title: Suppressor of Fused Chaperones Gli Proteins To Generate Transcriptional Responses to Sonic Hedgehog Signaling.
abstract: Cellular responses to the graded Sonic Hedgehog (Shh) morphogenic signal are orchestrated by three Gli genes that give rise to both transcription activators and repressors. An essential downstream regulator of the pathway, encoded by the tumor suppressor gene Suppressor of fused (Sufu), plays critical roles in the production, trafficking, and function of Gli proteins, but the mechanism remains controversial. Here, we show that Sufu is upregulated in active Shh responding tissues and accompanies Gli activators translocating into and Gli repressors out of the nucleus. Trafficking of Sufu to the primary cilium, potentiated by Gli activators but not repressors, was found to be coupled to its nuclear import. We have identified a nuclear export signal (NES) motif of Sufu in juxtaposition to the protein kinase A (PKA) and glycogen synthase kinase 3 (GSK3) dual phosphorylation sites and show that Sufu binds the chromatin with both Gli1 and Gli3. Close comparison of neural tube development among individual Ptch1-/-, Sufu-/-, and Ptch1-/-; Sufu-/-double mutant embryos indicates that Sufu is critical for the maximal activation of Shh signaling essential to the specification of the most-ventral neurons. These data define Sufu as a novel class of molecular chaperone required for every aspect of Gli regulation and function.
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Ziyu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Longyan
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Kelvin
authors.initials: K
authors.lastname: Law
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Zengdi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xiaotong
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Hua
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Sanen
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Huijie
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Shen
authors.initials: S
authors.lastname: Yue
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, Canada.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Hui
authors.affiliation: Department of Developmental Genetics, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China sycheng@njmu.edu.cn.
authors.forename: Steven Y
authors.initials: SY
authors.lastname: Cheng
mesh_terms: D021581:Active Transport, Cell Nucleus; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D002923:Cilia / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D057809:HEK293 Cells; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D007700:Kinetics; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism*; D054259:Neural Tube / Q000378:metabolism; D049790:Nuclear Export Signals; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D021381:Protein Transport; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*; D014158:Transcription, Genetic; D015854:Up-Regulation; D000097606:Exportin 1 Protein
chemical_list: D002843:Chromatin; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D053823:Hedgehog Proteins; D028884:Karyopherins; D018832:Molecular Chaperones; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D015534:Trans-Activators; D000097606:Exportin 1 Protein; C465570:Shh protein, mouse; C490763:Sufu protein, mouse
keywords: Gli; Sonic Hedgehog; Suppressor of Fused; molecular chaperone; nucleocytoplasmic trafficking