| Substrate/target | E3 complex (SCF/CUL1-SKP1-RBX1 vs CRL4A/CUL4A-DDB1) | Ubiquitin linkage / modification type | Biological context/pathway | Key experimental evidence (assays) | Key quantitative/statistical findings | Primary citation with year, journal, DOI/URL |
|---|---|---|---|---|---|---|
| AQP3 | SCF^FBXW5^ (SKP1-CUL1-RBX1-FBXW5) | Degradative ubiquitination; AQP3 K282 identified as major ubiquitin acceptor site; linkage type not specified in cited excerpt | Autophagic cell death in hepatocellular carcinoma via PDPK1-AKT-MTOR suppression after AQP3 accumulation | Co-localization, co-IP in HEK293T, FBXW5 knockdown/overexpression, cycloheximide chase, ubiquitination assays, mutational mapping of AQP3 K282, rescue with ATG5 or AQP3 knockdown; figure model and ubiquitination panels identify K282 and pathway logic (pqac-00000001, pqac-00000004, pqac-00000023) | FBXW5 knockdown increased AQP3, reduced p-AKT and downstream p-RPS6KB/p70S6K and p-EIF4EBP1; CUL1/RBX1/SKP1 depletion phenocopied FBXW5 loss; AQP3 knockdown reversed FBXW5-loss autophagy/cell-death phenotypes (pqac-00000001, pqac-00000004) | Liang et al., 2024, *Autophagy*, doi:10.1080/15548627.2024.2353497, https://doi.org/10.1080/15548627.2024.2353497 (pqac-00000001, pqac-00000004, pqac-00000023) |
| LATS1 | FBXW5 E3 ligase activity reported; cited pages support ubiquitin-proteasome degradation but do not explicitly document SCF vs CRL4 composition in these experiments | Ubiquitination with proteasomal degradation; linkage type not specified | Hippo pathway repression in gastric cancer; increased nuclear YAP1 and CTGF/CYR61/c-Myc output | Co-IP, WD40-domain mapping, cycloheximide chase, MG132 rescue, in vivo ubiquitination assays, LATS1 knockdown epistasis, YAP1 rescue, xenograft/IHC analyses | High FBXW5 expression associated with poorer prognosis: HR 1.42 (95% CI 1.13-1.79), log-rank p=0.0025; lymph node metastasis p<0.001; TNM stage p=0.018 and p=0.001 in two cohorts; training/validation survival p=0.020 and p=0.025; ~60% of GC samples showed moderate-to-high FBXW5 expression (pqac-00000007, pqac-00000008, pqac-00000009) | Yao et al., 2022, *Cell Death Discovery*, doi:10.1038/s41420-022-00868-y, https://doi.org/10.1038/s41420-022-00868-y (pqac-00000006, pqac-00000007, pqac-00000008, pqac-00000009) |
| ASK1 | SCF^FBXW5^ (Skp1-Cul1-F-box/FBXW5) | Lys63-linked polyubiquitination activating ASK1 signaling rather than degrading ASK1 | NASH/hepatocyte stress signaling; ASK1-JNK/p38 MAPK activation, inflammation, lipid accumulation | Direct interaction/ubiquitination assays, hepatocyte-specific FBXW5 overexpression and deletion in mice, pathway readouts, inhibitory N-terminal/C-terminal FBXW5 fragments (S1/S3) | Hepatocyte-specific FBXW5 overexpression worsened diet-induced hepatic/metabolic pathology; hepatocyte-specific deletion was protective; FBXW5(S1) and FBXW5(S3) inhibited ASK1 activation/NASH progression (pqac-00000005) | Bai et al., 2019, *Hepatology*, doi:10.1002/hep.30537, https://doi.org/10.1002/hep.30537 (pqac-00000005) |
| DLC1 | CRL4A-FBXW5 (CUL4A-DDB1-FBXW5) | Polyubiquitination leading to proteasomal degradation; linkage type not specified | NSCLC growth, RhoA signaling, tumor-suppressor loss | MG132 accumulation, in vivo ubiquitination, co-IP with CUL4A/DDB1/FBXW5, domain mapping (WD40 required; ΔF retained binding), FBXW5 knockdown, half-life/stability assays, soft-agar rescue by simultaneous DLC1 suppression | DLC1 frequently reduced in lung tumors (65% adenocarcinoma, 79% squamous); FBXW5 suppression caused ~90% reduction in soft-agar colony formation, with ~90% restoration by concurrent DLC1 suppression; CUL4A or DDB1 depletion increased DLC1, whereas CUL4B did not (pqac-00000011, pqac-00000013, pqac-00000014) | Kim et al., 2013, *PNAS*, doi:10.1073/pnas.1306358110, https://doi.org/10.1073/pnas.1306358110 (pqac-00000011, pqac-00000013, pqac-00000014) |
