title: Hedgehog signal transduction via Smoothened association with a cytoplasmic complex scaffolded by the atypical kinesin, Costal-2.
abstract: The seven-transmembrane protein Smoothened (Smo) transduces extracellular activation of the Hedgehog (Hh) pathway by an unknown mechanism to increase transcriptional activity of the latent cytoplasmic transcription factor Ci (Cubitus interruptus). Here, we present evidence that Smo associates directly with a Ci-containing complex that is scaffolded and stabilized by the atypical kinesin, Costal-2 (Cos2). This complex constitutively suppresses pathway activity, but Hh signaling reverses its regulatory effect to promote Ci-mediated transcription. In response to Hh activation of Smo, Cos2 mediates accumulation and phosphorylation of Smo at the membrane as well as phosphorylation of the cytoplasmic components Fu and Su(fu). Positive response of Cos2 to Hh stimulation requires a portion of the Smo cytoplasmic tail and the Cos2 cargo domain, which interacts directly with Smo.
authors.affiliation: Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
authors.forename: Chi
authors.initials: C
authors.lastname: Zhang
authors.forename: Sekyung
authors.initials: S
authors.lastname: Oh
authors.forename: Randall K
authors.initials: RK
authors.lastname: Mann
authors.forename: Doris P
authors.initials: DP
authors.lastname: von Kessler
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
authors.forename: Frances
authors.initials: F
authors.lastname: Weis-Garcia
authors.forename: Ruoyu
authors.initials: R
authors.lastname: Gong
authors.forename: Baolin
authors.initials: B
authors.lastname: Wang
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology; D004628:Embryonic Structures / Q000033:anatomy & histology / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D017930:Genes, Reporter; D053823:Hedgehog Proteins; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction / Q000502:physiology*; D000072086:Smoothened Receptor; D014157:Transcription Factors
chemical_list: D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D046911:Macromolecular Substances; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C491023:SMO protein, human; C490764:SUFU protein, human; D000072086:Smoothened Receptor; C097059:Su(fu) protein, Drosophila; D014157:Transcription Factors; C092937:ci protein, Drosophila; C107452:cos protein, Drosophila; C100664:smo protein, Drosophila; C077245:hh protein, Drosophila; C085770:fu protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D016547:Kinesins