otherwise downregulated by Patched. Demonstrating properties of a self-correcting system, the Hedgehog signaling pathway adjusts the concentrations of Smoothened and Patched to each other and to that of the Hedgehog signal, which ensures that activation of Hedgehog target genes by Smoothened signaling becomes strictly dependent on Hedgehog.
Alcedo
J
J
Institute for Molecular Biology, University of Zürich, Switzerland.
Zou
Y
Y
Noll
M
M
D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000196:embryology* / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000502:physiology; D005656:Fungal Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D006358:Hot Temperature; D019476:Insect Proteins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D016296:Mutagenesis; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D005656:Fungal Proteins; C052130:GAL4 protein, S cerevisiae; D053823:Hedgehog Proteins; D019476:Insect Proteins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D029701:Saccharomyces cerevisiae Proteins; D000072086:Smoothened Receptor; D014157:Transcription Factors; C070844:ptc protein, Drosophila; C100664:smo protein, Drosophila; C077245:hh protein, Drosophila; D017868:Cyclic AMP-Dependent Protein Kinases