FAM83F regulates canonical Wnt signalling through an interaction with CK1α

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 CK1 alpha at the plasma membrane. This interaction with CK1 alpha is essential for FAM83F to activate Wnt signalling, and FAM83F mutants that do not interact with CK1 alpha fail to induce axis duplication in Xenopus embryos and to activate Wnt signalling in cells. FAM83F acts upstream of GSK-3 beta 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-CK1 alpha complex away from the plasma membrane and significantly attenuates Wnt signalling, indicating that FAM83F exerts its effects on Wnt signalling at the plasma membrane.

Automated summary

FAM83F protein interacts with CK1 alpha at the plasma membrane to activate Wnt signaling, leading to axis duplication in Xenopus embryos, and its effects on Wnt signaling are mediated through farnesylation at the plasma membrane.