| Function/role | Molecular mechanism (SCF components, substrate recognition features) | Key substrates/interactors | Upstream regulation (p53, phosphorylation, miRNA, localization signals) | Pathways/biological processes affected | Experimental evidence type | Key quantitative/statistical notes | Primary sources (with DOI URLs, year) |
|---|---|---|---|---|---|---|---|
| Substrate receptor in an SCF E3 ubiquitin ligase that promotes VPS34 turnover | FBXL20 acts as the F-box substrate-recognition subunit of a CUL1-SKP1-FBXL20 SCF complex; the FBXL20 C-terminal LRR region is required to bind VPS34, and VPS34 uses its C2 domain for the interaction; SCF reconstitution with CUL1, SKP1, FBXL20, E1, and Ubc5c supports VPS34 ubiquitination in vitro (pqac-00000001, pqac-00000002, pqac-00000009) | VPS34/PIK3C3; SKP1; CUL1 (pqac-00000001, pqac-00000002, pqac-00000009) | FBXL20 expression is induced by p53 after DNA damage; transient p53 knockdown abolishes inducibility; FBXL20 is also reported as a miR-3151 target (pqac-00000002, pqac-00000003) | Autophagy control and receptor degradation/endocytosis via regulation of class III PI3K abundance (pqac-00000001, pqac-00000003, pqac-00000006) | Co-immunoprecipitation, shRNA/siRNA knockdown, overexpression, in vitro ubiquitination reconstitution, proteasome inhibition with MG132 (pqac-00000001, pqac-00000002, pqac-00000009) | Quantification reported as mean ± SD from 3 independent experiments with significance thresholds P < 0.05 and P < 0.01; MG132 rescues FBXL20-driven VPS34 reduction (pqac-00000002) | Xiao et al., 2015, Genes and Development, DOI: https://doi.org/10.1101/gad.252528.114 (pqac-00000001, pqac-00000002) |
| DNA-damage-responsive checkpoint suppressing autophagy | DNA damage activates CDK-dependent phosphorylation of VPS34 at T159, creating a phospho-dependent signal for FBXL20 binding and ubiquitination; nonphosphorylatable VPS34 T159A is largely resistant, whereas phosphomimetic T159E remains sensitive to CPT-induced reduction (pqac-00000003, pqac-00000004) | VPS34/PIK3C3; CDK1 activity inferred from roscovitine sensitivity; FBXL20-SCF complex (pqac-00000003, pqac-00000004) | Upstream inputs include DNA damage, p53-dependent FBXL20 transcriptional induction, and CDK-mediated VPS34 phosphorylation; roscovitine suppresses the pathway (pqac-00000003, pqac-00000004) | Inhibition of autophagy under genotoxic stress through reduced PtdIns3P production and loss of VPS34 (pqac-00000001, pqac-00000004) | DNA-damage treatments with camptothecin, phosphomutant analysis, pharmacologic CDK inhibition, ubiquitination assays, PtdIns3P readout with FYVE reporters (pqac-00000004) | CPT treatment reduced FYVE-positive PtdIns3P puncta and these effects were reversed by FBXL20 knockdown; statistical significance reported qualitatively with P < 0.05 or P < 0.01 (pqac-00000004) | Xiao et al., 2015, Genes and Development, DOI: https://doi.org/10.1101/gad.252528.114 (pqac-00000003, pqac-00000004) |
| Negative regulator of receptor endocytosis and degradation through VPS34 depletion | By lowering VPS34, FBXL20 reduces endosomal PtdIns3P-dependent receptor trafficking; FBXL20 knockdown increases VPS34 and accelerates EGF-stimulated EGFR degradation, while CPT-induced FBXL20 and VPS34 regulation slows EGFR degradation (pqac-00000003, pqac-00000006) | VPS34/PIK3C3; EGFR as downstream receptor-trafficking readout (pqac-00000003) | p53 knockdown in CPT-treated cells accelerates EGFR degradation, consistent with p53 to FBXL20 to VPS34 control; DNA damage is the main upstream trigger shown (pqac-00000003) | Receptor endocytosis and receptor degradation, especially EGFR trafficking (pqac-00000001, pqac-00000003, pqac-00000006) | RNAi perturbation, DNA-damage treatment, receptor degradation assays with EGF stimulation (pqac-00000003) | ImageJ-based quantification from 2 independent experiments reported with P < 0.05 or P < 0.01 (pqac-00000003) | Xiao et al., 2015, Genes and Development, DOI: https://doi.org/10.1101/gad.252528.114; Mason and Laman, 2020, Open Biology, DOI: https://doi.org/10.1098/rsob.200319 (pqac-00000003, pqac-00000006) |
