Notch signaling is antagonized by SAO-1, a novel GYF-domain protein that interacts with the E3 ubiquitin ligase SEL-10 in Caenorhabditis elegans.
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.
Department of Biology, Amherst College, Amherst, Massachusetts 01002, USA.
Valerie A
VA
Hale
Evan L
EL
Guiney
Lindsey Y
LY
Goldberg
Josephine H
JH
Haduong
Callie S
CS
Kwartler
Katherine W
KW
Scangos
Caroline
C
Goutte
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D017173:Caenorhabditis elegans / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics; D023061:Gene Order; D005804:Genes, Lethal; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
C405066:APH-1 protein, C elegans; D048868:Adaptor Proteins, Signal Transducing; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D000067757:Glucagon-Like Peptide-1 Receptor; D018398:Homeodomain Proteins; C099355:LAG-1 protein, C elegans; D018027:Receptors, Glucagon; D051880:Receptors, Notch; C574024:SAO-1 protein, C elegans; C109554:SEL-10 protein, C elegans; D044767:Ubiquitin-Protein Ligases