RT Journal Article
SR Electronic
T1 IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202000804
DO 10.26508/lsa.202000804
VO 4
IS 2
A1 Karen Dunbar
A1 Thomas J Macartney
A1 Gopal P Sapkota
YR 2021
UL https://www.life-science-alliance.org/content/4/2/e202000804.abstract
AB Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling the recruitment of neo-substrates, such as CK1α, 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 CK1α. We demonstrate that IMiD-induced FAM83F degradation requires its association with CK1α. 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 CK1α from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. Intriguingly, the expression of FAM83G, which also binds to CK1α, appears to attenuate the IMiD-induced degradation of CK1α, suggesting a protective role for FAM83G on CK1α. 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.