| Membrane-localized FBXL adaptor with localization-dependent substrate control | High-authority review evidence states FBXL20 contains a CAAX motif that undergoes isoprenylation, directing FBXL20 to membranes; this membrane localization is required for ubiquitylation-dependent degradation of RIM1 (pqac-00000007) | RIM1; membrane compartment; SCF context implied for FBXL proteins (pqac-00000007) | CAAX motif-dependent isoprenylation controls localization and function (pqac-00000007) | Spatial control of ubiquitylation; synaptic protein turnover in the cited review context (pqac-00000007, pqac-00000008) | Review synthesis of prior mechanistic studies (pqac-00000007, pqac-00000008) | No numerical effect sizes reported in the cited review excerpt (pqac-00000007) | Skaar et al., 2013, Nature Reviews Molecular Cell Biology, DOI: https://doi.org/10.1038/nrm3582; Sato and Yoshida, 2010, International Journal of Oncology, DOI: https://doi.org/10.3892/ijo_00000758 (pqac-00000007, pqac-00000008) |
| Cytoplasmic FBXL family member linked to oncogenic and Wnt/autophagy-related functions | Review table annotates FBXL20 as cytoplasmic and lists E-cadherin and VPS34 as substrate or pathway-linked targets; mechanistic depth is limited in this source, so these associations should be treated as curated review-level summaries rather than stand-alone primary proof (pqac-00000005) | E-cadherin; VPS34 (pqac-00000005) | Cytoplasmic localization annotated; no additional upstream regulators provided in the excerpt (pqac-00000005) | Wnt signaling pathway and autophagy (pqac-00000005) | Review table curation (pqac-00000005) | No quantitative or statistical data in the cited table excerpt (pqac-00000005) | Tekcham et al., 2020, Theranostics, DOI: https://doi.org/10.7150/thno.42735 (pqac-00000005) |
| Current consensus role in autophagy literature | Multiple reviews summarize FBXL20 as a Cul1-based E3 adaptor that targets VPS34/PIK3C3 for ubiquitination and degradation, positioning FBXL20 as a negative regulator of autophagy initiation and execution by limiting VPS34 complex abundance (pqac-00000002, pqac-00000006) | VPS34/PIK3C3; Cul1-SKP1-FBXL20 SCF machinery (pqac-00000002, pqac-00000006) | p53 induction after DNA damage is the main upstream regulator repeatedly highlighted; VPS34 phosphorylation state determines recognition (pqac-00000002, pqac-00000004, pqac-00000006) | Autophagy, proteostasis, receptor degradation; often discussed as part of Cullin-RING ligase and autophagy crosstalk (pqac-00000002, pqac-00000006) | Review synthesis anchored in Xiao et al. 2015 primary data (pqac-00000002, pqac-00000006) | No new quantitative values in reviews beyond citing the primary study; emphasis is on pathway placement and mechanistic interpretation (pqac-00000006) | Mason and Laman, 2020, Open Biology, DOI: https://doi.org/10.1098/rsob.200319; Chen et al., 2019, Journal of Biomedical Science, DOI: https://doi.org/10.1186/s12929-019-0569-y; Lu et al., 2021, Trends in Cell Biology, DOI: https://doi.org/10.1016/j.tcb.2021.01.005; Jee and Cheong, 2023, Cancers, DOI: https://doi.org/10.3390/cancers15041112; Wu et al., 2024, Journal of Translational Medicine, DOI: https://doi.org/10.1186/s12967-024-05565-1 (pqac-00000006, pqac-00000002, pqac-00000004) |


*Table: This table summarizes experimentally supported functions and regulatory mechanisms of human FBXL20/Q96IG2, emphasizing the primary Xiao et al. 2015 study and high-authority reviews. It separates direct primary evidence from review-level annotations to keep the functional claims evidence-based.*