The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling

Chen Shen, Anmada Nayak, Leif R. Neitzel, Amber A. Adams, Maya Silver-Isenstadt, Leah M. Sawyer, Hassina Benchabane, Huilan Wang, Nawat Bunnag, Bin Li, Daniel T. Wynn, Fan Yang, Marta Garcia-Contreras, Charles H. Williams, Sivanesan Dakshanamurthy, Charles C. Hong, Nagi G. Ayad, Anthony J. Capobianco, Yashi Ahmed, Ethan Lee and David J. Robbins ()
Additional contact information
Chen Shen: University of Miami
Anmada Nayak: University of Miami
Leif R. Neitzel: University of Maryland
Amber A. Adams: Dartmouth College
Maya Silver-Isenstadt: University of Maryland
Leah M. Sawyer: Vanderbilt University
Hassina Benchabane: Dartmouth College
Huilan Wang: University of Miami
Nawat Bunnag: Dartmouth College
Bin Li: University of Miami
Daniel T. Wynn: University of Miami
Fan Yang: University of Miami
Marta Garcia-Contreras: University of Miami
Charles H. Williams: University of Maryland
Sivanesan Dakshanamurthy: Georgetown University
Charles C. Hong: University of Maryland
Nagi G. Ayad: Georgetown University
Anthony J. Capobianco: University of Miami
Yashi Ahmed: Dartmouth College
Ethan Lee: Vanderbilt University
David J. Robbins: University of Miami

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25634-z

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