PUBLICATION
The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling
- Authors
- Shen, C., Nayak, A., Neitzel, L.R., Adams, A.A., Silver-Isenstadt, M., Sawyer, L.M., Benchabane, H., Wang, H., Bunnag, N., Li, B., Wynn, D.T., Yang, F., Garcia-Contreras, M., Williams, C.H., Dakshanamurthy, S., Hong, C.C., Ayad, N.G., Capobianco, A.J., Ahmed, Y., Lee, E., Robbins, D.J.
- ID
- ZDB-PUB-210908-4
- Date
- 2021
- Source
- Nature communications 12: 5263 (Journal)
- Registered Authors
- Hong, Charles
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/chemistry
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism*
- Animals
- Casein Kinase Ialpha/metabolism
- Drosophila Proteins/genetics
- Drosophila melanogaster/genetics
- Embryo, Nonmammalian
- Evolution, Molecular
- HEK293 Cells
- Humans
- Immunologic Factors/chemistry
- Immunologic Factors/pharmacology
- Lenalidomide/chemistry
- Lenalidomide/pharmacology
- Mice
- Organoids
- Peptide Hydrolases/genetics*
- Peptide Hydrolases/metabolism
- Ubiquitin-Protein Ligases/chemistry
- Ubiquitin-Protein Ligases/genetics
- Ubiquitin-Protein Ligases/metabolism*
- Ubiquitination
- Wnt Signaling Pathway/physiology*
- Zebrafish/embryology
- Zebrafish/genetics
- Zebrafish Proteins/genetics*
- Zebrafish Proteins/metabolism
- PubMed
- 34489457 Full text @ Nat. Commun.
Citation
Shen, C., Nayak, A., Neitzel, L.R., Adams, A.A., Silver-Isenstadt, M., Sawyer, L.M., Benchabane, H., Wang, H., Bunnag, N., Li, B., Wynn, D.T., Yang, F., Garcia-Contreras, M., Williams, C.H., Dakshanamurthy, S., Hong, C.C., Ayad, N.G., Capobianco, A.J., Ahmed, Y., Lee, E., Robbins, D.J. (2021) The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling. Nature communications. 12:5263.
Abstract
Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the β-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping