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dc.contributor.authorShen, Chen
dc.contributor.authorNayak, Anmada
dc.contributor.authorNeitzel, Leif R
dc.contributor.authorAdams, Amber A
dc.contributor.authorSilver-Isenstadt, Maya
dc.contributor.authorSawyer, Leah M
dc.contributor.authorBenchabane, Hassina
dc.contributor.authorWang, Huilan
dc.contributor.authorBunnag, Nawat
dc.contributor.authorLi, Bin
dc.contributor.authorWynn, Daniel T
dc.contributor.authorYang, Fan
dc.contributor.authorGarcia-Contreras, Marta
dc.contributor.authorWilliams, Charles H
dc.contributor.authorDakshanamurthy, Sivanesan
dc.contributor.authorHong, Charles C
dc.contributor.authorAyad, Nagi G
dc.contributor.authorCapobianco, Anthony J
dc.contributor.authorAhmed, Yashi
dc.contributor.authorLee, Ethan
dc.contributor.authorRobbins, David J
dc.date.accessioned2021-09-13T14:15:43Z
dc.date.available2021-09-13T14:15:43Z
dc.date.issued2021-09-06
dc.identifier.urihttp://hdl.handle.net/10713/16589
dc.description.abstractImmunomodulatory 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.en_US
dc.description.urihttps://doi.org/10.1038/s41467-021-25634-zen_US
dc.language.isoenen_US
dc.publisherSpringer Natureen_US
dc.relation.ispartofNature Communicationsen_US
dc.rights© 2021. The Author(s).en_US
dc.subjectcereblon (CRBN)en_US
dc.subject.meshUbiquitin-Protein Ligasesen_US
dc.subject.meshWnt Signaling Pathway--physiologyen_US
dc.titleThe E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signalingen_US
dc.typeArticleen_US
dc.identifier.doi10.1038/s41467-021-25634-z
dc.identifier.pmid34489457
dc.source.volume12
dc.source.issue1
dc.source.beginpage5263
dc.source.endpage
dc.source.countryUnited States
dc.source.countryEngland


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