ArticleScience signaling2019
Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling.
Article in Science signaling, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Targeting notch signaling pathway in esophageal cancer: from molecular insights to therapies.Oncology reviews · 2026Review
- The unique functions of Runx1 in skeletal muscle maintenance and regeneration are facilitated by an ETS interaction domain.Development (Cambridge, England) · 2024Article
- Role of cell rearrangement and related signaling pathways in the dynamic process of tip cell selection.Cell communication and signaling : CCS · 2024Review
- Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy.Frontiers in immunology · 2024Review
- New tricks for an old pathway: emerging Notch-based biotechnologies and therapeutics.Trends in pharmacological sciences · 2023Review
- LST-1 is a bifunctional regulator that feeds back on Notch-dependent transcription to regulateProceedings of the National Academy of Sciences of the United States of America · 2023Article
- Targetable NOTCH1 rearrangements in reninoma.Nature communications · 2023Article
- Kindlin-2 controls angiogenesis through modulating Notch1 signaling.Cellular and molecular life sciences : CMLS · 2023Article
- Notch-dependent and -independent functions of transcription factor RBPJ.Nucleic acids research · 2022Article
- Notch signaling determines cell-fate specification of the two main types of vomeronasal neurons of rodents.Development (Cambridge, England) · 2022Article
- Targeting circular RNA-MET for anti-angiogenesis treatment via inhibiting endothelial tip cell specialization.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Ankyrin repeats in context with human population variation.PLoS computational biology · 2021Article
- Differential gene regulation in DAPT-treated Hydra reveals candidate direct Notch signalling targets.Journal of cell science · 2021Article
- Review
- Biophysics of Notch Signaling.Annual review of biophysics · 2021Review
- MAML1: a coregulator that alters endometrial epithelial cell adhesive capacity.Fertility research and practice · 2021Article
- Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Canonical Notch signaling relies on regulated proteolysis of the receptor Notch to generate a nuclear effector that induces the transcription of Notch-responsive genes. In higher organisms, one Notch-responsive gene that is activated in many different cell types encodes the Notch-regulated ankyrin repeat protein (NRARP), which acts as a negative feedback regulator of Notch responses. Here, we showed that NRARP inhibited the growth of Notch-dependent T cell acute lymphoblastic leukemia (T-ALL) cell lines and bound directly to the core Notch transcriptional activation complex (NTC), requiring both the transcription factor RBPJ and the Notch intracellular domain (NICD), but not Mastermind-like proteins or DNA. The crystal structure of an NRARP-NICD1-RBPJ-DNA complex, determined to 3.75 Å resolution, revealed that the assembly of NRARP-NICD1-RBPJ complexes relied on simultaneous engagement of RBPJ and NICD1, with the three ankyrin repeats of NRARP extending the Notch1 ankyrin repeat stack. Mutations at the NRARP-NICD1 interface disrupted entry of the proteins into NTCs and abrogated feedback inhibition in Notch signaling assays in cultured cells. Forced expression of NRARP reduced the abundance of NICD in cells, suggesting that NRARP may promote the degradation of NICD. These studies establish the structural basis for NTC engagement by NRARP and provide insights into a critical negative feedback mechanism that regulates Notch signaling.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.