TableEdit

Hale, VA, Guiney, EL, Goldberg, LY, Haduong, JH, Kwartler, CS, Scangos, KW and Goutte, C (2012) Notch signaling is antagonized by SAO-1, a novel GYF-domain protein that interacts with the E3 ubiquitin ligase SEL-10 in Caenorhabditis elegans. Genetics 190:1043-57

Notch signaling pathways can be regulated through a variety of cellular mechanisms, and genetically compromised systems provide useful platforms from which to search for the responsible modulators. The Caenorhabditis elegans gene aph-1 encodes a component of γ-secretase, which is essential for Notch signaling events throughout development. By looking for suppressors of the incompletely penetrant aph-1(zu147) mutation, we identify a new gene, sao-1 (suppressor of aph-one), that negatively regulates aph-1(zu147) activity in the early embryo. The sao-1 gene encodes a novel protein that contains a GYF protein-protein interaction domain and interacts specifically with SEL-10, an Fbw7 component of SCF E3 ubiquitin ligases. We demonstrate that the embryonic lethality of aph-1(zu147) mutants can be suppressed by removing sao-1 activity or by mutations that disrupt the SAO-1-SEL-10 protein interaction. Decreased sao-1 activity also influences Notch signaling events when they are compromised at different molecular steps of the pathway, such as at the level of the Notch receptor GLP-1 or the downstream transcription factor LAG-1. Combined analysis of the SAO-1-SEL-10 protein interaction and comparisons of sao-1 and sel-10 genetic interactions suggest a possible role for SAO-1 as an accessory protein that participates with SEL-10 in downregulation of Notch signaling. This work provides the first mutant analysis of a GYF-domain protein in either C. elegans or Drosophila and introduces a new type of Fbw7-interacting protein that acts in a subset of Fbw7 functions.

PubMed PMC3296241 Online version:10.1534/genetics.111.136804

Amino Acid Sequence; Animals; Caenorhabditis elegans/embryology; Caenorhabditis elegans/genetics; Caenorhabditis elegans/metabolism; Caenorhabditis elegans Proteins/chemistry; Caenorhabditis elegans Proteins/genetics; Caenorhabditis elegans Proteins/metabolism; Carrier Proteins/chemistry; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cell Cycle Proteins/metabolism; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Embryonic Development/genetics; Gene Order; Genes, Lethal; Homeodomain Proteins/genetics; Homeodomain Proteins/metabolism; Molecular Sequence Data; Mutation; Protein Binding; Protein Structure, Tertiary; Receptors, Glucagon/genetics; Receptors, Glucagon/metabolism; Receptors, Notch/antagonists & inhibitors; Receptors, Notch/metabolism; Sequence Alignment; Signal Transduction; Ubiquitin-Protein Ligases/metabolism