Shen C, Nayak A, Neitzel LR, Adams AA, Silver-Isenstadt M, Sawyer LM, Benchabane H, Wang H, Bunnag N, Li B, Wynn DT, Yang F, Garcia-Contreras M, Williams CH, Dakshanamurthy S, Hong CC, Ayad NG, Capobianco AJ, Ahmed Y, Lee E, Robbins DJ

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 ...

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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 1? (CK1?), a negative regulator of Wnt signaling that functions as a key component of the ?-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1? 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 CK1? stability in the absence of Wnt, and in recruiting CRBN to target CK1? 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: Dec. 06, 2020

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