title: Smoothened regulates activator and repressor functions of Hedgehog signaling via two distinct mechanisms.
abstract: The secreted protein Hedgehog (Hh) plays an important role in metazoan development and as a survival factor for many human tumors. In both cases, Hh signaling proceeds through the activation of the seven-transmembrane protein Smoothened (Smo), which is thought to convert the Gli family of transcription factors from transcriptional repressors to transcriptional activators. Here, we provide evidence that Smo signals to the Hh signaling complex, which consists of the kinesin-related protein Costal2 (Cos2), the protein kinase Fused (Fu), and the Drosophila Gli homolog cubitus interruptus (Ci), in two distinct manners. We show that many of the commonly observed molecular events following Hh signaling are not transmitted in a linear fashion but instead are activated through two signals that bifurcate at Smo to independently affect activator and repressor pools of Ci.
authors.affiliation: Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
authors.forename: Stacey K
authors.initials: SK
authors.lastname: Ogden
authors.forename: David J
authors.initials: DJ
authors.lastname: Casso
authors.forename: Manuel
authors.initials: M
authors.lastname: Ascano
authors.forename: Mark M
authors.initials: MM
authors.lastname: Yore
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Kornberg
authors.forename: David J
authors.initials: DJ
authors.lastname: Robbins
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D003001:Cloning, Molecular; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism* / Q000502:physiology*; D053823:Hedgehog Proteins; D006801:Humans; D016547:Kinesins / Q000378:metabolism*; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D018715:Microscopy, Video; D008954:Models, Biological; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D019076:Transgenes; D014921:Wings, Animal
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D014157:Transcription Factors; C092937:ci protein, Drosophila; C107452:cos protein, Drosophila; C100664:smo protein, Drosophila; C077245:hh protein, Drosophila; D004247:DNA; D016547:Kinesins