FAM83F regulates canonical Wnt signalling through an interaction with CK1α

TY - JOUR

T1 - FAM83F regulates canonical Wnt signalling through an interaction with CK1α

AU - Dunbar, Karen

AU - Jones, Rebecca A.

AU - Dingwell, Kevin

AU - Macartney, Thomas J.

AU - Smith, James C.

AU - Sapkota, Gopal

N1 - Karen Dunbar is supported by an MRC Career Development Fellowship. GPS is supported by the U.K. Medical Research Council (grant number MC_UU_00018/6 and MC_UU_12016/3) and the pharmaceutical companies supporting the DSTT (Boehringer-Ingelheim, GlaxoSmithKline, Merck-Serono). RAJ, Kevin Dingwell and JCS are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK [FC001-157], the UK MRC [FC001-157], and the Wellcome Trust [FC001-157].

PY - 2021/2

Y1 - 2021/2

N2 - The function of the FAM83F protein, like the functions of many members of the FAM83 family, is poorly understood. Here, we show that injection of Fam83f mRNA into Xenopus embryos causes axis duplication, a phenotype indicative of enhanced Wnt signalling. Consistent with this, overexpression of FAM83F activates Wnt signalling, whereas ablation of FAM83F from human colorectal cancer (CRC) cells attenuates it. We demonstrate that FAM83F is farnesylated and interacts and co-localises with CK1α at the plasma membrane. This interaction with CK1α is essential for FAM83F to activate Wnt signalling, and FAM83F mutants that do not interact with CK1α fail to induce axis duplication in Xenopus embryos and to activate Wnt signalling in cells. FAM83F acts upstream of GSK-3β because the attenuation of Wnt signalling caused by loss of FAM83F can be rescued by GSK-3 inhibition. Introduction of a farnesyl-deficient mutant of FAM83F in cells through CRISPR/Cas9 genome editing redirects the FAM83F-CK1α complex away from the plasma membrane and significantly attenuates Wnt signalling, indicating that FAM83F exerts its effects on Wnt signalling at the plasma membrane.

AB - The function of the FAM83F protein, like the functions of many members of the FAM83 family, is poorly understood. Here, we show that injection of Fam83f mRNA into Xenopus embryos causes axis duplication, a phenotype indicative of enhanced Wnt signalling. Consistent with this, overexpression of FAM83F activates Wnt signalling, whereas ablation of FAM83F from human colorectal cancer (CRC) cells attenuates it. We demonstrate that FAM83F is farnesylated and interacts and co-localises with CK1α at the plasma membrane. This interaction with CK1α is essential for FAM83F to activate Wnt signalling, and FAM83F mutants that do not interact with CK1α fail to induce axis duplication in Xenopus embryos and to activate Wnt signalling in cells. FAM83F acts upstream of GSK-3β because the attenuation of Wnt signalling caused by loss of FAM83F can be rescued by GSK-3 inhibition. Introduction of a farnesyl-deficient mutant of FAM83F in cells through CRISPR/Cas9 genome editing redirects the FAM83F-CK1α complex away from the plasma membrane and significantly attenuates Wnt signalling, indicating that FAM83F exerts its effects on Wnt signalling at the plasma membrane.

KW - Colorectal cancer

KW - Xenopus axis duplication

KW - farnesylation

KW - plasma membrane

UR - https://www.scopus.com/pages/publications/85099078385

U2 - 10.26508/lsa.202000805

DO - 10.26508/lsa.202000805

M3 - Article

C2 - 33361109

SN - 2575-1077

VL - 4

JO - Life Science Alliance

JF - Life Science Alliance

IS - 2

M1 - e202000805

ER -