Wnt signalling pathway is fundamental during development but it’s overactivity drives many cancers, particularly colorectal cancers (CRCs). New research led by Karen Dunbar (postdoctoral fellow in Sapkota lab) has uncovered FAM83F as a novel mediator of the Wnt signalling pathway. Through a collaboration with Smith lab (The Francis Crick Institute), the team were able to demonstrate that FAM83F was critical in driving Wnt signalling in both Xenopus embryos and many different cancer cell lines.
FAM83F protein belongs to the poorly characterised FAM83 family of related proteins. Previous research from Sapkota lab had discovered that the FAM83 proteins are key regulators of the serine/threonine kinase CK1 family and determine the subcellular distribution of specific CK1 proteins (Fulcher et al, 2018). This way, specific FAM83 proteins are able to modulate unique CK1α-dependent signalling processes, such as mitosis (FAM83D; Fulcher et al., 2019) and Wnt signalling (FAM83G; Bozatzi et al., 2018, Wu et al., 2019), through interaction with and regulation of CK1α function.
Karen found that FAM83F directs CK1α primarily to the plasma membrane. Both FAM83F-CK1α interaction and membrane localisation of CK1α were critical for driving Wnt signalling.
These findings are published in the current issue of Life Science Alliance.
In a second, related study, Karen unearthed the FAM83F-CK1α complex as a novel target for degradation by the IMiD compounds.
The IMiD compounds are frontline drugs to treat multiple myeloma and are currently among the best-selling drugs worldwide. IMiDs act as molecular glue between the E3 ubiquitin ligase component CRBN and target proteins, thus causing the destruction of the target protein through the ubiquitin proteasome system. Previous research had shown that CK1α protein was a target of IMiD-induced degradation and this partially explained the efficacy of IMiDs against Myelodysplastic syndrome, which is a form of acute myeloid leukaemia with very low levels of CK1α, thus making further depletion by IMiDs catastrophic for cell survival.
As Sapkota lab has shown that CK1α in cells exists in distinct complexes with the eight FAM83 proteins, Karen was able to demonstrate that only the FAM83F-CK1α complex was susceptible to IMiD-induced degradation. Other FAM83-CK1α complexes were not only spared from IMiD-induced degradation but their abundance, especially that of FAM83G, could predict the extent to which CK1α was protected from degradation.
Importantly, IMiD-induced degradation of FAM83F-CK1α led the inhibition of Wnt signalling in colorectal cancer cells, replicating the phenotypes observed with genetic ablation of FAM83F.
These findings are also published in the current issue of Life Science Alliance.
Karen said, “Wnt signalling has crucial roles in stem cell maintenance and tissue homeostasis and, as such, is often hyperactivated in cancers, specifically colorectal cancers. Excitingly, we have identified a new mediator of the pathway and, through IMiD treatment, we can induce FAM83F protein degradation and reduce Wnt signalling in colorectal cancer cells. We are now itching to explore if targeting FAM83F could have therapeutic potential in CRCs.”
Gopal Sapkota added, “Karen’s work further consolidates our work on establishing the crucial roles that FAM83 proteins play in regulating CK1 biology. Her exciting findings that FAM83F-CK1α complex regulates Wnt signalling, and the fact that IMiDs target FAM83F but not any other FAM83 protein for destruction offers an opportunity to target FAM83F-CK1α complex in Wnt-driven cancers. I am grateful to everyone who contributed to these studies, particularly Tom Macartney (MRC-PPU Reagents & Services) and collaborators Rebecca Jones, Kevin Dingwell and Prof. Sir Jim Smith (The Francis Crick Institute).”
Both studies were supported by the UK Medical Research Council grant awarded to Gopal Sapkota (MC_UU_00018/6).