IMiDs induce FAM83F degradation via an interaction with CK1? to attenuate Wnt signalling.

Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling the recruitment of neo-substrates, such as CK1?, and their degradation via the ubiquitinproteasome system. Here, we report FAM83F as such a neo-substrate. The eight FAM83 proteins (A-H) interact with and regulate the subcellular distribution ...
of CK1?. We demonstrate that IMiD-induced FAM83F degradation requires its association with CK1?. However, no other FAM83 protein is degraded by IMiDs. We have recently identified FAM83F as a mediator of the canonical Wnt signalling pathway. The IMiD-induced degradation of FAM83F attenuated Wnt signalling in colorectal cancer cells and removed CK1? from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. Intriguingly, the expression of FAM83G, which also binds to CK1?, appears to attenuate the IMiD-induced degradation of CK1?, suggesting a protective role for FAM83G on CK1?. Our findings reveal that the efficiency and extent of target protein degradation by IMiDs depends on the nature of inherent multiprotein complex in which the target protein is part of.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Base Sequence, Casein Kinase Ialpha, Cell Line, Tumor, Cell Membrane, Gene Knock-In Techniques, Humans, Imides, Immunologic Factors, Intracellular Signaling Peptides and Proteins, Neoplasm Proteins, Proteasome Endopeptidase Complex, Protein Binding, Protein Stability, Proteolysis, Ubiquitin-Protein Ligases, Wnt Signaling Pathway
Life Sci Alliance
Date: Dec. 01, 2020
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