{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T10:26:18Z","timestamp":1787567178555,"version":"build-2736575974"},"reference-count":67,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BB\/V014218\/1"],"award-info":[{"award-number":["BB\/V014218\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]},{"award":["BB\/V014218\/1"],"award-info":[{"award-number":["BB\/V014218\/1"]}],"id":[{"id":"https:\/\/ror.org\/00cwqg982","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"crossref","award":["BB\/P000215\/1"],"award-info":[{"award-number":["BB\/P000215\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"crossref"}]},{"award":["BB\/P000215\/1"],"award-info":[{"award-number":["BB\/P000215\/1"]}],"id":[{"id":"https:\/\/ror.org\/00cwqg982","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>\n                    Activating mutations of Notch are drivers of the blood cell cancer, T-ALL, and some solid tumours. The negative regulatory region (NRR) of the extracellular domain (ECD) and the PEST region of the intracellular domain (ICD) are mutation hot spots which can act synergistically in T-ALL. The NRR, comprised of a heterodimerisation domain (HD) and three Lin12\/Notch repeats (LNR A-C), masks the S2 cleavage site, normally only exposed following ligand binding and cleaved as the first step that ultimately leads to ICD release.\n                    <jats:italic>Drosophila<\/jats:italic>\n                    mutants have played a key role in analysing Notch structure\/function, but there have been few mutational studies of the NRR. Here, we expressed, in S2 cells, over 20 cancer mutations located in the HD, LNR and LNR\/HD interface, introduced into\n                    <jats:italic>Drosophila<\/jats:italic>\n                    Notch. Mutations in the HD domain core did not activate, likely due to absence in\n                    <jats:italic>Drosophila<\/jats:italic>\n                    of an S1 cleavage within the HD required for mammalian Notch activity. In contrast, mutations in the LNR\/HD interface behaved similarly to T-ALL, activating constitutively with no further ligand induction and were synergistic with PEST deletion. Mutations of surface-exposed residues of LNR-C also activated constitutively but remained inducible both by ligand and by an intracellular endocytic regulator, Deltex, and were not synergistic with PEST deletions. These mutations caused elevated Notch levels and decreased turnover, suggesting a novel regulatory mechanism. Our results, therefore, uncover a variety of outcomes arising from perturbations of the NRR and will facilitate the establishment of\n                    <jats:italic>Drosophila<\/jats:italic>\n                    cancer models and the development of mutant-specific approaches to effective therapies.\n                  <\/jats:p>","DOI":"10.7554\/elife.108812","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T14:30:13Z","timestamp":1763562613000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.108812","source":"Crossref","is-referenced-by-count":0,"title":["Analysis of cancer mutations introduced into the Drosophila melanogaster Notch negative regulatory region uncovers a diversity of regulatory outcomes"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9426-8651","authenticated-orcid":true,"given":"Hideyuki","family":"Shimizu","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027m9bs27","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester","place":["Manchester, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7375-5784","authenticated-orcid":true,"given":"Martin","family":"Baron","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/027m9bs27","id-type":"ROR","asserted-by":"publisher"}],"name":"School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester","place":["Manchester, United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1158\/2326-6066.CIR-19-0866","type":"journal-article","article-title":"Mammalian SWI\/SNF complex genomic alterations and immune checkpoint blockade in solid tumors","volume":"8","author":"Abou Alaiwi","year":"2020","journal-title":"Cancer Immunology Research"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"3918","DOI":"10.1182\/blood-2008-10-184069","type":"journal-article","article-title":"NOTCH1\/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study","volume":"113","author":"Asnafi","year":"2009","journal-title":"Blood"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1146\/annurev-pathol-052016-100127","type":"journal-article","article-title":"The varied roles of notch in cancer","volume":"12","author":"Aster","year":"2017","journal-title":"Annual Review of Pathology"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1534\/genetics.118.300223","type":"journal-article","article-title":"Drosophila as a genetic model for hematopoiesis","volume":"211","author":"Banerjee","year":"2019","journal-title":"Genetics"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1038\/nrc.2016.63","type":"journal-article","article-title":"The genetics and mechanisms of T cell acute lymphoblastic leukaemia","volume":"16","author":"Belver","year":"2016","journal-title":"Nature Reviews. 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