Academic journal article Genetics

Notch Signaling Is Antagonized by SAO-1, a Novel GYF-Domain Protein That Interacts with the E3 Ubiquitin Ligase SEL-10 in Caenorhabditis Elegans

Academic journal article Genetics

Notch Signaling Is Antagonized by SAO-1, a Novel GYF-Domain Protein That Interacts with the E3 Ubiquitin Ligase SEL-10 in Caenorhabditis Elegans

Article excerpt

ABSTRACT 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 g-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.

THE Notch signaling pathway plays a critical role in many cell-fate choices during animal development. Pathway activation begins with the interaction of a DSL (Delta/Serrate/ Lag-2) ligand and a cell-surface Notch receptor. Upon ligand binding, the Notch receptor undergoes two sequential proteolytic cleavages: an ADAM-protease releases the extracellular domain and then g-secretase releases the intracellular domain, which translocates to the nucleus. g-Secretase is a complex of four integral membrane proteins (presenilin, APH-1, APH-2/Nicastrin, and PEN-2), which also cleaves a variety of other transmembrane protein substrates, including ERBB4 receptor tyrosine kinase, N-cadherin, and the amyloid-b precursor protein (APP) associated with Alzheimer's disease (Parks and Curtis 2007). Once in the nucleus, the Notch intracellular domain interacts with the conserved transcription factor CSL (CBF1/Suppressor of Hairless/LAG-1) to regulate transcription of target genes (reviewed in Kopan and Ilagan 2009).

There are two related Notch receptors in C. elegans, GLP-1 and LIN-12, which mediate a variety of cell interactions throughout development. In the early embryo, at least six distinct cell interactions are mediated by GLP-1 or LIN-12 and they serve to pattern the developmental fate of embryonic cells (reviewed in Priess 2005). The first two such signaling events occur at the 4-cell and 12-cell stages of embryogenesis and are mediated by maternally supplied signaling components including GLP-1. Removal of maternal GLP-1 or LAG-1, or any of the four g-secretase components, prevents Notch signaling in these early stages of embryogenesis, resulting in misspecification of several blastomere fates and eventual arrest of the embryo (Priess 2005). At least some of the later embryonic signaling events can be mediated by either GLP-1 or LIN-12, such that a mutant phenotype is only apparent in these cell-fate choices if both receptors are absent (Lambie and Kimble 1991).

During postembryonic development GLP-1 and LIN-12 have distinct roles. GLP-1 activation is required continuously to induce germ cell proliferation in the distal gonad, thus playing a critical role in regulating the balance between proliferation and meiosis (Kimble and Crittenden 2005). Loss of GLP-1 activity results in sterility due to germ line under proliferation, whereas hyperactive GLP-1 protein causes overproliferation of the germ line at the expense of germ cell differentiation (Berry et al. …

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