| Substrate/target | Modification | Key mechanistic details | Model system | Biological outcome/pathway | Reference |
|---|---|---|---|---|---|
| FBXL7 | Polyubiquitylation leading to proteasomal degradation; ubiquitin acceptor Lys109 on FBXL7 | FBXL18 recognizes an N-terminal **FQ motif** in FBXL7; mutation of the FQ motif disrupts binding, and **Lys109** is required as an acceptor site for ubiquitin conjugation | Human HeLa cells; co-IP, peptide pull-down, CHX chase, shRNA depletion | Limits FBXL7-driven apoptosis and affects cell-cycle-associated survival signaling | Liu et al., 2015, *Cell Death & Disease*, https://doi.org/10.1038/cddis.2014.585 (pqac-00000008) |
| AKT | **K63-linked ubiquitination** of AKT; signaling activation rather than degradation | FBXL18 interacts strongly with AKT; knockdown reduces EGF-induced K63 ubiquitination and decreases AKT and FOXO3a phosphorylation; increases **BCL2L11/Bim** expression | Human glioma cell lines U251 and T98; co-IP, ubiquitin mutant assays, Annexin V/PI, soft agar | Promotes glioma growth/survival through the **AKT–FOXO3a–Bim** axis and suppresses apoptosis | Zhang et al., 2017, *FEBS Letters*, https://doi.org/10.1002/1873-3468.12521 (pqac-00000001, pqac-00000004, pqac-00000007) |
| PTEN | **K63-linked ubiquitination** of PTEN; reported inhibition of PTEN activity without marked degradation | FBXL18 binds PTEN, with mapping to the **PTEN C-terminal region/C-tail and PDZ-binding domain**; CHX assays indicate no major shortening of PTEN half-life, consistent with non-proteolytic ubiquitination | HEK293T biochemical assays; human NSCLC cell lines A549, H1299, H460, SPCA-1; 47 paired NSCLC and adjacent tissues | Activates **PI3K/AKT** signaling, increases p-AKT, promotes NSCLC proliferation; high FBXL18 associated with poorer LUAD prognosis | Liu et al., 2024 preprint, https://doi.org/10.21203/rs.3.rs-4980695/v1 (pqac-00000002, pqac-00000003, pqac-00000009, pqac-00000010) |
| XPB / ERCC3 | **K48-linked polyubiquitination** leading to proteasomal degradation | FBXL18 acts in **SCF^FBXL18** (Skp1–Cul1–FBXL18–Rbx1); spironolactone-induced degradation requires **CDK7** activity and **XPB Ser90**; MLN4924 and Cul1 depletion suppress the effect; in vitro ubiquitination supports SCF^FBXL18 specificity | Human cells including HEK293T; siRNA screen of F-box proteins; in vitro ubiquitination; NER/transcription assays under spironolactone treatment | Loss of XPB impairs **NER** and transcriptional functions of TFIIH; sensitizes cells to cisplatin/oxaliplatin and other DNA-damaging stress | Ueda et al., 2019, *Genes to Cells*, https://doi.org/10.1111/gtc.12674 (pqac-00000012, pqac-00000013, pqac-00000014, pqac-00000016, pqac-00000017, pqac-00000018) |
| FBXL18 localization note | Cytoplasm and nucleus | Review table annotation for FBXL18 subcellular localization; not itself a substrate experiment, but consistent with roles in cytoplasmic AKT/PTEN signaling and nuclear XPB regulation | Review synthesis of FBXL proteins | Supports interpretation that FBXL18 can function in both signaling and nuclear quality-control/transcription-related contexts | Tekcham et al., 2020, *Theranostics*, https://doi.org/10.7150/thno.42735 (pqac-00000005) |


*Table: This table summarizes the main experimentally supported substrates, ubiquitin linkages, mechanistic details, and biological consequences reported for human FBXL18. It is useful for functional annotation because it distinguishes degradative versus non-degradative ubiquitination and links each target to specific pathways and disease contexts.*