| Substrate/Process | Evidence type | Key recognition motif/degron | Pathway/biological context | Subcellular location notes | Disease relevance | Key citation (paper, year, DOI/URL) |
|---|---|---|---|---|---|---|
| **HES1 (direct substrate)** | siRNA knockdown of **FBXL14**, **CUL1**, **RBX1**; co-IP; in vivo ubiquitination assay; CHX chase; proteasome inhibition (MG132); neuronal differentiation assays in mES/F9 cells | **C-terminal WRPW motif** in HES1 required for FBXL14 binding and ubiquitination; FBXL14 **F-box** required for SCF activity; modeling supports WRPW interaction with FBXL14 **LRR** domain | **Notch/HES1 oscillation** and repression of proneural genes; SCF^FBXL14 promotes **neuronal differentiation** by destabilizing HES1 | Specific FBXL14 localization not emphasized in this study; assays support action within **SCF(CUL1-SKP1-RBX1)-FBXL14** complex | Functional relevance to **development/neurogenesis**; cited in relation to neurological phenotypes | Chen et al., 2017, *J Biol Chem*, doi:10.1074/jbc.M117.815001, https://doi.org/10.1074/jbc.M117.815001 (pqac-00000002, pqac-00000003, pqac-00000005, pqac-00000016) |
| **SNAIL1 (direct substrate)** | Interaction and ubiquitination/degradation assays summarized in review of primary work; shRNA inhibition stabilizes ectopic and endogenous SNAIL1; domain mapping of minimal region required for FBXL14-mediated degradation | Minimal SNAIL1 region for FBXL14-mediated degradation maps to **aa 120-151**; both **phosphorylated and unphosphorylated** SNAIL1 can be targeted | **EMT** regulation; hypoxia/HIF-1α/TWIST1 axis represses FBXL14, stabilizing SNAIL1 | FBXL14 reported as **cytoplasmic** by immunofluorescence; proposed to act on newly synthesized cytoplasmic SNAIL1 | Linked to **tumor hypoxia**, EMT, invasion, and poorer prognosis when FBXL14 is downregulated | Viñas-Castells et al., 2010, *J Biol Chem*, doi:10.1074/jbc.M109.065995, https://doi.org/10.1074/jbc.M109.065995; summarized with localization/mechanism in later review (pqac-00000000, pqac-00000001) |
| **c-Myc / Myc (direct substrate, supported mainly through cited primary studies and reviews)** | Review-cited primary studies report FBXL14-mediated **ubiquitination** of Myc; overexpression promotes differentiation and suppresses glioma stem-cell growth/tumorigenicity; effects reversed by degradation-resistant **c-Myc T58A** mutant | Recognition linked to **Thr58-phosphorylated c-Myc**; USP13 antagonizes FBXL14-mediated Myc ubiquitination | **Glioblastoma stem-cell maintenance/differentiation**; FBXL14 acts opposite to USP13 on Myc stability | No firm FBXL14 localization detail extracted from recent review excerpts | Lower FBXL14 in **glioma stem cells**; FBXL14 overexpression suppresses tumor-forming capacity, while **USP13** counteracts this axis | Tao et al., 2023, *Oncol Lett*, doi:10.3892/ol.2023.14191, https://doi.org/10.3892/ol.2023.14191; review cites primary glioblastoma studies including J Exp Med 2017. Supporting cancer review: Yumimoto et al., 2020, doi:10.3390/cancers12051249, https://doi.org/10.3390/cancers12051249 (pqac-00000010, pqac-00000011, pqac-00000012, pqac-00000014) |
| **3D genome regulation / inter-TAD insulation (functional hit, not established direct substrate)** | **HiDRO/Oligopaint** high-throughput depletion screen; validation across multiple genomic boundaries; knockdown increased inter-TAD interactions | No direct degron/substrate motif established for this phenotype | FBXL14 emerged as representative **ubiquitin ligase-class** regulator of **chromatin folding/3D genome organization** | No direct localization claim in excerpt; functional phenotype is genome-architecture associated | Identified as a potentially **druggable** 3D genome regulator; disease relevance indirect/technology-enabling rather than substrate-level | Park et al., 2023, *Nature*, doi:10.1038/s41586-023-06340-w, https://doi.org/10.1038/s41586-023-06340-w (pqac-00000009) |
| **Broad protein-destabilization capacity (functional association, not a specific substrate assignment)** | Proteome-scale and proximity-dependent **degradation-effector** screens; activity tested against **10 model substrates** with different localizations | No specific degron defined; screen measures proximity-induced destabilization | Positions FBXL14 as a candidate **targeted protein degradation (TPD)** effector / E3-recruitment module | Active across model substrates with varied **subcellular localizations** | Translational relevance for **TPD/E3-ligase harnessing** rather than endogenous biology alone | Hermanns & Hofmann, 2024, *Signal Transduct Target Ther*, doi:10.1038/s41392-024-01884-3, https://doi.org/10.1038/s41392-024-01884-3 (summarizing Poirson et al., 2024, *Nature*) (pqac-00000008) |


*Table: This table summarizes the best-supported functions and reported substrates or associations for human FBXL14, distinguishing direct substrates from broader functional hits. It highlights the evidence base, recognition motifs, pathway context, localization clues, and disease relevance for rapid functional annotation.*