SACK1F

FAM83F is a membrane- and lysosome-targeted signalling scaffold that couples casein kinase 1α (CK1α) to multiple growth-control pathways and influences cell proliferation, survival, and stress responses (PMID:33361109, PMID:30692643). It is farnesylated, which targets a FAM83F–CK1α complex to the plasma membrane; this localization is essential for FAM83F to activate canonical Wnt signalling upstream of GSK-3β, since a farnesyl-deficient mutant redirects the complex away from the membrane and attenuates Wnt output (PMID:33361109). The CK1α association also confers a specific vulnerability: among FAM83 family members, only FAM83F is degraded by immunomodulatory imide drugs via the CRBN-Cul4A E3 ligase, with degradation requiring the CK1α interaction and phenocopying genetic FAM83F loss by removing CK1α from the membrane and attenuating Wnt signalling (PMID:33361334). Independently of Wnt, FAM83F stabilizes p53 by reducing its ubiquitination and proteasomal degradation following DNA damage, thereby promoting p53 target-gene transcription and restraining proliferation (PMID:30692643), and it activates MAPK signalling through physical interaction with BRAF/RAF (PMID:30881348). FAM83F is transcriptionally induced by c-Myc and drives Wnt/β-catenin-dependent proliferation and glycolysis (PMID:38104106), and is also post-transcriptionally repressed by miR-143 (PMID:26758433). A C-terminal signal sequence directs FAM83F to the lysosome, where it supports autophagy and modulates sensitivity to ionizing radiation (PMID:39437839).

1. 2016 Medium

   Established a layer of post-transcriptional control over FAM83F and linked its abundance to a proliferative phenotype, framing it as a cancer-relevant effector.

   Evidence Luciferase 3'-UTR reporter and miR-143 gain/loss-of-function with proliferation, migration, invasion, and cell-cycle assays in esophageal squamous cell carcinoma cells

   PMID:26758433

   Open questions at the time

   • Does not define the molecular function of the FAM83F protein itself
   • No mechanism connecting FAM83F level to the proliferative output
2. 2019 High

   Identified the first direct molecular activity of FAM83F — stabilizing p53 by limiting its ubiquitination — assigning it a role in the DNA-damage response.

   Evidence Co-IP and ubiquitination assays with FAM83F overexpression/knockdown, zebrafish embryo overexpression, and p53 target-gene transcription readouts

   PMID:30692643

   Open questions at the time

   • Mechanism by which FAM83F reduces p53 ubiquitination (direct vs. via an E3/DUB) not resolved
   • Relationship to FAM83F's other signalling roles unclear
3. 2019 Medium

   Linked FAM83F to RAS/MAPK signalling via BRAF/RAF binding and showed it can drive dedifferentiation and chemoresistance, broadening its pathway connectivity beyond p53.

   Evidence Stable PCCL3 overexpression, co-IP with BRAF/RAF, gene-expression, migration, and apoptosis assays in thyroid follicular cells

   PMID:30881348

   Open questions at the time

   • Direct vs. indirect nature of BRAF/RAF interaction not dissected
   • Single overexpression model in one cell type
   • No structural or mutational mapping of the interaction
4. 2020 High

   Defined the core mechanism: farnesylation targets a FAM83F–CK1α complex to the plasma membrane to activate canonical Wnt signalling upstream of GSK-3β.

   Evidence Co-localization, co-IP, CRISPR farnesyl-deficient mutant, Xenopus axis-duplication assay, and GSK-3-inhibition rescue in colorectal cancer cells

   PMID:33361109

   Open questions at the time

   • How membrane-localized CK1α activates Wnt mechanistically not fully defined
   • Relationship between this Wnt role and the p53/MAPK roles unresolved
5. 2020 High

   Showed FAM83F is a CK1α-dependent, IMiD-responsive degron target unique among FAM83 proteins, providing a pharmacological route to suppress its Wnt activity.

   Evidence IMiD treatment with CRBN-Cul4A degradation assays, Western blot, Wnt reporter, and subcellular fractionation in colorectal cancer cells

   PMID:33361334

   Open questions at the time

   • Structural basis of CRBN recognition of FAM83F–CK1α not defined
   • Whether IMiD degradation affects p53/MAPK roles not tested
6. 2023 Medium

   Placed FAM83F downstream of c-Myc transcriptionally and confirmed Wnt/β-catenin-dependent control of proliferation and glycolysis in vivo.

   Evidence ChIP of c-Myc at the FAM83F promoter, knockdown/overexpression, XAV939 rescue, glycolysis assays, and xenograft model in cervical cancer

   PMID:38104106

   Open questions at the time

   • Whether c-Myc induction operates in non-cancer contexts unknown
   • Direct metabolic targets of FAM83F not identified
7. 2024 Medium

   Revealed a second subcellular pool of FAM83F at the lysosome, dependent on a C-terminal signal, and tied it to autophagy and radiation sensitivity.

   Evidence fam83f knockout zebrafish with transcriptomics, overexpression localization and C-terminal deletion in HEK293T, and ionizing-radiation assays

   PMID:39437839

   Open questions at the time

   • Mechanism by which lysosomal FAM83F supports PI(3)P-binding proteins/autophagy unknown
   • Relationship between lysosomal and plasma-membrane pools unresolved
8. 2025 Low

   Identified KIF23 as a FAM83F interactor in an exosome-mediated stromal-to-tumor transfer context, hinting at intercellular signalling roles.

   Evidence Co-IP of FAM83F–KIF23, CAF-derived exosome transfer, KIF23 overexpression rescue, and xenograft assays in NSCLC

   PMID:39867833

   Open questions at the time

   • Single Co-IP without reciprocal validation of the FAM83F–KIF23 interaction
   • Functional consequence of the interaction at the molecular level undefined
   • Single lab

• How FAM83F's distinct activities — plasma-membrane CK1α/Wnt scaffolding, p53 stabilization, MAPK activation, and lysosomal autophagy support — are integrated and partitioned in a single cell remains unresolved.
• No unified model linking the membrane and lysosomal pools
• Whether p53 stabilization and Wnt activation are mechanistically connected is unknown
• No structural characterization of FAM83F or its complexes