{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T15:59:05Z","timestamp":1769011145591,"version":"3.49.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2019,11,1]],"date-time":"2019-11-01T00:00:00Z","timestamp":1572566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>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.<\/jats:p>","DOI":"10.1534\/g3.119.400471","type":"journal-article","created":{"date-parts":[[2019,9,14]],"date-time":"2019-09-14T02:55:11Z","timestamp":1568429711000},"page":"3567-3574","source":"Crossref","is-referenced-by-count":9,"title":["A Screen of the Conserved Kinome for Negative Regulators of LIN-12 Negative Regulatory Region (\u201cNRR\u201d)-Missense Activity in<i>Caenorhabditis elegans<\/i>"],"prefix":"10.1093","volume":"9","author":[{"given":"Yuting","family":"Deng","sequence":"first","affiliation":[{"name":"Dept. of Biological Sciences and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katherine Leisan","family":"Luo","sequence":"additional","affiliation":[{"name":"Integrated Program in Cellular, Molecular and Biophysical Studies, Columbia University, NY 10027"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3962-6903","authenticated-orcid":false,"given":"Daniel D","family":"Shaye","sequence":"additional","affiliation":[{"name":"Dept. of Biological Sciences and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iva","family":"Greenwald","sequence":"additional","affiliation":[{"name":"Dept. of Biological Sciences and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,11,1]]},"reference":[{"key":"2021042011011955800_bib1","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1097\/MOH.0000000000000254","article-title":"Oncogenic Notch signaling in T-cell and B-cell lymphoproliferative disorders.","volume":"23","author":"Chiang","year":"2016","journal-title":"Curr. 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