title: Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination.
abstract: Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues.
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Tongchao
authors.initials: T
authors.lastname: Li
authors.affiliation: Markey Cancer Center and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Junkai
authors.initials: J
authors.lastname: Fan
authors.affiliation: Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States of America.
authors.forename: Bernardo
authors.initials: B
authors.lastname: Blanco-Sánchez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Giagtzoglou
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Guang
authors.initials: G
authors.lastname: Lin
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.
authors.forename: Shinya
authors.identifier: 0000-0003-2172-8036
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Manish
authors.initials: M
authors.lastname: Jaiswal
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Kuchuan
authors.initials: K
authors.lastname: Chen
authors.affiliation: Markey Cancer Center and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lewis
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Groves
authors.affiliation: Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States of America.
authors.forename: Monte
authors.initials: M
authors.lastname: Westerfield
authors.affiliation: Markey Cancer Center and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.
authors.forename: Jianhang
authors.initials: J
authors.lastname: Jia
authors.affiliation: Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.|Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.|Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America.|Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Bellen
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development; D005123:Eye / Q000254:growth & development / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000235:genetics; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010786:Photoreceptor Cells / Q000378:metabolism; D025821:Polyubiquitin; D059748:Proteolysis; D034741:RNA, Small Interfering; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D054875:Ubiquitination; D015027:Zebrafish / Q000235:genetics
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D034741:RNA, Small Interfering; C107452:cos protein, Drosophila; D025821:Polyubiquitin; C522185:UBR3 protein, mouse; D044767:Ubiquitin-Protein Ligases; C543639:Kif7 protein, mouse; D016547:Kinesins