The DOI matches its Crossref record; 53 of the 53 references it cites were found in a registry or an index.
Mammalian Numb Proteins Promote Notch1 Receptor Ubiquitination and Degradation of the Notch1 Intracellular Domain
Open accessAbstract
The cell fate determinant Numb influences developmental decisions by antagonizing the Notch signaling pathway. However, the underlying molecular mechanism of this inhibition is poorly understood. Here we report that the mammalian Numb protein promotes the ubiquitination of membrane-bound Notch1 receptor. Furthermore, Numb expression resulted in the degradation of the Notch intracellular domain following activation, which correlated with a loss of Notch-dependent transcriptional activation of the Hes1 promoter as measured by a Hes1 luciferase reporter assay. The phosphotyrosine-binding (PTB) domain of Numb was required for both Notch1 ubiquitination and down-regulation of Notch1 nuclear activity. Numb-mediated ubiquitination of Notch1 was not dependent on the PEST region, which was previously shown to mediate Sel10-dependent ubiquitination of Notch in the nucleus, suggesting a distinct E3 ubiquitin ligase is involved. In agreement we demonstrate that Numb interacts with the cytosolic HECT domain-containing E3 ligase Itch and that Numb and Itch act cooperatively to promote ubiquitination of membrane-tethered Notch1. These results suggest that Numb recruits components of the ubiquitination machinery to the Notch receptor thereby facilitating Notch1 ubiquitination at the membrane, which in turn promotes degradation of the intracellular domain circumventing its nuclear translocation and downstream activation of Notch1 target genes.
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Cites
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A Novel Proteolytic Cleavage Involved in Notch Signaling
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A Ligand-Induced Extracellular Cleavage Regulates γ-Secretase-like Proteolytic Activation of Notch1
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Cited by
Notch signalling: a simple pathway becomes complex
Bray, S. J. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2009 · Cited by 2,620
Boulter, L., Govaere, O., Bird, T. G., Radulescu, S., Ramachandran, P., Pellicoro, A., Ridgway, R. A., Seo, S. S., Spee, B., Van Rooijen, N., et al. (2012) · Nature Medicine · doi:10.1038/nm.2667 · Cited by 747
Notch signaling in the mammalian central nervous system: insights from mouse mutants
Yoon, K., & Gaiano, N. (2005) · Nature Neuroscience · doi:10.1038/nn1475 · Cited by 587
The HECT Family of E3 Ubiquitin Ligases: Multiple Players in Cancer Development
Bernassola, F., Karin, M., Ciechanover, A., & Melino, G. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.06.001 · Cited by 541
Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia
Grabher, C., von Boehmer, H., & Look, A. T. (2006) · Nature Reviews Cancer · doi:10.1038/nrc1880 · Cited by 425
Metadata
- Authors
- McGill, M. A., & McGlade, C. J.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 278
- Issue
- 25
- Pages
- 23196-23203
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W1974096298
- Cited by
- 457
- References
- 53
- FWCI
- 6.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- McGill, M. A., & McGlade, C. J. (2003). Mammalian Numb Proteins Promote Notch1 Receptor Ubiquitination and Degradation of the Notch1 Intracellular Domain. Journal of Biological Chemistry. https://doi.org/10.1074/jbc.m302827200
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