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

Autor: Shen C; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.; The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, FL, USA., Nayak A; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA., Neitzel LR; Department of Medicine, University of Maryland, Baltimore, MD, USA., Adams AA; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA., Silver-Isenstadt M; Department of Medicine, University of Maryland, Baltimore, MD, USA., Sawyer LM; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA., Benchabane H; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA., Wang H; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA., Bunnag N; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA., Li B; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA., Wynn DT; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA., Yang F; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.; The Sheila and David Fuente Graduate Program in Cancer Biology, Miller School of Medicine, University of Miami, Miami, FL, USA., Garcia-Contreras M; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA., Williams CH; Department of Medicine, University of Maryland, Baltimore, MD, USA., Dakshanamurthy S; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA., Hong CC; Department of Medicine, University of Maryland, Baltimore, MD, USA., Ayad NG; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.; Center for Therapeutic Innovation, Department of Neurological Surgery, Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Capobianco AJ; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA., Ahmed Y; Department of Molecular and Systems Biology and the Norris Cotton Cancer Center, Geisel School of Medicine, Dartmouth College, Hanover, NH, USA., Lee E; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA., Robbins DJ; Molecular Oncology Program, The DeWitt Daughtry Family Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA. dr956@georgetown.edu.; Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA. dr956@georgetown.edu.; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA. dr956@georgetown.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Sep 06; Vol. 12 (1), pp. 5263. Date of Electronic Publication: 2021 Sep 06.
DOI: 10.1038/s41467-021-25634-z
Abstrakt: 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 CRL4 CRBN 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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