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

Hale, Valerie A.; Guiney, Evan L.; Goldberg, Lindsey Y.; HaDuong, Josephine H.; Kwartler, Callie S.; Goutte, Caroline

doi:10.1534/genetics.111.136804

Cited by 7 publications

(8 citation statements)

References 64 publications

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“…Such context-specific effects have been observed for some genes identified in other screens for interactions with C. elegans Notch genes [ e.g. (Hale et al 2012; Safdar et al 2016)]. VPCs are polarized epithelial cells, which may be of particular relevance in considering the question of other cell contexts in which these kinases may influence Notch activity.…”

Section: Resultsmentioning

confidence: 71%

A Screen of the Conserved Kinome for Negative Regulators of LIN-12 Negative Regulatory Region (“NRR”)-Missense Activity inCaenorhabditis elegans

Deng¹,

Luo

Shaye³

et al. 2019

G3 Genes|Genomes|Genetics

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Genetic analysis of LIN-12/Notch signaling in C. elegans has provided many insights into human biology. Activating missense mutations in the Negative Regulatory Region (NRR) of the ectodomain of LIN-12/Notch were first described in C. elegans, and similar mutations in human Notch were later found to cause T-cell acute lymphoblastic leukemia (T-ALL). The ubiquitin ligase sel-10/Fbw7 is the prototype of a conserved negative regulator of lin-12/Notch that was first defined by loss-of-function mutations that enhance lin-12 NRR-missense activity in C. elegans, and then demonstrated to regulate Notch activity in mammalian cells and to be a bona fide tumor suppressor in T-ALL. Here, we report the results of an RNAi screen of 248 C. elegans protein kinase-encoding genes with human orthologs for enhancement of a weakly activating NRR-missense mutation of lin-12 in the Vulval Precursor Cells. We identified, and validated, thirteen kinase genes whose loss led to increase lin-12 activity; eleven of these genes have never been implicated previously in regulating Notch activity in any system. Depleting the activity of five kinase genes (cdk-8, wnk-1, kin-3, hpo-11, and mig-15) also significantly enhanced the activity of a transgene in which heterologous sequences drive expression of the untethered intracellular domain of LIN-12, suggesting that they increase the activity or stability of the signal-transducing form of LIN-12/Notch. Precedents set by other regulators of lin-12/Notch defined through genetic interactions in C. elegans suggest that this new set of genes may include negative regulators that are functionally relevant to mammalian development and cancer.

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Section: Resultsmentioning

confidence: 71%

A Screen of the Conserved Kinome for Negative Regulators of LIN-12 Negative Regulatory Region (“NRR”)-Missense Activity inCaenorhabditis elegans

Deng¹,

Luo

Shaye³

et al. 2019

G3 Genes|Genomes|Genetics

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“…The cell cortex gene wsp-1 , for example, colocalizes with actin at cell boundaries and activates the Arp2/3 complex that affects actin nucleation and branching ( Sawa et al 2003 ; Lundquist 2006 ). Additional genes in the cell cortex category include cav-1 , which regulates progression through the meiotic cell cycle, suggesting it likely has an indirect role in regulating RNP remodeling ( Govindan et al 2009 ), and sao-1 which encodes a GYF domain-containing protein that functions with sel-10 to negatively regulate the Notch receptor signaling pathway in the embryo ( Hale et al 2012 ).…”

Section: Resultsmentioning

confidence: 99%

RNAi Screen Identifies Novel Regulators of RNP Granules in theCaenorhabditis elegansGerm Line

Wood

Hollis

Severance

et al. 2016

G3 Genes|Genomes|Genetics

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Complexes of RNA and RNA binding proteins form large-scale supramolecular structures under many cellular contexts. In Caenorhabditis elegans, small germ granules are present in the germ line that share characteristics with liquid droplets that undergo phase transitions. In meiotically-arrested oocytes of middle-aged hermaphrodites, the germ granules appear to aggregate or condense into large assemblies of RNA-binding proteins and maternal mRNAs. Prior characterization of the assembly of large-scale RNP structures via candidate approaches has identified a small number of regulators of phase transitions in the C. elegans germ line; however, the assembly, function, and regulation of these large RNP assemblies remain incompletely understood. To identify genes that promote remodeling and assembly of large RNP granules in meiotically-arrested oocytes, we performed a targeted, functional RNAi screen and identified over 300 genes that regulate the assembly of the RNA-binding protein MEX-3 into large granules. Among the most common GO classes are several categories related to RNA biology, as well as novel categories such as cell cortex, ER, and chromosome segregation. We found that arrested oocytes that fail to localize MEX-3 into cortical granules display reduced oocyte quality, consistent with the idea that the larger RNP assemblies promote oocyte quality when fertilization is delayed. Interestingly, a relatively small number of genes overlap with the regulators of germ granule assembly during normal development, or with the regulators of solid RNP granules in cgh-1 oocytes, suggesting fundamental differences in the regulation of RNP granule phase transitions during meiotic arrest.

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“…Another screen in this category was based on suppression of the maternal effect lethal phenotype of a hypomorphic allele of the aph-1 component of γ-secretase (Hale et al, 2012). This screen identified sao-1, which physically interacts with SEL-10.…”

Section: Negative Modulators: Suppressors Of Reduced Notch Activitymentioning

confidence: 99%

Notch signaling: genetics and structure

Greenwald

Kovall

2013

WormBook

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Receptors of the Notch family mediate cell-cell interactions during animal development, and aberrations in Notch signaling have been implicated in human disease. Studies in Caenorhabdits elegans have made essential contributions towards understanding the biological roles and molecular mechanism of this fundamental signaling system. A major development in the field since the original version of this chapter (LIN-12/Notch signaling in C. elegans) has been an explosion in information about the structural biology of Notch signaling; crystallographic determinations of structures, including structures of C. elegans components, have contributed much to the current understanding of molecular mechanism. Thus, here, we not only cover the genetics of Notch in C. elegans, focusing on conserved core components and modulators, we have also included structural information about these components, describing the key events occurring during ligand binding and transcriptional control of target genes. In addition to text, we include Tables listing core components and key modulators of the signaling pathway along with their orthologs in Drosophila and mammals, a Table listing validated target genes in various processes in C. elegans, and animated features to illustrate structural attributes.

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

Cited by 7 publications

References 64 publications

A Screen of the Conserved Kinome for Negative Regulators of LIN-12 Negative Regulatory Region (“NRR”)-Missense Activity inCaenorhabditis elegans

A Screen of the Conserved Kinome for Negative Regulators of LIN-12 Negative Regulatory Region (“NRR”)-Missense Activity inCaenorhabditis elegans

RNAi Screen Identifies Novel Regulators of RNP Granules in theCaenorhabditis elegansGerm Line

Notch signaling: genetics and structure

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