| TSC2 | CRL4A/CUL4A-DDB1-FBW5 supported directly; possible minor CUL1/SCF contribution also noted | Ubiquitination with proteasome-dependent degradation; linkage type not specified | mTOR/autophagy regulation through TSC1-TSC2 complex turnover | Co-IP of TSC1/TSC2 with DDB1/CUL4A, FBW5ΔF mutant retaining DDB1-CUL4A bridging but losing SKP1 binding, overexpression/degradation assays, MG132 sensitivity | ~10% of total TSC2 associated with DDB1-CUL4A; CUL4A and FBW5/FBW5ΔF lowered TSC2 steady-state levels more strongly than CUL1; degradation was MG132-sensitive (pqac-00000012, pqac-00000015) | Hu, 2007 dissertation text summarizing primary findings on CUL4-DDB1-FBW5-TSC2, doi:10.17615/n4gy-cg97, https://doi.org/10.17615/n4gy-cg97; foundational TSC2-FBW5 finding also referenced in later reviews/primary papers (pqac-00000011, pqac-00000012, pqac-00000015) |
| MCAK / KIF2C | SCF^FBXW5^ (neddylated Cul1-Rbx1-Skp1-Fbxw5) | K48 polyubiquitylation | G2-phase proteasomal control, basal body MCAK abundance, ciliogenesis | ProtoArray substrate screen (>9,000 proteins), in vitro reconstitution with neddylated SCF^FBXW5^ and Cdc34, validation with purified HA-substrates, cell-based degradation studies, ciliogenesis rescue by codepletion of MCAK/KIF2A/KIF2B | 161 candidate SCF^FBXW5^ substrates identified; loss of FBXW5 increased MCAK at basal bodies and impaired ciliogenesis in subsequent G1/G0; ubiquitination reconstituted with defined enzyme concentrations in vitro (pqac-00000002, pqac-00000003) | Schweiggert et al., 2021, *The EMBO Journal*, doi:10.15252/embj.2021107735, https://doi.org/10.15252/embj.2021107735 (pqac-00000002, pqac-00000003) |
| KIF2A / KIF2B | SCF^FBXW5^ | Efficient polyubiquitylation in vitro; specific chain type not stated in cited excerpt | Ciliogenesis/basal body microtubule regulation | In vitro reconstitution and rescue experiments showing codepletion of KIF2A or KIF2B can rescue ciliogenesis defects caused by FBXW5 loss | Codepletion of KIF2A or KIF2B rescued ciliogenesis defects in FBXW5-loss background; identified alongside MCAK as closely related kinesin-13 substrates (pqac-00000002) | Schweiggert et al., 2021, *The EMBO Journal*, doi:10.15252/embj.2021107735, https://doi.org/10.15252/embj.2021107735 (pqac-00000002) |
| HsSAS-6 / SASS6 | SCF^FBXW5^ | Ubiquitination/degradation; linkage type not stated in cited excerpt | Centrosome duplication control | Referred to as a previously reported validated SCF^FBXW5^ target in later primary literature and family summaries | Functional role summarized as controlling centrosome duplication; substrate appears recurrently in FBXW5 annotations and review tables (pqac-00000002, pqac-00000018) | Puklowski et al., 2011, *Nature Cell Biology*, doi:10.1038/ncb2282, https://doi.org/10.1038/ncb2282; cited as prior validated substrate in Schweiggert et al. 2021 and family overview sources (pqac-00000002, pqac-00000018) |


*Table: This table summarizes experimentally supported human FBXW5 substrates, the E3 ligase context in which FBXW5 acts, the type of ubiquitin modification reported, and the biological pathways affected. It is useful for distinguishing well-supported SCF versus CRL4A functions and for linking each substrate to the key assays and quantitative findings in the primary literature.*