IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling

Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling neo-substrate recruitment and degradation via the ubiquitin-proteasome system. Here, we report FAM83F as such a neo-substrate. We demonstrate here that IMiD-induced FAM83F degradation requires its association with CK1α. FAM83F is localised to the plasma membrane, and consistent with this, IMiD treatment results in depletion of both FAM83F and CK1α levels from the plasma membrane. 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 CK1α from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. The IMiD-induced degradation of CK1α is only modest and incomplete in many cells and the expression of FAM83G, which also binds to CK1α, prevents the IMiD-induced degradation of CK1α. Our findings suggest that the efficiency of target protein degradation by IMiDs, and perhaps other degraders such as PROTACs, relies on the nature of the inherent multiprotein complex in which the target protein exists.