Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Dunbar K

PROVIDER: S-EPMC7768194 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Dunbar Karen K Macartney Thomas J TJ Sapkota Gopal P GP

Life science alliance 20201223 2

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 IMiD ...[more]

PMID: 33361334

Similar Datasets

Project description:Background: Two recessive mutations in the FAM83G gene, causing A34E and R52P amino acid substitutions in the DUF1669 domain of the PAWS1 protein, are associated with palmoplantar keratoderma (PPK) in humans and dogs respectively. We have previously reported that PAWS1 associates with the Ser/Thr protein kinase CK1α through the DUF1669 domain to mediate canonical Wnt signalling. Methods: Co-immunoprecipitation was used to investigate possible changes to PAWS1 interactors caused by the mutations. We also compared the stability of wild-type and mutant PAWS1 in cycloheximide-treated cells. Effects on Wnt signalling were determined using the TOPflash luciferase reporter assay in U2OS cells expressing PAWS1 mutant proteins. The ability of PAWS1 to induce axis duplication in Xenopus embryos was also tested. Finally, we knocked-in the A34E mutation at the native gene locus and measured Wnt-induced AXIN2 gene expression by RT-qPCR. Results: We show that these PAWS1 A34E and PAWS1 R52P mutants fail to interact with CK1α but, like the wild-type protein, do interact with CD2AP and SMAD1. Like cells carrying a PAWS1 F296A mutation, which also abolishes CK1α binding, cells carrying the A34E and R52P mutants respond poorly to Wnt signalling to an extent resembling that observed in FAM83G gene knockout cells. Consistent with this observation, these mutants, in contrast to the wild-type protein, fail to induce axis duplication in Xenopus embryos. We also found that the A34E and R52P mutant proteins are less abundant than the native protein and appear to be less stable, both when overexpressed in FAM83G-knockout cells and when knocked-in at the native FAM83G locus. Ala 34 of PAWS1 is conserved in all FAM83 proteins and mutating the equivalent residue in FAM83H (A31E) also abolishes interaction with CK1 isoforms. Conclusions: We propose that mutations in PAWS1 cause PPK pathogenesis through disruption of the CK1α interaction and attenuation of Wnt signalling.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets