title: UBR-5, a Conserved HECT-Type E3 Ubiquitin Ligase, Negatively Regulates Notch-Type Signaling in Caenorhabditis elegans.
abstract: Notch-type signaling mediates cell-cell interactions important for animal development. In humans, reduced or inappropriate Notch signaling activity is associated with various developmental defects and disease states, including cancers. Caenorhabditis elegans expresses two Notch-type receptors, GLP-1 and LIN-12. GLP-1 mediates several cell-signaling events in the embryo and promotes germline proliferation in the developing and adult gonad. LIN-12 acts redundantly with GLP-1 in certain inductive events in the embryo and mediates several cell-cell interactions during larval development. Recovery of genetic suppressors and enhancers of glp-1 or lin-12 loss- or gain-of-function mutations has identified numerous regulators of GLP-1 and LIN-12 signaling activity. Here, we report the molecular identification of sog-1, a gene identified in screens for recessive suppressors of conditional glp-1 loss-of-function mutations. The sog-1 gene encodes UBR-5, the sole C. elegans member of the UBR5/Hyd family of HECT-type E3 ubiquitin ligases. Molecular and genetic analyses indicate that the loss of ubr-5 function suppresses defects caused by reduced signaling via GLP-1 or LIN-12. In contrast, ubr-5 mutations do not suppress embryonic or larval lethality associated with mutations in a downstream transcription factor, LAG-1. In the gonad, ubr-5 acts in the receiving cells (germ cells) to limit GLP-1 signaling activity. SEL-10 is the F-box component of SCF(SEL-10) E3 ubiquitin-ligase complex that promotes turnover of Notch intracellular domain. UBR-5 acts redundantly with SEL-10 to limit Notch signaling in certain tissues. We hypothesize that UBR-5 activity limits Notch-type signaling by promoting turnover of receptor or limiting its interaction with pathway components.
authors.affiliation: Department of Biology, Syracuse University, New York 13244.
authors.forename: Komal
authors.initials: K
authors.lastname: Safdar
authors.affiliation: Department of Biology, Syracuse University, New York 13244.
authors.forename: Anniya
authors.initials: A
authors.lastname: Gu
authors.affiliation: Department of Biology, Syracuse University, New York 13244.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Vinci
authors.initials: V
authors.lastname: Au
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Jon
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Stephane
authors.initials: S
authors.lastname: Flibotte
authors.affiliation: Department of Zoology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Donald G
authors.initials: DG
authors.lastname: Moerman
authors.affiliation: Department of Biology, Syracuse University, New York 13244 emmaine@syr.edu.
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Maine
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D006066:Gonads / Q000254:growth & development / Q000378:metabolism; D007814:Larva / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D009154:Mutation; D051880:Receptors, Notch / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C060620:Glp-1 protein, C elegans; C099355:LAG-1 protein, C elegans; C082460:Lin-12 protein, C elegans; D051880:Receptors, Notch; C109554:SEL-10 protein, C elegans; C000624625:UBR-5 protein, C elegans; D044767:Ubiquitin-Protein Ligases
keywords: GLP-1; HECT domain; LIN-12; Notch; germ cell