FAM53C

FAM53C is a cytoplasmic anchoring protein and negative regulator of DYRK1A kinase activity that functions in cell cycle control. FAM53C binds directly to the catalytic kinase domain of DYRK1A, inhibits both DYRK1A autophosphorylation and its phosphorylation of the substrate Tau, and sequesters DYRK1A in the cytoplasm, thereby also preventing DYRK1A-dependent nuclear translocation of the scaffold protein DCAF7/WDR68 (PMID:37802655). FAM53C, DYRK1A, and DCAF7/WDR68 assemble into a ternary complex in which DYRK1A bridges FAM53C (via its kinase domain) and DCAF7/WDR68 (via its N-terminal domain), with no direct FAM53C–DCAF7/WDR68 contact (PMID:37802655). FAM53C is required for the G1/S cell cycle transition upstream of the CyclinD–CDK4/6–RB axis, as FAM53C depletion causes G1 arrest that is rescued by DYRK1A kinase inhibition, and FAM53C loss in human cortical organoids and knockout mice produces proliferation and growth defects (PMID:39713326).

1. 2000 Medium

   Identification of FAM53C as a novel gene on chromosome 5q31 with a predicted bipartite NLS and proline-rich region established the gene's existence but left its function entirely unknown.

   Evidence cDNA cloning and genomic characterization

   PMID:11087669

   Open questions at the time

   • No functional data beyond sequence prediction
   • Predicted nuclear localization not experimentally validated
   • No interacting partners identified
2. 2023 High

   Discovery that FAM53C directly binds the DYRK1A kinase domain, inhibits its autophosphorylation and Tau-directed kinase activity, and anchors DYRK1A in the cytoplasm established FAM53C as a bona fide kinase inhibitor and subcellular localization regulator, resolving why endogenous DYRK1A is cytoplasmic despite possessing nuclear targeting signals.

   Evidence Co-immunoprecipitation with domain mapping, in vitro kinase assays, fluorescence microscopy of co-expressed proteins, subcellular fractionation

   PMID:37802655

   Open questions at the time

   • Structural basis of FAM53C–DYRK1A kinase domain interaction not resolved
   • Endogenous stoichiometry and regulation of the FAM53C–DYRK1A interaction unknown
   • Functional significance of FAM53C interaction with DYRK1B not explored
3. 2023 High

   Demonstration that FAM53C, DYRK1A, and DCAF7/WDR68 form a ternary complex — with DYRK1A bridging the other two via distinct domains — defined the architecture of a regulatory module and explained how FAM53C indirectly controls DCAF7/WDR68 localization.

   Evidence Binary and ternary co-immunoprecipitation with domain truncation constructs

   PMID:37802655

   Open questions at the time

   • Whether the ternary complex exists at endogenous expression levels in vivo not shown
   • Downstream targets of the DCAF7/WDR68 arm of the complex not identified
   • No structural model of the ternary complex
4. 2024 High

   Linking FAM53C to the G1/S transition upstream of CyclinD–CDK4/6–RB, and showing that DYRK1A kinase inhibition rescues FAM53C-depletion-induced G1 arrest, established a physiological cell cycle role and placed FAM53C and DYRK1A in a genetic epistasis pathway controlling proliferation.

   Evidence (preprint) siRNA knockdown, flow cytometry, pharmacological rescue with DYRK1A inhibitor, CRISPR knockout in human cortical organoids, Fam53c knockout mice

   PMID:39713326

   Open questions at the time

   • Preprint not yet peer-reviewed
   • Molecular mechanism linking DYRK1A inhibition to CyclinD–CDK4/6–RB axis not delineated
   • Whether FAM53C operates through DYRK1A kinase inhibition or cytoplasmic sequestration (or both) in cell cycle control is unresolved

• The structural basis of the FAM53C–DYRK1A interaction, the identity of physiological DYRK1A substrates regulated by FAM53C, and the precise mechanism through which the FAM53C–DYRK1A axis feeds into CyclinD–CDK4/6–RB signaling remain unknown.
• No crystal or cryo-EM structure of FAM53C or its complex with DYRK1A
• Endogenous DYRK1A substrates whose phosphorylation is controlled by FAM53C not identified
• Tissue-specific and developmental regulation of FAM53C expression and function not systematically characterized