ArticleThe Journal of biological chemistry2017
Mammalian Numb protein antagonizes Notch by controlling postendocytic trafficking of the Notch ligand Delta-like 4.
Article in The Journal of biological chemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 26 citations in OpenAlex.
- Aberrant neuronal differentiation and splicing defects in Congenital Myotonic Dystrophy (DM1) iPSC models.bioRxiv : the preprint server for biology · 2026Article
- Mutation of Tubgcp6 induces hematopoietic stem and progenitor cell exhaustion in zebrafish.Communications biology · 2026Article
- Endocytic Adaptor Proteins in Vascular Diseases: Critical Role of Intracellular Trafficking in Regulating Pathobiology of Vascular Disorders.Cardiology discovery · 2026Review
- From basic biology to engineered therapies: the keratinocyte stem cell playbook.Frontiers in medical technology · 2026Review
- NUMB in Endometrial Pathology: From Adenomyosis Expression Patterns to Endometrial Cancer Survival Implications.Current issues in molecular biology · 2025Article
- Chemically engineered antibodies for autophagy-based receptor degradation.Nature chemical biology · 2025Article
- Canonical and noncanonical NOTCH signaling in the nongenetic resistance of cancer: distinct and concerted control.Frontiers of medicine · 2025Review
- Menopause mysteries: the exosome-inflammation connection.Journal of ovarian research · 2025Review
- Article
- NOTCH localizes to mitochondria through the TBC1D15-FIS1 interaction and is stabilized via blockade of E3 ligase and CDK8 recruitment to reprogram tumor-initiating cells.Experimental & molecular medicine · 2024Article
- Review
- Trafficking in blood vessel development.Angiogenesis · 2022Review
- Dysregulation of Notch-FGF signaling axis in germ cells results in cystic dilation of the rete testis in mice.Journal of cell communication and signaling · 2022Article
- Article
- The role of NUMB/NUMB isoforms in cancer stem cells.BMB reports · 2021Review
- Human endogenous retroviruses in cancer: Expression, regulation and function.Oncology letters · 2021Review
- Notch in mechanotransduction - from molecular mechanosensitivity to tissue mechanostasis.Journal of cell science · 2020Review
- NUMB enhances Notch signaling by repressing ubiquitination of NOTCH1 intracellular domain.Journal of molecular cell biology · 2020Article
- The Role of DLLs in Cancer: A Novel Therapeutic Target.OncoTargets and therapy · 2020Review
- Endocytic Adaptor Proteins in Health and Disease: Lessons from Model Organisms and Human Mutations.Cells · 2019Review
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The biological antagonism between the signaling proteins Numb and Notch has been implicated in the regulation of many developmental processes, especially in asymmetric cell division. Mechanistic studies show that Numb inactivates Notch via endocytosis and proteasomal degradation that directly reduce Notch protein levels at the cell surface. However, some aspects of how Numb antagonizes Notch remain unclear. Here, we report a novel mechanism in which Numb acts as a Notch antagonist by controlling the intracellular destination and stability of the Notch ligand Delta-like 4 (Dll4) through a postendocytic-sorting process. We observed that Numb/Numblike knockdown increases the stability and cell-surface accumulation of Dll4. Further study indicated that Numb acts as a sorting switch to control the postendocytic trafficking of Dll4. Of note, the Numb/Numblike knockdown decreased Dll4 delivery to the lysosome, while increasing the recycling of Dll4 to the plasma membrane. Moreover, we demonstrate that this enrichment of Dll4 at the cell surface within Numb/Numblike knockdown cells could activate Notch signaling in neighboring cells. We also provide evidence that Numb negatively controls the Dll4 plasma membrane recycling through a well-documented recycling regulator protein AP1. In conclusion, our study has uncovered a molecular mechanism whereby Numb regulates the endocytic trafficking of the Notch ligand Dll4. Our findings provide a new perspective on how Numb counteracts Notch signaling and sheds additional critical insights into the antagonistic relationship between Numb and Notch signaling.
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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.